Nils Tore Vethe

• Averina, Maria; Brun, Atle; Skadberg, Øyvind; Løfblad, Lena; Michaelsen, Anette Kristine & Bergan, Stein [Show all 15 contributors for this article] (2026). Performance of the European Kidney Function Consortium (EKFC) creatinine-based eGFR equation and other eGFR equations in a north European population. A multicentre study in Norway. Clinical Chemistry and Laboratory Medicine. ISSN 1434-6621. doi: 10.1515/cclm-2026-0464. Full text in Research Archive Show summary

  Objectives Accurate estimation of glomerular filtration rate (eGFR) is necessary for early detection and staging of chronic kidney disease (CKD), risk stratification, and guiding therapies that prevent complications and progression to advanced CKD. This study aimed to evaluate the performance of different eGFR equations in a large national cohort. Methods This multicentre study was conducted at six university hospitals in Norway. Retrospective data from patient’s medical records from 2005 to 2024 for 5,552 adults and 2,981 children were used to validate several creatinine-based eGFR equations against measured GFR (mGFR) by Iohexol clearance. Performance was assessed using median bias and P30 accuracy (proportion of eGFR within ±30 % of mGFR). Results The European Kidney Function Consortium (EKFC) creatinine-based eGFR equation outperformed the CKD-EPI 2009 and 2021, the Modification of Diet in Renal Disease (MDRD) in adults, the Schwarts bedside and the CKiD U25 equations in children ≥2 years and was comparable to the Lund-Malmö equation (LM) in adults. Both CKD-EPI equations had the lowest accuracy and were overestimating GFR in young people (<25 years) and elderly patients (≥65 years). Replacing the CKD-EPI equations with the EKFC equation will result in lower eGFR values and a higher prevalence of CKD stages 3–5. Replacing the LM and MDRD with the EKFC equation will result in higher eGFR and a lower prevalence of CKD stages 3–5. Conclusions The EKFC equation was overall the best suited creatinine-based eGFR equation for this Norwegian population from 2 years of age. Clinicians should be informed about clinical implications of shifting from other equations to the EKFC equation.

• Slørdahl, Tobias S.; Askeland, Frida Bugge; Hanssen, Margrete Sofie Sætre; Hov, Håkon; Sundt-Hansen, Stine Marie & Lindahl, Sofia [Show all 13 contributors for this article] (2025). Combined Proteasome and Autophagy Inhibition in Relapsed/Refractory Multiple Myeloma—A Phase I Trial of Hydroxychloroquine, Carfilzomib, and Dexamethasone. eJHaem. 6(1). doi: 10.1002/jha2.1091. Full text in Research Archive Show summary

  Multiple myeloma is characterized by malignant cells which produce high amounts of monoclonal immunoglobulin. Myeloma cells are, therefore, dependent on effective protein degradation. Proteasomal protein degradation is targeted by proteasome inhibitors in routine care. Autophagic protein degradation is currently not targeted in myeloma treatment. This Phase I trial showed that the combination of the proteasome inhibitor carfilzomib and the autophagy inhibitor hydroxychloroquine was well tolerated in patients with relapsed/refractory multiple myeloma. Adverse events were mostly Grades 1 and 2. An overall response rate of 44% indicates a meaningful clinical efficacy of this combination. Trial Registration : The study was registered at clinicaltrials.gov # NCT04163107.

• Folkestad, Oddry H; Sponheim, Jon; Åvitsland, Tone Lise; Mordal, Kjerstin Elisabeth Skrede; Vethe, Nils Tore & Thiis-Evensen, Espen (2025). The relationship between dose, concentration and toxicity of everolimus in the treatment of neuroendocrine tumors: A prospective observational study. Journal of Neuroendocrinology (JNE). ISSN 0953-8194. 38(1). doi: 10.1111/jne.70107. Full text in Research Archive Show summary

  Abstract Everolimus is used in the treatment of patients with advanced neuroendocrine tumors (NET) and is administered at fixed doses despite known interpatient pharmacokinetic variability. This may affect both efficacy and tolerability. We wanted to investigate the relationship between prescribed dose, blood trough concentrations ( C trough ), and toxicity in NET patients receiving everolimus in routine clinical practice. In this prospective observational study NET patients were treated with everolimus, mostly as third‐ or fourth‐line therapy. Dose was adjusted according to adverse effects and tumor response. Concentrations ( C trough ) of everolimus were measured at each routine follow‐up and correlated to dose and cumulative adverse event (cAE) scores. Associations were evaluated using linear and generalized linear mixed models which accounted for repeated measurements within patients and varying dose regimens over time. Thirty‐six patients were included. Everolimus dose was a significant predictor of C trough ( p  < .001), but considerable interindividual variability was observed. Median C trough levels increased with dose: 3.9, 5.1, 7.4, and 16.4 ng/mL for 2.5, 5.0, 7.5, and 10.0 mg per day, respectively. Considerable overlap in blood concentration was observed across dose groups; patients receiving 2.5 mg reached levels as high as 8.6 ng/mL, while those on 5 mg exhibited a wide range from 1.1 to 21.2 ng/mL. C trough ≥ 6.0 ng/mL was associated with increased toxicity ( p  = .03), whereas nominal dose was not a reliable independent predictor of adverse events. Although median blood concentrations increased with higher doses, there was considerable variation between patients, resulting in overlapping concentration ranges across all dose groups. This indicates that fixed‐dose regimens may not reliably predict systemic drug exposure. Everolimus blood concentrations were superior to dose levels in predicting adverse events. Therapeutic drug monitoring and individualized dose adjustment may improve the balance between efficacy and toxicity in NET patients treated with everolimus.

• Munkhaugen, John; Kristensen, Anna Meta D.; Halvorsen, Sigrun; Holmager, Therese; Olsen, Michael Hecht & Bakken, Arnhild [Show all 64 contributors for this article] (2025). Beta-Blockers after Myocardial Infarction in Patients without Heart Failure. New England Journal of Medicine. ISSN 0028-4793. 393(19), p. 1901–1911. doi: 10.1056/nejmoa2505985. Full text in Research Archive Show summary

  Background: The evidence supporting beta-blocker therapy after myocardial infarction was established before the introduction of modern coronary reperfusion therapy and secondary prevention strategies. Methods: In an open-label, randomized trial with blinded end-point evaluation, conducted in Denmark and Norway, we assigned patients who had had a myocardial infarction and who had a left ventricular ejection fraction of at least 40%, in a 1:1 ratio, to receive long-term beta-blocker therapy within 14 days after the event or no beta-blocker therapy. The primary end point was a composite of death from any cause or major adverse cardiovascular events (new myocardial infarction, unplanned coronary revascularization, ischemic stroke, heart failure, or malignant ventricular arrhythmias). Results: A total of 5574 patients underwent randomization and were included in the main analyses - 2783 in the beta-blocker group and 2791 in the no-beta-blocker group. After a median follow-up of 3.5 years (interquartile range, 2.2 to 4.6), a primary end-point event had occurred in 394 patients (14.2%) in the beta-blocker group and in 454 patients (16.3%) in the no-beta-blocker group (hazard ratio, 0.85; 95% confidence interval [CI], 0.75 to 0.98; P = 0.03). Death from any cause occurred in 4.2% of the patients in the beta-blocker group and in 4.4% of those in the no-beta-blocker group; myocardial infarction occurred in 5.0% and 6.7%, respectively (hazard ratio, 0.73; 95% CI, 0.59 to 0.92), unplanned coronary revascularization in 3.9% and 3.9%, ischemic stroke in 1.6% and 1.3%, heart failure in 1.5% and 1.9%, and malignant ventricular arrhythmias in 0.5% and 0.6%. No apparent differences in safety outcomes were observed between the groups. Conclusions: Among patients with a myocardial infarction and a left ventricular ejection fraction of at least 40%, beta-blocker therapy led to a lower risk of death or major adverse cardiovascular events than no beta-blocker therapy

• Pivoriunas, Jonas; Engebretsen, Ingrid; Vethe, Nils Tore; Kristiansen, Oscar; Dammen, Toril & Husebye, Einar [Show all 9 contributors for this article] (2025). Statin adherence in coronary outpatients: The relationship between a novel blood test and pharmacy registry data. Atherosclerosis. ISSN 0021-9150. 403. doi: 10.1016/j.atherosclerosis.2025.119138. Full text in Research Archive
• Pivoriunas, Jonas; Vethe, Nils Tore; Kristiansen, Oscar; Bergan, Stein; Husebye, Einar & Munkhaugen, John [Show all 7 contributors for this article] (2025). Low-Density Lipoprotein Cholesterol Increases Significantly During Brief Discontinuation of Atorvastatin and Correlates With Metabolite Half-Lives. Pharmacology Research & Perspectives. 13(2). doi: 10.1002/prp2.70082. Full text in Research Archive Show summary

  Variability in low-densitylipoprotein cholesterol (LDL-C) has emerged as a potential independent cardiovascular risk factor, but the impact of short-term discontinuation of statins on LDL-C remains to be defined. Furthermore, the relationship between individual statin metabolites and changes in LDL-C has not yet been examined. The present study aimed to investigate changes in LDL-C concentrations during a four-day discontinuation of atorvastatin therapy and to examine correlations between the half-lives of atorvastatin metabolites and LDL-C concentrations. This pharmacokinetic intervention study included 60 adults with confirmed adherence to atorvastatin, using doses of 20 mg (N = 20), 40 mg (N = 20), or 80 mg (N = 20) at study start. Atorvastatin was then discontinued, and blood samples were collected from day zero to day four. We assessed daily concentrations of LDL-C and of atorvastatin with its metabolites by liquid chromatography–tandem mass spectrometry. The mean (SD) LDL-C at baseline was 1.84 (0.6) mmol/L. LDL-C increased on average by 0.50 mmol/L (27%) from day zero to day four. The increase in LDL-C was significant already 48 h after the last statin intake and was affected by individual variation in baseline concentrations and the slope of the daily increase. A moderate correlation was found between differences in LDL-C concentrations and the half-lives of hydroxylated atorvastatin metabolites. In conclusion, 4 days without atorvastatin resulted in an almost 30% increase in LDL-C concentrations, and the increase was significant already after the first omitted dose. The half-lives of hydroxylated atorvastatin metabolites showed a moderate correlation with the increase in LDL-C concentrations.

• Drevland, Ole Martin; Grasdal, Marte; Carlsen, Rasmus Kirkeskov; Midtvedt, Karsten; Robertsen, Ida & Jenssen, Trond [Show all 10 contributors for this article] (2024). Patiromer Does Not Alter Tacrolimus Pharmacokinetics in Kidney Transplant Recipients When Administered Three Hours Post–Tacrolimus. Transplantation direct. 10(12). doi: 10.1097/TXD.0000000000001733. Full text in Research Archive Show summary

  Background. Hyperkalemia is common in kidney transplant (KTx) recipients. Patiromer, a potassium-binding polymer used to treat acute and chronic hyperkalemia, has the potential to bind charged particles in the gastrointestinal tract and thereby potentially affect the absorption of coadministered drugs. The immunosuppressive drug tacrolimus (Tac) has a narrow therapeutic window, is susceptible to drug-drug interactions (DDIs), and a potential gastrointestinal interaction with patiromer could elevate the risk of allograft rejection. We aimed to investigate the potential DDI between patiromer and Tac pharmacokinetics in KTx with hyperkalemia by sampling capillary blood using volumetric absorptive microsampling (VAMS). Methods. Thirteen KTx recipients on Tac twice daily (BID) with plasma potassium levels of >4.6 mmol/L were included. Two 12 h Tac pharmacokinetic investigations were performed with and without 8.4 mg patiromer/d for 1 wk. Oral Tac dose remained unchanged and patiromer was administered 3 h after Tac dose. Tac sampling was self-conducted using VAMS after mastering the technique. Results. Ten patients provided 2 evaluable pharmacokinetic profiles. The Tac area under the curve (AUC)0–12 ratio (AUCTac+patiromer/AUCTac) was 0.99 (90% confidence interval [CI], 0.86-1.14), and the Cmax ratio was 1.01 (90% CI, 0.86-1.19). Tac C0 and C12 fulfilled the bioequivalence criteria with a ratio of 0.98 (90% CI, 0.90-1.07) and 0.93 (90% CI, 0.83-1.04), respectively. Conclusions. When administered 3 h after the Tac morning dose, patiromer has no clinically relevant impact on Tac pharmacokinetics. We demonstrate that VAMS is a well-suited sampling method to simplify the execution of DDI studies.

