Ida Robertsen

• Izat, Nihan; Kangne, Haribhau; Jansson‐Löfmark, Rasmus; Hertel, Jens Kristoffer; Rostami‐Hodjegan, Amin & Robertsen, Ida [Show all 7 contributors for this article] (2026). Application of Virtual Twin PBPK Models in Individuals with Obesity via CYP3A4 Phenotyping Using Endogenous Biomarker Data. Clinical Pharmacology and Therapeutics. ISSN 0009-9236. doi: 10.1002/cpt.70369. Full text in Research Archive Show summary

  Plasma 4β‐hydroxycholesterol (4β‐OHC) normalized for the levels of its parent cholesterol (4β‐OHC/C) is an endogenous biomarker for hepatic CYP3A4. This study evaluated CYP3A4 activity longitudinally in individuals while their obesity status was changing. 4β‐OHC/C was measured pre‐surgery ( n  = 54) and 2 years after Roux‐en‐Y gastric bypass ( n  = 30) and used as an input for creating virtual twins of each patient within physiologically‐based pharmacokinetic (VT‐PBPK) models, alongside other available data (e.g., demographics). Additionally, individual CYP3A4 abundance quantified from liver biopsies during surgery was available. Predicted CYP3A4 abundance using 4β‐OHC/C was within twofold of the measured abundance in 85% of the individuals ( n  = 54). Pre‐surgery VT‐PBPK models informed by biomarker data predicted area under curve after intravenous midazolam (AUC inf,iv ) within twofold of observed values in 85% of individuals (geometric mean fold error (GMFE) = 1.58). VT‐PBPK models using CYP3A4 protein measurements showed similar performance (83% within twofold, GMFE = 1.66), verifying the biomarker approach. The post‐surgery VT‐PBPK models were revised to reflect surgery‐related alterations and changes in obesity status. Hepatic CYP3A4 activity at 2 years was predicted from 4β‐OHC/C measured in the same individuals. Biomarker‐informed models predicted midazolam AUC inf,iv within twofold for 87% of individuals (GMFE = 1.48; n  = 30). ~60% of observed oral midazolam PK parameters were predicted within twofold, improving to 70% when the surgery model assumed full intestinal CYP3A4/5 recovery. This study highlights the utility of 4β‐OHC/C for continuous monitoring of CYP3A4 activity and possibility to use biomarker‐informed VT‐PBPK models for individual dose requirements of intravenously administered CYP3A