• Pivoriunas, Jonas; Vethe, Nils Tore; Husebye, Einar; Fagerland, Morten; Bergan, Stein & Kristiansen, Oscar [Show all 8 contributors for this article] (2024). Validation of a novel direct method to determine reduced adherence to atorvastatin therapy. European Heart Journal (EHJ) - Cardiovascular Pharmacotherapy. ISSN 2055-6837. 10(4), p. 307–315. doi: 10.1093/ehjcvp/pvae001. Full text in Research Archive Show summary

  Aims Objective methods to determine statin adherence are requested to improve lipid management. We have recently established a method to detect reduced adherence to atorvastatin therapy with cut‐off values based on the sum of atorvastatin and its major metabolites in blood. We aimed to validate this method in patients with and without cardiovascular disease, and optimize previous cut-off values. Methods and results The pharmacokinetic study included 60 participants treated with atorvastatin 20 mg (N=20), 40 mg (N=20), and 80 mg (N=20). Atorvastatin was then stopped and blood samples collected from day zero to day four. Quantification of the parent drug and its metabolites in blood plasma was performed with a liquid chromatography-tandem mass spectrometry assay. The cut-off values for reduced adherence were validated and optimized by calculating diagnostic sensitivity and specificity. Our candidate cut-off value of dose-normalized six-component sum of atorvastatin plus metabolites <0.10 nM/mg provided a sensitivity of 97% and a specificity of 93% for detecting ≥2 omitted doses. An optimized cut-off <0.062 nM/mg provided a sensitivity of 90% and a specificity of 100%. An alternative simplified two-component metabolite sum with cut-off value <0.05 nM/mg provided a sensitivity of 98% and a specificity of 76%. An optimized cut-off <0.02 nM/mg provided a sensitivity of 97% and a specificity of 98%. Conclusion This validation study confirms that our direct method discriminates reduced adherence from adherence to atorvastatin therapy with high diagnostic accuracy. The method may improve lipid management in clinical practice and serve as a useful tool in future studies.

• Lauritzen, Trine; Munkhaugen, John; Bergan, Stein; Peersen, Kari; Svarstad, Anja Camilla & Andersen, Anders Mikal [Show all 9 contributors for this article] (2024). The atorvastatin metabolite pattern in muscle tissue and blood plasma is associated with statin muscle side effects in patients with coronary heart disease; An exploratory case-control study. Atherosclerosis Plus. ISSN 2667-0909. 55, p. 31–38. doi: 10.1016/j.athplu.2024.01.001. Full text in Research Archive Show summary

  Background and aims Statin-associated muscle symptoms (SAMS) is a prevalent cause of statin discontinuation. It is challenging and time-consuming for clinicians to assess whether symptoms are caused by the statin or not, and diagnostic biomarkers are requested. Atorvastatin metabolites have been associated with SAMS. We aimed to compare atorvastatin pharmacokinetics between coronary heart disease (CHD) patients with and without clinically statin intolerance and statin-dependent histopathological alterations in muscle tissue. Secondarily we aimed to assess genetic variants relevant for the observed pharmacokinetic variables. Methods Twenty-eight patients with CHD and subjective SAMS were included in the exploratory MUSE biomarker study in 2020. Participants received atorvastatin 40 mg/day for seven weeks followed by no statins for eight weeks. Muscle biopsies and blood were collected at the end of each period. Four patients were categorized as clinically intolerant to ≥3 statins prior to study start whereas four patients had signs of muscle cell damage during treatment. Results We found significantly lower levels of atorvastatin acids, and higher lactone/acid ratios in the statin intolerant, both in muscle and plasma. With optimal cut-off, the combination of 2-OH-atorvastatin acid and the 2-OH-atorvastatin lactone/acid ratio provided sensitivity, specificity, and predictive values of 100 %. Patients with variants in UGT1A1 and UGT1A3 had higher lactone metabolite levels than those with wild type, both in muscle and plasma. Conclusion Atorvastatin metabolites appear promising as biomarkers for the identification of clinical statin intolerance in patients with self-perceive

• Lauritzen, Trine; Munkhaugen, John; Bergan, Stein; Sverre, Elise Christine Bjørkholen; Peersen, Kari & Lindahl, Sofia [Show all 8 contributors for this article] (2024). Mevalonate in blood and muscle: Response to atorvastatin treatment and the relationship to statin intolerance in patients with coronary heart disease. Clinical and Translational Science (CTS). ISSN 1752-8054. 17:e70025(10), p. 1–9. doi: 10.1111/cts.70025. Full text in Research Archive Show summary

  Statin-associated muscle symptoms are frequently reported and often lead to discontinuation of statin therapy with an increased risk of cardiovascular events. In vitro studies suggest that statin-mediated inhibition of the mevalonate pathway leads to muscle cell toxicity. We aimed to determine the relationship between mevalonate, LDL-cholesterol, and atorvastatin metabolites in patients with coronary heart disease and self-perceived muscle side effects. Furthermore, we assessed the correlation between mevalonate in blood and muscle and the relationship to statin intolerance due to muscle symptoms. We used blood plasma from a randomized crossover trial (n = 70) and muscle biopsies and plasma from a subgroup in a subsequent open intervention study (n = 26). Both studies tested atorvastatin 40 mg/day. Seven patients did not tolerate ≥3 statins throughout the follow-up and were classified as statin-intolerant. Mevalonate in blood plasma decreased during atorvastatin treatment (median difference −38%, range −77% to 43%, p < 0.001), whereas mevalonate in muscle tissue was not lowered (0.05%, range −47% to 145%). Mevalonate correlated poorly with LDL-cholesterol and atorvastatin metabolites (Spearman's rho −0.28 to 0.10). The statin-intolerant patients had a smaller reduction in circulating mevalonate compared with the tolerant patients; median difference −8.1 (−22 to 3.5) nmol/L versus −25 (−93 to 12) nmol/L, p = 0.028. A similar observation was made for LDL-cholesterol. Cutoffs based on these biomarkers classified >50% correctly as tolerant. Inhibition of the mevalonate pathway does not appear to be the mechanism underlying statin intolerance in the present study. Further studies of mevalonate as a biomarker for statin tolerance are needed to clarify the potential.

• Bergan, Stein & Vethe, Nils Tore (2024). The potential for therapeutic drug monitoring of belatacept and other biologicals in solid organ transplantation. British Journal of Clinical Pharmacology. ISSN 0306-5251. doi: 10.1111/bcp.16170. Full text in Research Archive
• Vethe, Nils Tore; Åsberg, Anders; Bergan, Stein; Robertsen, Ida & Midtvedt, Karsten (2024). Implementation of Volumetric Finger-Prick Self-Sampling for Therapeutic Drug Monitoring of Immunosuppressants After Kidney Transplantation: Lessons Learned From the Practice. Therapeutic Drug Monitoring. ISSN 0163-4356. 47(1), p. 98–104. doi: 10.1097/FTD.0000000000001281. Full text in Research Archive
• Lauritzen, Trine; Munkhaugen, John; Peersen, Kari; Kristiansen, Oscar; Sverre, Elise Christine Bjørkholen & Nebauer, Shane Desmond [Show all 13 contributors for this article] (2023). Atorvastatin Metabolite Pattern in Skeletal Muscle and Blood from Patients with Coronary Heart Disease and Statin-Associated Muscle Symptoms. Clinical Pharmacology and Therapeutics. ISSN 0009-9236. 113(4), p. 887–895. doi: 10.1002/cpt.2844. Full text in Research Archive Show summary

  Self-perceived statin-associated muscle symptoms (SAMS) are prevalent, but only a minority is drug-dependent. Diagnostic biomarkers are not yet identified. The local statin exposure in skeletal muscle tissue may correlate to the adverse effects. We aimed to determine whether atorvastatin metabolites in blood reflect the corresponding metabolite levels in skeletal muscle, and whether genetic variants of statin transporters modulate this relationship. We also addressed atorvastatin metabolites as potential objective biomarkers of SAMS. Muscle symptoms were examined in patients with coronary disease and self-perceived SAMS during 7 weeks of double-blinded treatment with atorvastatin 40 mg/day and placebo in randomized order. A subset of 12 patients individually identified with more muscle symptoms on atorvastatin than placebo (confirmed SAMS) and 15 patients with no difference in muscle symptom intensity (non-SAMS) attended the present follow-up study. All received 7 weeks of treatment with atorvastatin 40 mg/day followed by 8 weeks without statins. Biopsies from the quadriceps muscle and blood plasma were collected after each treatment period. Strong correlations (rho > 0.7) between muscle and blood plasma concentrations were found for most atorvastatin metabolites. The impact of the SLCO1B1 c.521T>C (rs4149056) gene variant on atorvastatin's systemic pharmacokinetics was translated into muscle tissue. The SLCO2B1 c.395G>A (rs12422149) variant did not modulate the accumulation of atorvastatin metabolites in muscle tissue. Atorvastatin pharmacokinetics in patients with confirmed SAMS were not different from patients with non-SAMS. In conclusion, atorvastatin metabolite levels in skeletal muscle and plasma are strongly correlated, implying that plasma measurements are suitable proxies of atorvastatin exposure in muscle tissue. The relationship between atorvastatin metabolites in plasma and SAMS deserves further investigation.

• Sverre, Elise Christine Bjørkholen; Munkhaugen, John; Kristiansen, Oscar; Weedon-Fekjær, Harald; Peersen, Kari & Gjertsen, Erik [Show all 10 contributors for this article] (2023). Plasma concentration of atorvastatin metabolites correlates with low-density lipoprotein cholesterol reduction in patients with coronary heart disease. Pharmacology Research & Perspectives. 11(3). doi: 10.1002/prp2.1089. Full text in Research Archive Show summary

  In this exploratory study from a randomized double-blinded crossover trial including 70 patients with coronary heart disease and self-perceived muscular side effects of statins, we aimed to determine the relationship between low-density lipoprotein cholesterol (LDL-C) reduction and atorvastatin metabolite plasma concentrations. All patients underwent a 7 weeks treatment period with atorvastatin 40 mg/day and a 7 weeks placebo period in random order. Nonlinear regression with a three-parameter equation explored the relationship between percentage LDL-C reduction (statin vs. placebo) and the pharmacokinetic variables. Mean LDL-C reduction was 49% (range 12% to 71%). The sum of 4-OH-atorvastatin acid and lactone correlated moderately with the LDL-C response (Spearman ρ 0.27, 95% confidence interval [CI]: 0.03 to 0.48). Accordingly, nonlinear regression showed R2 of 0.14 (95% CI: 0.03 to 0.37, R2 adjusted equaled 0.11). Even a perfect underlying correlation of 1.0 showed R2 = 0.32 by simulation, using historical intra-individual LDL-C variation (8.5%). The 90% inhibitory concentration was 2.1 nmol/L, and the 4-OH-metabolite sum exceeded this threshold in 34% of the patients. In conclusion, trough plasma concentrations of 4-OH-atorvastatin metabolites correlated moderately to the LDL-C reduction. A plateau LDL-C response was observed above a pharmacokinetic threshold, below which the response was highly variable. The usefulness of monitoring concentrations of atorvastatin metabolites to optimize the individual dosage have limitations, but its supportive potential may be pursued in relevant patient subsets to achieve adequate efficacy at the lowest possible dose. The results add knowledge to the overall understanding of the variable LDL-C response mediated by atorvastatin.

• Vethe, Nils Tore; Åsberg, Anders; Andersen, Anders Mikal; Skauby, Ragnhild Kristine Heier; Bergan, Stein & Midtvedt, Karsten (2023). Clinical performance of volumetric finger-prick sampling for the monitoring of tacrolimus, creatinine and haemoglobin in kidney transplant recipients. British Journal of Clinical Pharmacology. ISSN 0306-5251. 89(12), p. 3690–3701. doi: 10.1111/bcp.15870. Full text in Research Archive Show summary

  Aims Finger‐prick sampling has emerged as an attractive tool for therapeutic drug monitoring and associated diagnostics. We aimed to validate the clinical performance of using two volumetric devices (Capitainer® qDBS and Mitra®) for monitoring tacrolimus, creatinine and haemoglobin in kidney transplant (KTx) recipients. Secondarily, we evaluated potential differences between finger‐prick sampling performed by healthcare professionals vs . self‐sampling, and differences between the two devices. Methods We compared finger‐prick and venous sampling in three settings: microsampling performed by healthcare personnel, self‐sampling under supervision, unsupervised self‐sampling. The finger‐prick samples were analysed with adapted methods and results compared to routine method analysis of the venous blood samples. Results Twenty‐five KTx recipients completed the main study and 12 KTx recipients completed a post hoc validation study. For tacrolimus measurements and predicted area under the curve, the proportions within ±20% difference were 79%–96% for Capitainer and 77%–95% for Mitra. For creatinine and haemoglobin, the proportions within ±15% were 92%–100% and 93%–100% for Capitainer and 79%–96% and 67%–92% for Mitra, respectively. Comparing sampling situations, the success rate was consistent for Capitainer (92%–96%), whereas Mitra showed 72%–88% and 52%–72% success rates with samples collected by healthcare personnel and the patients themselves. Conclusions Capitainer and Mitra are technically feasible for measuring tacrolimus, creatinine and haemoglobin. In the context of self‐sampling, Capitainer maintained consistent sampling success and analytical quality. Implementing volumetric finger‐prick self‐sampling for the monitoring of tacrolimus, creatinine and haemoglobin may simplify and improve the follow‐up of KTx recipients.

• Vethe, Nils Tore; Husebye, Einar; Andersen, Anders Mikal; Bergan, Stein; Kristiansen, Oskar & Fagerland, Morten [Show all 7 contributors for this article] (2022). Monitoring Simvastatin Adherence in Patients With Coronary Heart Disease: A Proof-of-Concept Study Based on Pharmacokinetic Measurements in Blood Plasma. Therapeutic Drug Monitoring. ISSN 0163-4356. 44(4), p. 558–567. doi: 10.1097/FTD.0000000000000992. Full text in Research Archive Show summary

  Background:  Poor statin adherence remains a public health concern associated with adverse outcomes. We evaluated the use of pharmacokinetic measurements to monitor adherence to simvastatin in patients with coronary heart disease (CHD). Methods:  Eighteen patients with CHD taking an evening dose of simvastatin 20 mg (n = 7), 40 mg (n = 5), or 80 mg (n = 6) were examined at steady-state pharmacokinetics. Ten patients were instructed to interrupt simvastatin dosing and return for blood sampling for the subsequent 3 days. Dose-normalized plasma concentrations of simvastatin lactone and simvastatin acid and the sum of the 2 were evaluated to discriminate between adherent dosing and dose omission. Bioanalytical quantification was performed using liquid chromatography–tandem mass spectrometry. Results:  A simvastatin acid cutoff of 1.0 × 10−2 nmol−1·L−1·mg−1 identified 100% of those omitting 2 doses and 60% of those omitting a single dose. Simvastatin acid showed superior ability to discriminate dose omission, as well as the best agreement between samples handled at ambient and cool temperatures (median deviation 3.5%; interquartile range −2.5% to 13%). The cutoff for a morning dose schedule, with a similar ability to discriminate, was estimated at 2.0 × 10−3 nmol−1·L−1·mg−1. Conclusions:  The present method discriminated between adherence and reduced adherence to simvastatin therapy in patients with CHD. Sample handling is feasible for routine practice, and the assessment of adherence can be performed by direct measurement of simvastatin acid in a blood sample, according to defined cutoff values. Further studies validating the cutoff value and utility for clinical application are encouraged.

• Sverre, Elise Christine Bjørkholen; Peersen, Kari; Kristiansen, Oscar; Fagerland, Morten; Perk, Joep & Husebye, Einar [Show all 9 contributors for this article] (2022). Tailored clinical management after blinded statin challenge improved the lipid control in coronary patients with self-perceived muscle side effects. Journal of Internal Medicine. ISSN 0954-6820. 291(6), p. 891–893. doi: 10.1111/joim.13454. Full text in Research Archive
• Skauby, Ragnhild Kristine Heier; Bergan, Stein; Andersen, Anders Mikal; Vethe, Nils Tore & Christensen, Hege (2021). In vitro assessments predict that CYP3A4 contributes to a greater extent than CYP3A5 to prednisolone clearance. Basic & Clinical Pharmacology & Toxicology. ISSN 1742-7835. 129(6), p. 427–436. doi: 10.1111/bcpt.13645. Full text in Research Archive Show summary

  Because several steroid hormones are metabolized to their respective 6β-hydroxy forms by CYP3A4 and CYP3A5, these isoenzymes have been assumed to metabolize the immunosuppressive drug prednisolone, with conflicting results in the literature with respect to their relative importance. A direct study of the metabolism of prednisolone by microsomal CYP3A4 and CYP3A5 is missing. The aim of this in vitro study was to investigate the relative importance of recombinant CYP3A4 and recombinant CYP3A5 in the metabolism of prednisolone and to compare the extent of formation of 6β-OH-prednisolone by the two enzymes. Through in vitro incubations using rCYP3A4 and rCYP3A5 enzymes, intrinsic clearance (CLint) of prednisolone was determined by the substrate depletion approach. Formation of the metabolite 6β-OH-prednisolone by rCYP3A4 and rCYP3A5, respectively, was compared. Prednisolone concentrations were measured, and its metabolite 6β-OH-prednisolone was identified using a HPLC-MS/MS in-house method. CLint for prednisolone by rCYP3A5 was less than 26% relative to rCYP3A4. Formation of 6β-OH-prednisolone by rCYP3A5 was less than 11% relative to rCYP3A4. The study indicates that 6β-hydroxylation of prednisolone assessed in vitro in recombinant CYP enzymes depends on rCYP3A4 rather than rCYP3A5 and that CYP3A5 may be responsible for the formation of other prednisolone metabolite(s) in addition to 6β-OH-prednisolone.

• Peersen, Kari; Munkhaugen, John; Sverre, Elise Christine Bjørkholen; Kristiansen, Oskar; Fagerland, Morten & Vethe, Nils Tore [Show all 9 contributors for this article] (2021). Clinical and psychological factors in coronary heart disease patients with statin associated muscle side-effects. BMC Cardiovascular Disorders. 21, p. 1–9. doi: 10.1186/s12872-021-02422-7. Full text in Research Archive Show summary

  Background: To compare clinical and psychological factors among patients with self-perceived statin-associated muscle symptoms (SAMS), confirmed SAMS, and refuted SAMS in coronary heart disease patients (CHD). Methods: Data were obtained from a cross-sectional study of 1100 CHD outpatients and a study of 71 CHD outpatients attending a randomized, double-blinded, placebo-controlled, crossover study to test effects of atorvastatin 40 mg/day on muscle symptom intensity. Clinical and psychosocial factors were compared between patients with and without SAMS in the cross-sectional study, and between patients with confirmed SAMS and refuted SAMS in the randomized study. Results: Bilateral, symmetric muscle symptoms in the lower extremities during statin treatment were more prevalent in patients with confirmed SAMS compared to patients with refuted SAMS (75% vs. 41%, p = 0.01) in the randomized study. No significant differences in psychological factors (anxiety, depression, worry, insomnia, type D personality characteristics) were detected between patients with and without self-perceived SAMS in the cross-sectional study, or between patients with confirmed SAMS and refuted SAMS, in the randomized study. Conclusions: Patients with confirmed SAMS more often present with bilateral lower muscle symptoms compared to those with refuted SAMS. Psychological factors were not associated with self-perceived SAMS or confirmed SAMS. A careful pain history and a search for alternative causes of muscle symptoms are likely to promote communication in patients with SAMS, and may reduce the risk for statin discontinuation.

• Kindem, Ingvild Andrea; Bjerre, Anna Kristina; Åsberg, Anders; Midtvedt, Karsten; Bergan, Stein & Vethe, Nils Tore (2021). Tacrolimus Measured in Capillary Volumetric Microsamples in Pediatric Patients—A Cross-Validation Study. Therapeutic Drug Monitoring. ISSN 0163-4356. 43(3), p. 371–375. doi: 10.1097/FTD.0000000000000873. Full text in Research Archive Show summary

  Background: Therapeutic drug monitoring of tacrolimus (Tac) is mandatory in solid organ transplant (SOT) recipients. Finger-prick microsampling is more flexible and tolerable during the therapeutic drug monitoring of tacrolimus and has been shown to be applicable in adult SOT recipients. In this study, a previously validated method applying volumetric absorptive microsampling (VAMS) to measure Tac in adults was cross-validated in a pediatric population. Methods: Patients with SOT scheduled for standard posttransplant follow-up visits were recruited. Blood samples were obtained by trained phlebotomists using standard venipuncture and capillary microsampling, before the morning dose of Tac as well as 2 and 5 hours after dosing. Tac concentrations were quantified using liquid chromatography–tandem mass spectrometry. Concordance between Tac concentrations obtained with venipuncture and VAMS was evaluated using Passing–Bablok regression, calculation of absolute and relative differences, and percentage of samples within ±20% and ±30% difference. Results: A total of 39 SOT patients aged 4–18 years (22 male) were included. The median (range) predose venous blood concentration was 4.8 (2.6–13.6) mcg/L, with a difference between VAMS and venous blood samples of −0.2 ± 0.7 mcg/L. The relative mean difference was −1.3% [95% confidence interval (CI), −5.9% to 3.4%]. Ninety-two percent and 97% of the sample pairs demonstrated differences within ±20% and ±30%, respectively. Postdose (2 hours and/or 5 hours, n = 17) median concentration in venous blood was 7.9 (4.8–19.2) mcg/L. The difference between VAMS and venous blood samples was 0.1 ± 1.0 mcg/L, with a relative mean difference of −2.5% (95% confidence interval, −8.8% to 3.8%). Eighty-eight percent of the postdose sample pairs were within ±20% difference, and all were within ±30% difference. Conclusions: Tac concentrations can be accurately measured using VAMS technology in pediatric SOT recipients. This makes home-based Tac monitoring feasible in the pediatric population.

• Kristiansen, Oskar; Sverre, Elise Christine Bjørkholen; Peersen, Kari; Fagerland, Morten; Gjertsen, Erik & Gullestad, Lars [Show all 11 contributors for this article] (2021). The relationship between directly measured statin adherence, self-reported adherence measures and cholesterol levels in patients with coronary heart disease. Atherosclerosis. ISSN 0021-9150. 336, p. 23–29. doi: 10.1016/j.atherosclerosis.2021.09.020. Full text in Research Archive Show summary

  Background and aims: We aimed to determine the relationship between statin adherence measured directly, and by self-report measures and serum cholesterol levels. Methods: Patients prescribed atorvastatin (N = 373) participated in a cross-sectional study 2–36 months after a coronary event. Self-reported adherence included statin adherence the past week, the 8-item Morisky medication adherence scale (MMAS-8), and the Gehi et al. adherence question. Atorvastatin was measured directly in spot blood plasma by a novel liquid chromatography tandem mass-spectrometry method discriminating adherence (0–1 doses omitted) and reduced adherence (≥2 doses omitted). Participants were unaware of the atorvastatin analyses at study participation. Results: Mean age was 63 (SD 9) years and 8% had reduced atorvastatin adherence according to the direct method. In patients classified with reduced adherence by the direct method, 40% reported reduced statin adherence, 32% reported reduced adherence with the MMAS-8 and 22% with the Gehi question. In those adherent by the direct method, 96% also reported high statin adherence, 95% reported high adherence on the MMAS-8 whereas 94% reported high adherence on the Gehi question. Cohen’s kappa agreement score with the direct method was 0.4 for self-reported statin adherence, 0.3 for the Gehi question and 0.2 for the MMAS-8. Adherence determined by the direct method, self-reported statin adherence last week, and the Gehi question was inversely related to LDL-cholesterol levels with a p-value of <0.001, 0.001 and 0.004, respectively. Conclusions: Plasma-statin measurements reveal reduced adherence with higher sensitivity than self-report measures, relate to cholesterol levels, and may prove to be a useful tool to improve lipid management.

• Bergan, Stein; Brunet, Mercé; Hesselink, Dennis A.; Johnson-Davis, Kamisha L; Kunicki, Pawel K & Lemaitre, Florian [Show all 38 contributors for this article] (2021). Personalized Therapy for Mycophenolate: Consensus Report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. Therapeutic Drug Monitoring. ISSN 0163-4356. 43(2), p. 150–200. doi: 10.1097/FTD.0000000000000871. Full text in Research Archive
• Andersen, Anders Mikal; Bergan, Stein; Gedde-Dahl, Tobias; Buechner, Jochen & Vethe, Nils Tore (2021). Fast and reliable quantification of busulfan in blood plasma using two-channel liquid chromatography tandem mass spectrometry: Validation of assay performance in the presence of drug formulation excipients. Journal of Pharmaceutical and Biomedical Analysis. ISSN 0731-7085. 203, p. 1–11. doi: 10.1016/j.jpba.2021.114216. Full text in Research Archive Show summary

  A fast and reliable method based on two-channel liquid chromatography coupled to tandem mass spectrometry was developed and successfully validated for quantification of busulfan. The drug vehicle polyethylene glycol 400 was quantified simultaneously in patient samples. The sample preparation consisted of simple protein precipitation using a mixture of methanol and zinc sulphate containing busulfan-d8 as internal standard. Chromatographic separation was performed on a short biphenyl column (30 mm × 3.0 mm, 5 μm particles) using a step gradient from 30 % to 85 % methanol, ensuring co-elution of the analyte and internal standard. Quantification was performed using the mass transition of 264.1 > 151.1 for busulfan and 272.1 > 159.1 for the internal standard. Using only 20 μL of plasma sample, the lower limit of quantification was 25 ng/mL. Signal to noise ratio at the lower limit of quantification exceeded 300. The assay performance was not adversely affected by matrix effects originating from drug formulation excipients or other sample components. The coefficient of variation was ≤4 % and the mean accuracy 101–108 % across the calibration range 25–5 000 ng/mL. Chromatographic run time was 2 min and 8 s, allowing an effective run-time of 1 min and 10 s when using two alternating LC-channels. The assay has been implemented in routine practice with accreditation according to the ISO 15189 standard, and performs well in external quality control assessments. We present for the first time that shortly after an IV infusion of busulfan, the plasma levels of polyethylene glycol 400 may be in the range of 400−800 mg/L. The presence of these levels of detergent in patient samples may have detrimental effects on assay performance in LC–MS/MS, not limited to busulfan assays. This may be a concern for any LC–MS/MS analysis performed on samples collected within the first 24 h after an IV infusion of busulfan.

• Amrutkar, Manoj; Vethe, Nils Tore; Verbeke, Caroline Sophie; Aasrum, Monica; Vefferstad, Anette & Santha, Petra [Show all 7 contributors for this article] (2020). Differential gemcitabine sensitivity in primary human pancreatic cancer cells and paired stellate cells is driven by heterogenous drug uptake and processing. Cancers. 12:3628(12), p. 1–18. doi: 10.3390/cancers12123628. Full text in Research Archive Show summary

  Gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) is attributed to cancer cell-intrinsic drug processing and the impact of the tumor microenvironment, especially pancreatic stellate cells (PSCs). This study uses human PDAC-derived paired primary cancer cells (PCCs) and PSCs from four different tumors, and the PDAC cell lines BxPC-3, Mia PaCa-2, and Panc-1, to assess the fate of gemcitabine by measuring its cellular uptake, cytotoxicity, and LC-MS/MS-based metabolite analysis. Expression analysis and siRNA-mediated knockdown of key regulators of gemcitabine (hENT1, CDA, DCK, NT5C1A) was performed. Compared to PSCs, both the paired primary PCCs and cancer cell lines showed gemcitabine-induced dose-dependent cytotoxicity, high uptake, as well as high and variable intracellular levels of gemcitabine metabolites. PSCs were gemcitabine-resistant and demonstrated significantly lower drug uptake, which was not influenced by co-culturing with their paired PCCs. Expression of key gemcitabine regulators was variable, but overall strong in the cancer cells and significantly lower or undetectable in PSCs. In cancer cells, hENT1 inhibition significantly downregulated gemcitabine uptake and cytotoxicity, whereas DCK knockdown reduced cytotoxicity. In conclusion, heterogeneity in gemcitabine processing among different pancreatic cancer cells and stellate cells results from the differential expression of molecular regulators which determines the effect of gemcitabine.

• Gustavsen, Marte Theie; Midtvedt, Karsten; Robertsen, Ida; Woillard, Jean-Baptiste; Debord, Jean & Klaasen, Rolf [Show all 9 contributors for this article] (2020). Fasting Status and Circadian Variation Must be Considered When Performing AUC-based Therapeutic Drug Monitoring of Tacrolimus in Renal Transplant Recipients. Clinical and Translational Science (CTS). ISSN 1752-8054. 13(6), p. 1327–1335. doi: 10.1111/cts.12833. Full text in Research Archive
• Skauby, Ragnhild Kristine Heier; Gustavsen, Marte Theie; Andersen, Anders Mikal; Bjerre, Anna Kristina; Åsberg, Anders & Midtvedt, Karsten [Show all 8 contributors for this article] (2020). Prednisolone and Prednisone Pharmacokinetics in Adult Renal Transplant Recipients. Therapeutic Drug Monitoring. ISSN 0163-4356. 43(2), p. 247–255. doi: 10.1097/FTD.0000000000000835. Full text in Research Archive
• Klaasen, Rolf; Bergan, Stein; Bremer, Sara; Hole, Kristine; Nordahl, Christine Berg & Andersen, Anders Mikal [Show all 9 contributors for this article] (2020). Pharmacodynamic assessment of mycophenolic acid in resting and activated target cell population during the first year after renal transplantation. British Journal of Clinical Pharmacology. ISSN 0306-5251. 86(6), p. 1100–1112. doi: 10.1111/bcp.14218. Full text in Research Archive
• Kristiansen, Oskar; Vethe, Nils Tore; Peersen, Kari; Fagerland, Morten; Sverre, Elise Christine Bjørkholen & Jensen, Elena Prunès [Show all 15 contributors for this article] (2020). Effect of Atorvastatin on Muscle Symptoms in Coronary Heart Disease Patients With Self-Perceived Statin Muscle Side-Effects: A Randomized, Double Blinded Crossover Trial. European Heart Journal (EHJ) - Cardiovascular Pharmacotherapy. ISSN 2055-6837. 7(6), p. 507–516. doi: 10.1093/ehjcvp/pvaa076. Full text in Research Archive Show summary

  Aims: To estimate the effect of atorvastatin on muscle symptom intensity in coronary heart disease (CHD) patients with self-perceived statin-associated muscle symptoms (SAMS) and to determine the relationship to blood levels of atorvastatin and/or metabolites. Methods and results: A randomized multi-center trial consecutively identified 982 patients with previous or ongoing atorvastatin treatment after a CHD event. Of these, 97 (9.9%) reported SAMS and 77 were randomized to 7-weeks double-blinded treatment with atorvastatin 40 mg/day and placebo in a crossover design. The primary outcome was the individual mean difference in muscle symptom intensity between the treatment periods, measured by visual-analogue scale (VAS) scores. Atorvastatin did not affect the intensity of muscle symptoms among 71 patients who completed the trial. Mean VAS difference [statin-placebo] was 0.31 (95% CI -0.24-0.86). The proportion with more muscle symptoms during placebo than atorvastatin was 17% (n = 12), 55% (n = 39) had the same muscle symptom intensity during both treatment periods whereas 28% (n = 20) had more symptoms during atorvastatin than placebo (confirmed SAMS). There were no differences in clinical or pharmacogenetic characteristics between these groups. The levels of atorvastatin and/or metabolites did not correlate to muscle symptom intensity among patients with confirmed SAMS (Spearmans rho ≤0.40, for all variables). Conclusion: Re-challenge with high-intensity atorvastatin did not affect the intensity of muscle symptoms in CHD patients with self-perceived SAMS during previous atorvastatin therapy. There was no relationship between muscle symptoms and the systemic exposure to atorvastatin and/or its metabolites. The findings encourage an informed discussion to elucidate other causes of muscle complaints and continued statin use.

• Lemaitre, Florian; Vethe, Nils Tore; DʼAvolio, Antonio; Tron, Camille; Robertsen, Ida & Winter, Brenda De [Show all 14 contributors for this article] (2020). Measuring intracellular concentrations of calcineurin inhibitors: Expert consensus from the international association of therapeutic drug monitoring and clinical toxicology expert panel. Therapeutic Drug Monitoring. ISSN 0163-4356. 42(5), p. 665–670. doi: 10.1097/FTD.0000000000000780. Full text in Research Archive
• Gustavsen, Marte Theie; Midtvedt, Karsten; Vethe, Nils Tore; Robertsen, Ida; Bergan, Stein & Åsberg, Anders (2020). Tacrolimus area under the concentration versus time curve monitoring, using home-based volumetric absorptive capillary microsampling. Therapeutic Drug Monitoring. ISSN 0163-4356. 42(3), p. 407–414. doi: 10.1097/FTD.0000000000000697. Full text in Research Archive
• Kvamsøe, Marianne Meling; Hansen, Kristina Ravnås; Skadberg, Øyvind; Vethe, Nils Tore & Brede, Cato (2020). Salting Out-Assisted Liquid–Liquid Extraction for Liquid Chromatography–Tandem Mass Spectrometry Measurement of Tacrolimus, Sirolimus, Everolimus, and Cyclosporine a in Whole Blood. Therapeutic Drug Monitoring. ISSN 0163-4356. 42(5), p. 695–701. doi: 10.1097/FTD.0000000000000794. Full text in Research Archive Show summary

  Background: Therapeutic drug monitoring of the immunosuppressants tacrolimus, sirolimus, everolimus, and cyclosporine A is effectively performed by analyzing whole-blood samples using liquid chromatography coupled with tandem mass spectrometry. Samples are usually prepared using simple protein precipitation (PPT) with methanol and zinc sulfate (ZnSO4). Significant sample dilution is necessary to obtain clean extracts but may increase the limit of quantification of the method. Salting out–assisted liquid–liquid extraction (SALLE) was explored as a novel sample preparation method for measuring these drugs in blood. Method: SALLE, which simply consists of LLE with a water-miscible solvent where phase separation is achieved by adding salt, was used to analyze treated blood samples. Results: SALLE allowed direct injection of a 5-µL extract from the upper solvent phase into a reversed phase LC column, which would not be feasible using standard LLE. Compared with PPT, SALLE provided better extraction efficiencies and more ion enhancement, resulting in limit of quantification of 0.4, 1.4, 0.06, and 0.4 ng/mL for tacrolimus, sirolimus, everolimus, and cyclosporine A, respectively. Full-method validation was performed, including a comparison of results with those of another laboratory. A ≤10% bias was observed for tacrolimus and cyclosporine A, whereas further investigation of that for sirolimus (−12%) and everolimus (−18%) revealed that it was caused by the different calibrators used. Conclusions: This is the first report of the use of SALLE for the measurement of tacrolimus, sirolimus, everolimus, and cyclosporine A in whole blood. The advantages of SALLE over PPT and conventional LLE would make it an attractive sample preparation method for clinical laboratories.

• Munkhaugen, John; Vethe, Nils Tore; Fagerland, Morten; Dammen, Toril; Perk, Joep & Gjertsen, Erik [Show all 10 contributors for this article] (2019). Statin-associated muscle symptoms in coronary patients: design of a randomized study. Scandinavian Cardiovascular Journal. ISSN 1401-7431. 53(3), p. 162–168. doi: 10.1080/14017431.2019.1612085. Full text in Research Archive Show summary

  Objectives. Estimate the effect of atorvastatin on muscular symptom intensity in coronary patients with subjective statin-associated muscle symptoms (SAMS) and to determine the association with blood levels of atorvastatin and its metabolites, to obtain an objective marker for true SAMS. Design. A randomized, double-blinded, cross-over study will include 80 coronary patients with subjectively reported SAMS during ongoing atorvastatin therapy or previous muscle symptoms that led to discontinuation of atorvastatin. Patients will be randomized to 7-weeks treatment with atorvastatin 40 mg/day in the first period and matched placebo in the second 7-weeks period, or placebo in the first period and atorvastatin in the second period. Each period is preceded by 1-week wash-out. A control group (n = 40) without muscle symptoms will have 7 weeks open treatment with atorvastatin 40 mg/day. Blood samples will be collected at baseline and at the end of each treatment period, and muscular symptoms will be rated by the patients weekly using a Visual Analogue Scale (VAS). The primary outcome is the difference in aggregated mean VAS scores between the last three weeks of atorvastatin treatment and of placebo treatment. The main purpose is to develop an objective marker for true SAMS, by comparing SAMS associated with blinded atorvastatin treatment with blood concentrations of atorvastatin and its metabolites. Diagnostic and discrimination performance will be determined. Conclusions. The study provides new knowledge on SAMS in coronary patients and may contribute to more personalized statin treatment and monitoring, fewer side-effects and consequently improved adherence and lipid management in future practice.

• Kristiansen, Oscar; Vethe, Nils Tore; Fagerland, Morten; Bergan, Stein; Munkhaugen, John & Husebye, Einar (2019). A novel direct method to determine adherence to atorvastatin therapy in patients with coronary heart disease. British Journal of Clinical Pharmacology. ISSN 0306-5251. p. 1–8. doi: 10.1111/bcp.14122. Full text in Research Archive Show summary

  Aims Objective methods to monitor statin adherence are needed. We have established a liquid chromatography–tandem mass spectrometry assay for quantification of atorvastatin and its metabolites in blood. This study aimed to develop an objective drug exposure variable with cut‐off values to discriminate among adherence, partial adherence and nonadherence to atorvastatin therapy in patients with coronary heart disease. Methods Twenty‐five patients treated with atorvastatin 10 mg (n = 5), 20 mg (n = 6), 40 mg (n = 7) and 80 mg (n = 7) participated in a directly observed atorvastatin therapy study to confirm baseline adherence. After the directly observed therapy, half of the patients (test group ) were instructed to stop taking atorvastatin and return for blood sample collection the subsequent 3 days. Levels of atorvastatin and metabolites were compared between the test group and the adherent control group. Results The sum of parent drug and all measured primary metabolites correlated well with the atorvastatin dose administered (Spearman's rho = 0.71, 95% CI 0.44–0.87). The dose‐normalized atorvastatin plus metabolites concentrations completely separated the partially adherent test group from the controls at 0.18 nM/mg after 3 days without atorvastatin. To reduce the risk of misinterpreting adherent patients as partially adherent, a corresponding cut‐off at 0.10 nM/mg is proposed. A metabolite level of 2‐OH atorvastatin acid <0.014 nmol/L provided the optimal cut‐off for nonadherence. Conclusion A direct method to discriminate among adherence, partial adherence and nonadherence to atorvastatin therapy in patients with coronary heart disease has been developed. This tool may be important for novel studies on adherence and potentially useful in clinical practice.

• Klaasen, Rolf; Egeland, Erlend Johannessen; Chan, Wai Joe; Midtvedt, Karsten; Svensson, My Hanna Sofia & Bolstad, Nils [Show all 12 contributors for this article] (2019). A Fully Automated Method for the Determination of Serum Belatacept and Its Application in a Pharmacokinetic Investigation in Renal Transplant Recipients. Therapeutic Drug Monitoring. ISSN 0163-4356. 41(1), p. 11–18. doi: 10.1097/FTD.0000000000000580. Full text in Research Archive
• Vethe, Nils Tore; Gustavsen, Marte Theie; Midtvedt, Karsten; Lauritsen, May Ellen; Andersen, Anders Mikal & Åsberg, Anders [Show all 7 contributors for this article] (2019). Tacrolimus Can Be Reliably Measured With Volumetric Absorptive Capillary Microsampling Throughout the Dose Interval in Renal Transplant Recipients. Therapeutic Drug Monitoring. ISSN 0163-4356. 41(5), p. 607–614. doi: 10.1097/FTD.0000000000000655. Full text in Research Archive
• Munkhaugen, John; Ruddox, Vidar; Halvorsen, Sigrun; Dammen, Toril; Fagerland, Morten & Hernæs, Kjersti Helene [Show all 23 contributors for this article] (2019). BEtablocker Treatment After acute Myocardial Infarction in revascularized patients without reduced left ventricular ejection fraction (BETAMI): Rationale and design of a prospective, randomized, open, blinded end-point study. American Heart Journal. ISSN 0002-8703. 208, p. 37–46. doi: 10.1016/j.ahj.2018.10.005. Full text in Research Archive Show summary

  Background - Current guidelines on the use of β-blockers in post–acute myocardial infarction (MI) patients without reduced left ventricular ejection fraction (LVEF) are based on studies before the implementation of modern reperfusion and secondary prevention therapies. It remains unknown whether β-blockers will reduce mortality and recurrent MI in contemporary revascularized post-MI patients without reduced LVEF. Design - BETAMI is a prospective, randomized, open, blinded end point multicenter study in 10,000 MI patients designed to test the superiority of oral β-blocker therapy compared to no β-blocker therapy. Patients with LVEF ≥40% following treatment with percutaneous coronary intervention or thrombolysis and/or no clinical signs of heart failure are eligible to participate. The primary end point is a composite of all-cause mortality or recurrent MI obtained from national registries over a mean follow-up period of 3 years. Safety end points include rates of nonfatal MI, all-cause mortality, ventricular arrhythmias, and hospitalizations for heart failure obtained from hospital medical records 30 days after randomization, and from national registries after 6 and 18 months. Key secondary end points include recurrent MI, heart failure, cardiovascular and all-cause mortality, and clinical outcomes linked to β-blocker therapy including drug adherence, adverse effects, cardiovascular risk factors, psychosocial factors, and health economy. Statistical analyses will be conducted according to the intention-to-treat principle. A prespecified per-protocol analysis (patients truly on β-blockers or not) will also be conducted. Conclusions - The results from the BETAMI trial may have the potential of changing current clinical practice for treatment with β-blockers following MI in patients without reduced LVEF. EudraCT number 2018-000590-75.

• Bergström, Marcus; Müller, Malin; Karlsson, Marie; Scholz, Hanne; Vethe, Nils Tore & Korsgren, Olle (2019). Comparing the Effects of the mTOR Inhibitors Azithromycin and Rapamycin on In Vitro Expanded Regulatory T Cells. Cell Transplantation. ISSN 0963-6897. 28(12), p. 1603–1613. doi: 10.1177/0963689719872488. Full text in Research Archive Show summary

  Adoptive transfer of autologous polyclonal regulatory T cells (Tregs) is a promising option for reducing graft rejection in allogeneic transplantation. To gain therapeutic levels of Tregs there is a need to expand obtained cells ex vivo, usually in the presence of the mTOR inhibitor Rapamycin due to its ability to suppress proliferation of non-Treg T cells, thus promoting a purer Treg yield. Azithromycin is a bacteriostatic macrolide with mTOR inhibitory activity that has been shown to exert immunomodulatory effects on several types of immune cells. In this study we investigated the effects of Azithromycin, compared with Rapamycin, on Treg phenotype, growth, and function when expanding bulk, naïve, and memory Tregs. Furthermore, the intracellular concentration of Rapamycin in CD4+ T cells as well as in the culture medium was measured for up to 48 h after supplemented. Treg phenotype was assessed by flow cytometry and Treg function was measured as inhibition of responder T-cell expansion in a suppression assay. The concentration of Rapamycin was quantified with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). Azithromycin and Rapamycin both promoted a FoxP3-positive Treg phenotype in bulk Tregs, while Rapamycin also increased FoxP3 and FoxP3+Helios positivity in naïve and memory Tregs. Furthermore, Rapamycin inhibited the expansion of naïve Tregs, but also increased their suppressive effect. Rapamycin was quickly degraded in 37°C medium, yet was retained intracellularly. While both compounds may benefit expansion of FoxP3+ Tregs in vitro, further studies elucidating the effects of Azithromycin treatment on Tregs are needed to determine its potential use.

• Vethe, Nils Tore; Munkhaugen, John; Andersen, Anders Mikal; Husebye, Einar & Bergan, Stein (2019). A Method for Direct Monitoring of Atorvastatin Adherence in Cardiovascular Disease Prevention: Quantification of the Total Exposure to Parent Drug and Major Metabolites Using 2-Channel Chromatography and Tandem Mass Spectrometry. Therapeutic Drug Monitoring. ISSN 0163-4356. 41(1), p. 19–28. doi: 10.1097/FTD.0000000000000578. Full text in Research Archive Show summary

  Background: Low adherence to statin therapy remains a public health concern associated with poor prognosis in cardiovascular disease patients. A feasible method for statin adherence monitoring in clinical practice has yet to be developed. In this article, we describe a novel method designed for the direct monitoring of atorvastatin adherence based on the sum of parent drug and major metabolites in blood samples. Methods: Acid and lactone forms of atorvastatin, 2-OH-atorvastatin, and 4-OH-atorvastatin were assayed. Plasma proteins were precipitated with an acidified mixture of methanol, acetonitrile, and aqueous zinc sulfate, and the supernatant was analyzed with 2-channel reversed-phase chromatography coupled to tandem mass spectrometry. Assay validation was performed according to the guidelines provided by the European Medicines Agency and the US Food and Drug Administration. Results: The effective run time was 1 minute and 45 seconds per sample. Mean accuracy ranged from 92% to 110%, and coefficients of variation were ≤8.1% over the measurement ranges for individual compounds. The sum of acids and corresponding lactones was stable in clinical plasma samples kept at ambient temperature for up to 6 days after blood sampling (mean sum within 96.6%–101% of baseline). Conclusions: A fast and reliable assay for the quantification of atorvastatin and its 5 major metabolites in clinical blood samples is reported. Limitations of preanalytical stability were solved using the sum of the acid and lactone forms. The assay is feasible for implementation in clinical practice, and the sum of parent drug and metabolites may be used for direct monitoring of atorvastatin adherence.

• Brunet, Mercé; Gelder, Teun van; Åsberg, Anders; Haufroid, Vincent; Hesselink, Dennis A. & Langman, Loralie [Show all 37 contributors for this article] (2019). Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report. Therapeutic Drug Monitoring. ISSN 0163-4356. 41(3), p. 261–307. doi: 10.1097/FTD.0000000000000640. Full text in Research Archive
• Krogstad, Veronica; Vethe, Nils Tore; Robertsen, Ida; Hasvold, Grete; Ose, Anne-Marthe Due & Hermann, Monica [Show all 12 contributors for this article] (2018). Determination of Tacrolimus Concentration and Protein Expression of P-Glycoprotein in Single Human Renal Core Biopsies. Therapeutic Drug Monitoring. ISSN 0163-4356. 40(3), p. 292–300. doi: 10.1097/FTD.0000000000000510. Full text in Research Archive
• Klaasen, Rolf; Bergan, Stein; Bremer, Sara; Daleq, Lina; Andersen, Anders Mikal & Midtvedt, Karsten [Show all 8 contributors for this article] (2018). Longitudinal Study of Tacrolimus in Lymphocytes During the First Year After Kidney Transplantation. Therapeutic Drug Monitoring. ISSN 0163-4356. doi: 10.1097/FTD.0000000000000539. Full text in Research Archive
• Bremer, Sara; Vethe, Nils Tore; Skauby, Morten Heier; Kasbo, Margrete; Johansson, Elisabet Dahl & Midtvedt, Karsten [Show all 7 contributors for this article] (2017). NFAT-regulated cytokine gene expression during tacrolimus therapy early after renal transplantation. British Journal of Clinical Pharmacology. ISSN 0306-5251. 83(11), p. 2494–2502. doi: 10.1111/bcp.13367. Full text in Research Archive
• Skauby, Ragnhild Kristine Heier; Bjerre, Anna Kristina; Sæves, Ingjerd; Vethe, Nils Tore; Bremer, Sara & Svarstad, Anja Camilla [Show all 7 contributors for this article] (2017). Prednisolone and Prednisone Pharmacokinetics in Pediatric Renal Transplant Recipients - A Prospective Study. Therapeutic Drug Monitoring. ISSN 0163-4356. 39(5), p. 472–482. doi: 10.1097/FTD.0000000000000439. Full text in Research Archive
• Kloster-Jensen, Kristine; Sahraoui, Afaf; Vethe, Nils Tore; Korsgren, Olle; Bergan, Stein & Foss, Aksel [Show all 7 contributors for this article] (2016). Treatment with tacrolimus and sirolimus reveals no additional adverse effects on human islets in vitro compared to each drug alone but they are reduced by adding glucocorticoids. Journal of Diabetes Research. ISSN 2314-6745. 2016. doi: 10.1155/2016/4196460. Full text in Research Archive Show summary

  Tacrolimus and sirolimus are important immunosuppressive drugs used in human islet transplantation; however, they are linked to detrimental effects on islets and reduction of long-term graft function. Few studies investigate the direct effects of these drugs combined in parallel with single drug exposure. Human islets were treated with or without tacrolimus (30 μg/L), sirolimus (30 μg/L), or a combination thereof for 24 hrs. Islet function as well as apoptosis was assessed by glucose-stimulated insulin secretion (GSIS) and Cell Death ELISA. Proinflammatory cytokines were analysed by qRT-PCR and Bio-Plex. Islets exposed to the combination of sirolimus and tacrolimus were treated with or without methylprednisolone (1000 μg/L) and the expression of the proinflammatory cytokines was investigated. We found the following: (i) No additive reduction in function and viability in islets existed when tacrolimus and sirolimus were combined compared to the single drug. (ii) Increased expression of proinflammatory cytokines mRNA and protein levels in islets took place. (iii) Methylprednisolone significantly decreased the proinflammatory response in islets induced by the drug combination. Although human islets are prone to direct toxic effect of tacrolimus and sirolimus, we found no additive effects of the drug combination. Short-term exposure of glucocorticoids could effectively reduce the proinflammatory response in human islets induced by the combination of tacrolimus and sirolimus.

• Bergan, Stein; Bremer, Sara & Vethe, Nils Tore (2016). Drug target molecules to guide immunosuppression. Clinical Biochemistry. ISSN 0009-9120. 49(4-5), p. 411–418. doi: 10.1016/j.clinbiochem.2015.10.001. Full text in Research Archive
• Robertsen, Ida; Vethe, Nils Tore; Midtvedt, Karsten; Falck, Pål; Christensen, Hege Staaland & Åsberg, Anders (2015). Closer to the site of action: everolimus concentrations in peripheral blood mononuclear cells correlate well with whole blood concentrations. Therapeutic Drug Monitoring. ISSN 0163-4356. 37(5), p. 675–680. doi: 10.1097/FTD.0000000000000185. Full text in Research Archive
• Robertsen, Ida; Åsberg, Anders; Olsen, Aleksander Ingerø; Vethe, Nils Tore; Bremer, Sara & Bergan, Stein [Show all 7 contributors for this article] (2015). Use of generic tacrolimus in elderly renal transplant recipients: Precaution is needed. Transplantation. ISSN 0041-1337. 99(3), p. 528–532. doi: 10.1097/TP.0000000000000384. Full text in Research Archive
• Kloster-Jensen, Kristine; Vethe, Nils Tore; Bremer, Sara; Abadpour, Shadab; Korsgren, Olle & Foss, Aksel [Show all 8 contributors for this article] (2015). Intracellular sirolimus concentration is reduced by tacrolimus in human pancreatic islets in vitro. Transplant International. ISSN 0934-0874. 28(10), p. 1152–1161. doi: 10.1111/tri.12617. Full text in Research Archive
• Vethe, Nils Tore; Ali, Mohamad; Reine, Pål Aarstrand; Andersen, Anders Mikal; Bremer, Sara & Line, Pål Dag [Show all 8 contributors for this article] (2014). Simultaneous Quantification of IMPDH Activity and Purine Bases in Lymphocytes Using LC-MS/MS: Assessment of Biomarker Responses to Mycophenolic Acid. Therapeutic Drug Monitoring. ISSN 0163-4356. 36, p. 108–118. doi: 10.1097/FTD.0b013e3182a13900. Full text in Research Archive
• Robertsen, Ida; Åsberg, Anders; Granseth, Tone; Vethe, Nils Tore; Akhlaghi, Fatemeh & Ghareeb, Mwlod [Show all 10 contributors for this article] (2014). More potent lipid-lowering effect by rosuvastatin compared with fluvastatin in everolimus-treated renal transplant recipients. Transplantation. ISSN 0041-1337. 97(12), p. 1266–1272. doi: 10.1097/01.TP.0000443225.66960.7e. Full text in Research Archive
• Sæves, Ingjerd; Line, Pål Dag; Bremer, Sara; Vethe, Nils Tore; Tveit, Ragnhild G & Meltevik, Tore J [Show all 7 contributors for this article] (2014). Tacrolimus exposure and mycophenolate pharmacokinetics and pharmacodynamics early after liver transplantation. Therapeutic Drug Monitoring. ISSN 0163-4356. 36(1), p. 46–53. doi: 10.1097/FTD.0b013e31829dcb66. Full text in Research Archive
• Reine, Pål Aarstrand; Vethe, Nils Tore; Kongsgaard, Ulf; Andersen, Anders Mikal; Line, Pål Dag & Ali, Mohamad [Show all 7 contributors for this article] (2013). Mycophenolate pharmacokinetics and inosine monophosphate dehydrogenase activity in liver transplant recipients with an emphasis on therapeutic drug monitoring. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 73(2), p. 117–124. doi: 10.3109/00365513.2012.745947. Full text in Research Archive
• Fagermoen, Frode Even; Sulheim, Dag; Winger, Anette; Andersen, Anders Mikal; Vethe, Nils Tore & Saul, J P [Show all 8 contributors for this article] (2012). Clonidine in the treatment of adolescent chronic fatigue syndrome: a pilot study for the NorCAPITAL trial. BMC Research Notes. 5. doi: 10.1186/1756-0500-5-418. Full text in Research Archive Show summary

  Background This pilot study (ClinicalTrials.gov ID: NCT01507701) assessed the feasibility and safety of clonidine in adolescent chronic fatigue syndrome (CFS). Specifically, we assessed clonidine dosage in relation to a) plasma concentration levels, b) orthostatic cardiovascular responses, and c) possible adverse effects. Findings Five adolescent CFS patients (14–19 years old) received 50 μg clonidine twice per day during 14 days in an open, uncontrolled design. Plasma concentration of clonidine was assayed by standard laboratory methods. Changes in orthostatic cardiovascular responses were assessed by a 20o head-up tilt-test (HUT). Adverse effects were mapped by a questionnaire. After 14 days, C0 median (range) of clonidine was 0.21 (0.18-0.36) μg/L, and Cmax median (range) of clonidine was 0.41 (0.38-0.56) μg/L. Also, supine blood pressures and heart rate were lower during clonidine treatment, and the HUT response was closer to the normal response. No serious adverse effects were registered. Conclusion Clonidine 50 μg BID seems to be safe enough to proceed from a pilot study to a controlled trial in a select group of adolescents with CFS (ClinicalTrials.gov ID: NCT01040429).

• Sæves, Ingjerd; Vethe, Nils Tore & Bergan, Stein (2011). Quantification of 6 Glucocorticoids in Human Plasma by Liquid Chromatography Tandem Mass Spectrometry: Method Development, Validation, and Assessment of Matrix Effects. Therapeutic Drug Monitoring. ISSN 0163-4356. 33(4), p. 402–410. doi: 10.1097/FTD.0b013e3182241799. Full text in Research Archive
• Midtvedt, Karsten; Jenssen, Trond Geir; Hartmann, Anders; Vethe, Nils Tore; Bergan, Stein & Havnes, Kjerstin [Show all 7 contributors for this article] (2011). No change in insulin sensitivity in renal transplant recipients converted from standard to once-daily prolonged release tacrolimus. Nephrology, Dialysis and Transplantation. ISSN 0931-0509. 26(11), p. 3767–3772. doi: 10.1093/ndt/gfr153. Full text in Research Archive
• Vethe, Nils Tore; Midtvedt, Karsten; Åsberg, Anders; Amundsen, Rune & Bergan, Stein (2011). Legemiddelinteraksjoner og immunsuppresjon hos organtransplanterte. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 131(20), p. 2000–2003. doi: 10.4045/tidsskr.11.0138. Full text in Research Archive
• Vethe, Nils Tore; Gjerdalen, LC & Bergan, Stein (2010). Determination of cyclosporine, tacrolimus, sirolimus and everolimus by liquid chromatography coupled to electrospray ionization and tandem mass spectrometry: Assessment of matrix effects and assay performance. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 70(8), p. 583–591. doi: 10.3109/00365513.2010.531141. Full text in Research Archive
• Amundsen, Rune; Åsberg, Anders; Robertsen, Ida; Vethe, Nils Tore; Bergan, Stein & Hartmann, Anders [Show all 7 contributors for this article] (2009). Rimonabant Affects Cyclosporine A, but Not Tacrolimus Pharmacokinetics in Renal Transplant Recipients. Transplantation. ISSN 0041-1337. 87(8), p. 1221–1224. Full text in Research Archive
• Bremer, Sara; Vethe, Nils Tore; Rootwelt, H; Jorgensen, PF; Stenstrom, J & Holdaas, H [Show all 8 contributors for this article] (2009). Mycophenolate pharmacokinetics and pharmacodynamics in belatacept treated renal allograft recipients - a pilot study. Journal of Translational Medicine. 7. doi: 10.1186/1479-5876-7-64. Full text in Research Archive
• Bremer, Sara; Vethe, Nils Tore; Rootwelt, Helge & Bergan, Stein (2009). Expression of IMPDH1 is regulated in response to mycophenolate concentration. International Immunopharmacology. ISSN 1567-5769. 9(2), p. 173–180. doi: 10.1016/j.intimp.2008.10.017. Full text in Research Archive
• Vethe, Nils Tore; Bremer, Sara & Bergan, Stein (2008). IMP dehydrogenase basal activity in MOLT-4 human leukaemia cells is altered by mycophenolic acid and 6-thioguanosine. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 68, p. 277–285. doi: 10.1080/00365510701724871. Full text in Research Archive
• Falck, Pål; Vethe, Nils Tore; Åsberg, Anders; Midtvedt, Karsten; Bergan, Stein & Reubsaet, Jan Leo [Show all 7 contributors for this article] (2008). Cinacalcet's effect on the pharmacokinetics of tacrolimus, cyclosporine and mycophenolate in renal transplant recipients. Nephrology, Dialysis and Transplantation. ISSN 0931-0509. 23, p. 1048–1053. doi: 10.1093/ndt/gfm632. Full text in Research Archive
• Bremer, Sara; Mandla, Randeep; Vethe, Nils Tore; Rasmussen, Ingrid; Rootwelt, Helge & Line, PD [Show all 8 contributors for this article] (2008). Expression of IMPDH1 and IMPDH2 after transplantation and initiation of immunosuppression. Transplantation. ISSN 0041-1337. 85(1), p. 55–61. doi: 10.1097/01.tp.0000296854.68123.03. Full text in Research Archive
• Vethe, Nils Tore; Mandla, Randeep; Line, Pål Dag; Midtvedt, Karsten; Hartmann, A. & Bergan, Stein (2006). Inosine monophosphate dehydrogenase activity in renal allograft recipients during mycophenolate treatment. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 66. Full text in Research Archive
• Vethe, Nils Tore & Bergan, Stein (2006). Determination of inosine monophosphate dehydrogenase activity in human CD4+cells isolated from whole blood during mycophenolic acid therapy. Therapeutic Drug Monitoring. ISSN 0163-4356. 28, p. 608–613. Full text in Research Archive

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• Uduma, Amara Synøve Øgaard; Sverre, Elise Christine Bjørkholen; Munkhaugen, John; Svarstad, Anja Camilla; Tuv, Silja Skogstad & Vethe, Nils Tore (2026). Effect of the ugt1a3*2 haplotype on pharmacokinetics and pharmacodynamics of atorvastatin in patients with coronary heart disease. European Journal of Preventive Cardiology (EJPC). ISSN 2047-4873. 33(Supplement_2). doi: 10.1093/eurjpc/zwag249.436. Full text in Research Archive Show summary

  Abstract Background Atorvastatin reduces the risk of atherosclerotic cardiovascular disease but exhibits wide interindividual variability in efficacy and adverse effects, possibly due to genetic predispositions. The SLCO1B1*5 variant causes higher systemic exposure to atorvastatin, and has been associated with increased risk of muscular side effects. The UGT1A3*2 haplotype potentially relate to poorer cholesterol response and increased risk of muscle toxicity by skewing the metabolism towards increased lactonization of atorvastatin metabolites. Purpose To explore the relationship between the UGT1A3*2 haplotype and the pharmacokinetics and pharmacodynamics of atorvastatin in patients with coronary heart disease. Methods We used data from the MUSE study, a double-blinded crossover trial in patients with coronary heart disease. The intervention group with statin-associated muscle symptoms (SAMS, n=70) underwent two 7-week periods with atorvastatin 40 mg and placebo. The control group with no history of SAMS (n=39) received atorvastatin 40 mg during an open-label 7-week period. Blood samples were collected 24h after atorvastatin administration, at the end of each period. We determined pharmacogenetic variants with a multiplex-PCR MALDI-TOF assay. Atorvastatin, its main metabolites, and mevalonate, were quantified with liquid chromatography mass spectrometry. Results Mean age was 64 years and 32% were females. UGT1A3*2 was present in 54% of patients, and the SLCO1B1*5, CYP3A4*22 and CYP3A7*1C variants were present in 29%, 8.3% and 13% (Table 1). In the SAMS group, atorvastatin versus placebo produced mean changes in mevalonate -34 ± 24%, LDL-C -47 ± 19%, and CK +10 ± 33%. In adjusted analysis, SLCO1B1*5 was consistently associated with higher concentrations of atorvastatin and in both acid and lactone form (Table 2). The UGT1A3*2 haplotype was associated with higher levels of hydroxylated atorvastatin and its metabolites. The effects of CYP3A4*22 and CYP3A7*1C were selective towards the non-hydroxylated atorvastatin lactone and 4-hydroxylated atorvastatin lactone, respectively. Regression analysis indicated a more pronounced reduction in mevalonate, a response marker of HMG-CoA reductase inhibition among carriers of UGT1A3*2 whereas none of the examined variants predicted LDL-C response. Unexpectedly, SLCO1B1*5 and CYP3A7*1C were associated with an atorvastatin-related decrease in CK. Conclusions UGT1A3*2 was observed in approximately half of the patients with coronary heart disease and is associated with higher concentrations of hydroxylated atorvastatin metabolites. This haplotype should be considered together with SLCO1B1*5 when predicting effects related to systemic exposure. The results indicate that UGT1A3*2 may have indirect impact on the pharmacodynamics of atorvastatin while further studies are needed to clarify clinical implications for LDL-C lowering and muscle safety.For image description, please refer to the figure legend and surrounding text.  For image description, please refer to the figure legend and surrounding text.

• Uduma, Amara Synnøve; Sverre, Elise Christine Bjørkholen; Munkhaugen, John; Svarstad, Anja Camilla; Tuv, Silja Skogstad & Vethe, Nils Tore (2026). Effect of the ugt1a3*2 haplotype on pharmacokinetics and pharmacodynamics of atorvastatin in patients with coronary heart disease. doi: https:/esc365.escardio.org/preventive-cardiology/sessions/18479-heterogeneity-of-vascular-and-atherosclerotic-risk-phenotypes. Full text in Research Archive
• Klevmoen, Marianne; Mulder, Janneke W.C.M.; Bogsrud, Martin Prøven; Retterstøl, Kjetil; Vesterbekkmo, Elisabeth Kleivhaug & Pedersen, Eva Ringdal [Show all 16 contributors for this article] (2025). Prospective study on breastfeeding, lipid profile and cardiovascular risk markers in women with familial hypercholesterolaemia: study protocol for the FH-FEMINA study. doi: 10.1136/bmjopen-2024-092208. Full text in Research Archive
• Uduma, Amara Synøve; Sverre, Elise Christine Bjørkholen; Munkhaugen, John; Retterstøl, Kjetil; Bogsrud, Martin Prøven & Holven, Kirsten Bjørklund [Show all 7 contributors for this article] (2025). More musculoskeletal disorders and poor pain management in patients with familial hypercholesterolemia and self-perceived side effects to cholesterol-lowering treatment. Full text in Research Archive Show summary

  Purpose: To compare clinical and psychosocial characteristics of patients with FH, with and without self-perceived side effects to cholesterol-lowering treatment. Methods: A group of 929 adult outpatients with confirmed genetic FH from a regional treatment register in Norway were invited to an observational study. The participants completed a digital questionnaire covering self-perceived side effects (any symptoms), use of cholesterol-lowering medications, musculoskeletal disorders or rheumatic diseases, and muscular symptoms and pain treatment. We collected data on FH diagnosis, comorbidities, and biomarkers in blood from the last consultation listed in the treatment register. Results: Mean age was 52 (SD 15) years, and 57% were women. Thirty-eight (15%) out of 255 participants reported self-perceived side effects to cholesterol-lowering treatment. Patients with self-perceived side effects were more frequently living alone (26% vs. 12%, p=0.025) and had slightly higher LDL-C than those without side effects, whereas no differences in creatine kinase or alanine transaminase were observed. Patients with self-perceived side effects had a higher frequency of musculoskeletal disorders or rheumatic diseases (58% vs. 37%, p<0.001) than those with no side effects (Table 1). They also reported more muscle symptoms the last month in general, and specifically from the hips, thighs, calves, shoulders, and neck. Median pain intensity the last 24-hours was significantly higher (3 vs. 1 on a 0 [no] to 10 [worst imaginable] numeric rating scale, p<0.001) in patients with side effects, and 58% currently used no pain medication (Table 2). Conclusions: Patients with FH and self-perceived side effects frequently have musculoskeletal disorders or rheumatic diseases and clinically significant pain without treatment. Our study suggests that a considerable proportion of patients misattribute muscle symptoms and pain to their cholesterol-lowering medications. Future work should focus on musculoskeletal- and rheumatic conditions as an alternative explanation for self-perceived side effects to cholesterol-lowering medication.

• Pivoriunas, Jonas; Engebretsen, Ingrid; Vethe, Nils Tore; Kristiansen, Oscar; Dammen, Toril & Fagerland, Morten Wang [Show all 9 contributors for this article] (2024). Statin adherence in coronary outpatients: a novel direct method compared with pharmacy registry data. European Journal of Preventive Cardiology (EJPC). ISSN 2047-4873. 31(Supplement_1). doi: 10.1093/eurjpc/zwae175.063. Full text in Research Archive
• Vethe, Nils Tore; Andersen, Anders Mikal; Gedde-Dahl, Tobias; Buechner, Jochen & Bergan, Stein (2024). Therapeutic Drug Monitoring of Intravenous Busulfan and Analytical Challenges due to the Drug Formulation Excipient PEG 400: Letter to the Editor. Therapeutic Drug Monitoring. ISSN 0163-4356. 46(3), p. 416–417. doi: 10.1097/FTD.0000000000001209. Full text in Research Archive
• Pivoriunas, Jonas; Engebretsen, Ingrid; Vethe, Nils Tore; Kristiansen, Oscar; Dammen, Toril & Husebye, Einar [Show all 9 contributors for this article] (2024). Statin adherence in coronary outpatients: the relationship between a novel direct method and pharmacy registry data. Full text in Research Archive Show summary

  Introduction An optimal method to assess adherence to statin therapy is needed. We developed a novel blood test to determine adherence to atorvastatin and simvastatin therapy. The relationship between statin adherence measured in blood and long-term adherence is yet to be defined. Purpose To compare statin adherence measured by single blood test with pharmacy registry data: i. the three months period prior to the blood test, and ii. from six months before until six months after the blood test. Methods In a cross-sectional study including 451 patients using either atorvastatin or simvastatin, a spot blood sample was collected median 18 months after a coronary heart disease event. Participants were unaware of the forthcoming statin analyses. Adherence (0 or 1 omitted dose) and reduced adherence, defined as ≥2 consecutively omitted doses of atorvastatin and simvastatin was determined by drug concentration measurements using liquid chromatography - tandem mass spectrometry. Study data was linked to the pharmacy registry. Indirect reduced adherence was defined as statin treatment gap exceeding 90 days. Results Thirty-nine (9%) out of 412 patients had reduced adherence to statins, determined by the novel blood test. Among patients classified as adherent by the blood test, only three (0.7%) had a treatment gap exceeding 90 days during the preceding three months. Correspondingly, of 39 patients with reduced adherence by the blood test, 11 (28%) had treatment gaps exceeding 90 days. The positive agreement between the methods was 96% and the negative agreement 42%. Among patients classified as adherent by the blood test, 21 (5%) had treatment gaps exceeding 90 days from six months before until six months after the blood test. Correspondingly, of 39 patients with reduced adherence by the blood test, 15 (39%) had at least one treatment gap exceeding 90 days. The positive agreement between measurements was 95% and the negative agreement 40%. Conclusions Among coronary patients classified as adherent by the statin blood test, registry data only identified three patients (0.7%) with a treatment gap exceeding 90 days in the three months prior to the blood test. The novel blood test emerges as a promising tool to identify patients adherent to statins, and thus may improve lipid management in clinical practice.

• Lauritzen, Trine; Munkhaugen, John; Lindahl, Sofia Helena; Bergan, Stein; Peersen, Kari & Husebye, Einar [Show all 7 contributors for this article] (2024). The effect of atorvastatin on mevalonate levels in blood plasma in patients with coronary heart disease and muscle side effects. European Journal of Preventive Cardiology (EJPC). ISSN 2047-4873. 31(Supplement_1). doi: 10.1093/eurjpc/zwae175.357. Full text in Research Archive
• Lauritzen, Trine; Munkhaugen, John; Peersen, Kari; Kristiansen, Oscar; Sverre, Elise Christine Bjørkholen & Andersen, Anders Mikal [Show all 10 contributors for this article] (2023). Atorvastatin lactone/acid ratios are promising biomarkers for statin dependent muscular side effects in patients with coronary heart disease. Full text in Research Archive
• Tuv, Silja Skogstad; Spigset, Olav; Jensen, Elena; Vethe, Nils Tore & Nordal, Kristin (2023). Nytt verktøy for tolkning av farmakogenetiske analyser. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 143(13). doi: 10.4045/tidsskr.23.0496. Full text in Research Archive Show summary

  Utilgjengelig kunnskap om tolkning av genvarianter som kan påvirke legemiddelrespons, er en barriere for implementering av farmakogenetikk. Vi har utviklet et nettbasert verktøy hvor man kan utføre spørringer og få evidensbaserte behandlingsråd ut fra påvist genotype. En viktig del av variasjonen i legemiddelrespons skyldes nedarvede genvarianter i leverenzymer (bl.a. CYP-enzymer) samt reseptor- og transportproteiner. Hele 96 % av befolkningen har minst én genetisk variant som endrer nedbrytingen av ett eller flere medikamenter (1). I dag utføres farmakogenetiske tester ved flere laboratorier i Norge. Det kan være krevende for rekvirenten å oversette genetiske testresultater til kliniske beslutninger, spesielt for legemidler der metabolismen er avhengig av flere gener. Manuell tolkning gis dersom rekvirenten har opplyst om aktuelt legemiddel. Dette er imidlertid tidkrevende, og nytten begrenses til behandlingen som er aktuell der og da.

• Lauritzen, Trine; Munkhaugen, John; Peersen, Kari; Andersen, Anders Mikal; Bergan, Stein & Husebye, Einar [Show all 7 contributors for this article] (2023). Atorvastatin lactonization is associated with statin-dependent muscular side effects in patient with coronary heart disease. Full text in Research Archive
• Munkhaugen, John; Kristiansen, Oscar; Pivoriunas, Jonas; Fagerland, Morten; Bergan, Stein & Sverre, Elise Christine Bjørkholen [Show all 8 contributors for this article] (2023). Validation of a novel direct method to determine reduced adherence to atorvastatin therapy. European Journal of Preventive Cardiology (EJPC). ISSN 2047-4873. 30. doi: 10.1093/eurjpc/zwad125.339. Full text in Research Archive
• Lauritzen, Trine; Munkhaugen, John; Peersen, Kari; Kristiansen, Oscar; Sverre, Elise Christine Bjørkholen & Andersen, Anders Mikal [Show all 10 contributors for this article] (2023). Atorvastatin lactone/acid ratios are promising biomarkers for statin dependent muscular side effects in patients with coronary heart disease. European Journal of Preventive Cardiology (EJPC). ISSN 2047-4873. 30. doi: 10.1093/eurjpc/zwad125.340. Full text in Research Archive
• Lauritzen, Trine; Munkhaugen, John; Peersen, Kari; Sverre, Elise Christine Bjørkholen; Kristiansen, Oscar & Jensen, Elena Prunès [Show all 9 contributors for this article] (2022). Clinical and pharmacological characteristics in plasma and mononuclear blood cells in patients with coronary heart disease and low statin tolerance. European Journal of Preventive Cardiology (EJPC). ISSN 2047-4873. 29. doi: 10.1093/eurjpc/zwac056.177. Full text in Research Archive Show summary

  Background Statin-associated muscle symptoms (SAMS) cover a broader range of clinical presentations, with normal or mildly elevated creatine kinase (CK) in blood, and is a prevalent challenge in clinical practice. Our understanding of the pathophysiology of SAMS remains largely unknown. Purpose To gain new knowledge on the molecular effects of atorvastatin in plasma and blood cells in patients with coronary heart disease (CHD) and SAMS, and to identify potential diagnostic biomarkers for statin-dependent SAMS. Methods In 2019, 71 consecutively recruited CHD patients with self-perceived SAMS were randomised to 7-weeks double-blinded treatment with atorvastatin 40 mg/day and placebo in a crossover design. The primary outcome was individual mean difference in muscle symptom intensity between treatment periods, measured weekly with a Visual Analogue Scale (VAS) (0= no to 10=maximal symptoms). Twenty patients were categorised as having statin-dependent SAMS and the remaining as non-SAMS. During trial and post-trial follow-up period, a subgroup of statin-dependent SAMS, who did not tolerate statins (N=7) or only rosuvastatin 5mg/day (N=2) was identified. Atorvastatin metabolites in plasma and peripheral blood mononuclear cells (PBMC) were measured with liquid chromatography tandem mass spectrometry in blood drawn two hours after tablet intake at the last day of the atorvastatin treatment period. Statistical analyses were performed with SPSS. Results Clinical and pharmacological characteristics in patients with low statin-tolerance (N=9) and those without (N=62) are summarised in Figure 1. The reduction in LDL cholesterol (LDL-C) from the placebo period to the atorvastatin period was significantly lower in the group with low statin tolerance, despite confirmed adherence to allocated treatment. The ratio between the sum of all atorvastatin- lactones and acids (SumLactones/SumAcids) was significantly higher in the group with low statin tolerance both in plasma and PBMC analyses compared to those who tolerated statins. The atorvastatin lactone and acid ratio (AL/AA) was borderline significant in both plasma and PBMC. ROC-analyses of these four variables are displayed in Figure 2. Areas under the curves (AUCs) are 0.71 for the sumLactones/sumAcids both in plasma and PBMC, and 0.69 for the AL/AS in plasma and PBMC. There were no significant differences between the groups regarding age, gender or known pharmacogenetic variants (CYP3A and SLCO1B1) or in the differences in creatine kinase (CK) level between the atorvastatin and placebo treatment periods. Conclusions The ratio between atorvastatin lactones and acids in plasma and in mononuclear blood cells is associated with low statin tolerance in patients with CHD. Excess lactone relative to acid metabolites may be involved in the pathophysiology of SAMS. Future studies in muscle tissue may further elucidate the relationship between SAMS and atorvastatin metabolites and other biomarkers in these patients.

• Brede, Cato; Vethe, Nils T. & Skadberg, Øyvind (2021). The Question of Accuracy Versus Interlaboratory Agreement for Monitoring the Immunosuppressants Everolimus and Sirolimus. Therapeutic Drug Monitoring. ISSN 0163-4356. 43(3), p. 444–446. doi: 10.1097/FTD.0000000000000892. Full text in Research Archive
• Robertsen, Ida; Åsberg, Anders; Jenssen, Trond Geir; Gence, Berfin; Vethe, Nils Tore & Midtvedt, Karsten [Show all 8 contributors for this article] (2021). Increased systemic exposure of once-daily tacrolimus in renal transplant recipients on marine omega-3 fatty acid supplementation. Transplant International. ISSN 0934-0874. doi: 10.1111/tri.13917. Full text in Research Archive
• Munkhaugen, John; Sverre, Elise Christine Bjørkholen; Kristiansen, Oscar; Fagerland, Morten; Peersen, Kari & Bergan, Stein [Show all 9 contributors for this article] (2020). Drug related metabolites and genetic polymorphisms predict low low-density lipoprotein cholesterol response to atorvastatin treatment in patients with coronary heart disease. European Heart Journal. ISSN 0195-668X. 41(Supplement_2). doi: 10.1093/ehjci/ehaa946.2985. Full text in Research Archive Show summary

  Abstract Background There is considerable individual variation in the low-density lipoprotein cholesterol (LDL-C) reduction at all classes and doses of statins. Knowledge of the determinants of individual variation LDL-C response upon statin treatment may pave the way for personalized and optimized statin treatment. Purpose We aimed to determine clinical and drug related predictors of variability of LDL-C response to atorvastatin 40 mg in patients with coronary heart disease. Methods This is an explorative study among 70 patients enrolled in the MUscle Side-Effects of atorvastatin in coronary patients (MUSE) randomized double blinded cross-over trial. Absolute and relative changes in LDL-C after 7 weeks treatment with atorvastatin 40 mg/day and 7 weeks treatment with placebo, were calculated for each patient. Linear regression analyses were applied to investigate the association between clinical (10 variables) and drug related (atorvastatin and/or metabolites, 18 variables) predictors and changes in LDL-C. Results Adherence to allocated treatment was high as confirmed by atorvastatin levels in blood and a mean proportion of days covered of 99% (range 91–100%). Mean reduction in LDL-C on atorvastatin treatment (LDL-C atorvastatin – LDL-C placebo) was 2.1 (SD 0.7, range 0.3 to 3.4) mmol/L. Mean percentage reduction in LDL-C was 51.1 (SD 11.2, range 29 to 60)%, and 37 patients (52.9%) had &lt;50% LDL-C reduction. Genetic polymorphisms in SLCO1B1 or CYP3A (B 0.06, 95% CI 0.01 to 0.12, p=0.026), increasing number of coronary events (B 0.06, 95% CI 0.002 to 0.10, p=0.005), increasing trough concentration of 4-OH atorvastatin lactone (B 0.05, 95% CI 0.01 to 0.08, p=0.005) and increasing trough concentration of 4-OH atorvastatin acid (B 0.05, 95% CI 0.01 to 0.08, p=0.006) were the significant determinants of lower relative change (%) in LDL-C, in adjusted analyses. Age, gender, somatic comorbidity, cardiovascular risk factors, statin dependent muscle side-effects and other clinical and drug related determinants were not associated with changes in LDL-C. Conclusions There is considerable inter-individual variation in the LDL-C response upon treatment with atorvastatin despite confirmed high statin adherence. This is the first study reporting that genetic polymorphisms involved in the metabolism of statins and atorvastatin metabolites predict lower LDL-C response. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): National Association of Health, Grant/Award

• Tuv, Silja Skogstad; Nordal, Kristin; Vethe, Nils Tore & Bergan, Stein (2019). Farmakogenetikk i persontilpasset legemiddelbehandling. 139(8), p. 1–5. doi: 10.4045/tidsskr.19.0055. Full text in Research Archive
• Bremer, Sara; Johansson, E.D.; Pham, L.; Vethe, Nils Tore; Line, Pål Dag & Midtvedt, Karsten [Show all 10 contributors for this article] (2013). NFAT-Regulated Cytokine Expression During Tacrolimus Therapy Early After Transplantation. Therapeutic Drug Monitoring. ISSN 0163-4356. 35(5), p. 668–668. Full text in Research Archive
• Robertsen, Ida; Åsberg, Anders; Granseth, Tone; Vethe, Nils Tore; Akhlaghi, Fatemeh & Ghareeb, Mwlod [Show all 10 contributors for this article] (2013). ROSUVASTATIN IS A POTENT LIPID-LOWERING STATIN IN RENAL TRANSPLANT RECIPIENTS RECEIVING EVEROLIMUS. Transplant International. ISSN 0934-0874. 26, p. 50–50. Full text in Research Archive
• Sæves, Ingjerd; Vethe, Nils Tore; Line, Pål Dag; Fosby, Bjarte & Bergan, Stein (2011). Variable pharmacokinetics of prednisolone and prednisone in liver transplant recipients early after transplantation. Therapeutic Drug Monitoring. ISSN 0163-4356. 33(4), p. 555–555. Full text in Research Archive
• Vethe, Nils Tore; Quiogue, A.M.; Hotvedt, S.A.; Gjerdalen, Laila Carol & Bergan, Stein (2011). Precise measurement of thiopurines by LC-MS/MS: usage of isotope-labelled internal standards and normalization to packed erythrocyte volume. Therapeutic Drug Monitoring. ISSN 0163-4356. 33(4), p. 553–553. Full text in Research Archive
• Vethe, Nils Tore; Ali, Mohamad A. & Bergan, Stein (2011). Simultaneous determination of IMPDH activity and purine bases in lymphocytes by LC-MS/MS: Assessment of mycophenolate pharmacodynamics. Therapeutic Drug Monitoring. ISSN 0163-4356. 33(4), p. 541–541. Full text in Research Archive
• Amundsen, Rune; Åsberg, Anders; Robertsen, Ida; Vethe, Nils Tore; Bergan, Stein & Hartmann, Anders [Show all 7 contributors for this article] (2009). Rimonabant Affects Cyclosporine A, but Not Tacrolimus Pharmacokinetics in Renal Transplant Recipients. American Journal of Transplantation. ISSN 1600-6135. 9, p. 394–395. Full text in Research Archive
• Bremer, Sara; Vethe, Nils Tore; Rootwelt, Helge; Jørgensen, Pål Foyn; Stenstrøm, Jean & Holdaas, Hallvard [Show all 8 contributors for this article] (2009). Mycophenolate Pharmacodynamics is Altered with Time Since Transplantation. Therapeutic Drug Monitoring. ISSN 0163-4356. 31(5), p. 620–620. Full text in Research Archive
• Amundsen, Rune; Åsberg, Anders; Robertsen, Ida; Vethe, Nils Tore; Bergan, Stein & Midtvedt, Karsten (2009). Rimonabant Affects Cyclosporine A, but Not Tacrolimus Pharmacokinetics in Renal Transplant Recipients. Full text in Research Archive
• Falck, Pål; Vethe, Nils Tore; Åsberg, Anders; Midtvedt, Karsten; Bergan, Stein & Reubsaet, Jan Leo [Show all 7 contributors for this article] (2007). Cinacalcet influences the pharmacokinetics of tacrolimus but not cyclosporine or mycophenolate in stable renal transplant recipients. Full text in Research Archive
• Holdaas, Hallvard; Falck, Pål; Vethe, Nils Tore; Åsberg, Anders; Reubsaet, Jan Leo & Bergan, Stein [Show all 7 contributors for this article] (2007). Impact of cinacalcet on pharmacokinetics of calcineurin inhibitors in renal transplanted patients. Full text in Research Archive
• Lauritzen, Trine & Vethe, Nils Tore (2025). New pathophysiological knowledge and diagnostic biomarkers for atorvastatin-dependent muscle side effects in patients with coronary heart disease. Universitetet i Oslo. ISSN 9788234806605. Full text in Research Archive Show summary

  Statins are central to secondary prevention of coronary heart disease, yet statin-associated muscle symptoms (SAMS) often result in discontinuation of treatment. SAMS often have non-statin causes, and no validated objective test distinguishes them from true intolerance. This thesis lies at the intersection of cardiovascular disease prevention and clinical pharmacology and sought to clarify mechanisms behind SAMS and to assess whether a simple blood test can separate atorvastatin intolerance from symptoms of other origin. The results are based on a randomised, double-blind crossover trial in patients with SAMS (MUSE RCT) and a sub-study with paired plasma and muscle biopsies (MUSE BmS). The patients were clinically categorised as statin-tolerant or intolerant. Using LC-MS/MS, we measured mevalonate and atorvastatin acid with its metabolites in plasma and muscle. We also genotyped variants affecting statin metabolism and distribution and examined muscle histology. Plasma- and muscle concentrations were strongly correlated, indicating plasma can proxy muscle exposure. Compared with tolerant patients, statin-intolerant patients had lower levels of active (acid) metabolites and higher lactone/acid ratios, consistent with a shift toward myotoxic metabolites. Some of the genetic variants were associated with higher lactone levels. Mevalonate and LDL-cholesterol fell with statin treatment, but less in the intolerant group, mirroring lower atorvastatin acid exposure. Biopsies were not decisive; occasional necrotic fibres on-statin did not match clinical intolerance. In sum, a blood-based signature—low acid metabolites, elevated lactone/acid ratio, and a lesser fall in mevalonate and LDL-C—might be a tool to rule out many statin-tolerant patients and focus evaluation and follow-up on the intolerant. Validation in larger cohorts is needed; if confirmed, this approach could enable more personalised therapy, reduce unnecessary discontinuation, and improve cardiovascular outcomes.

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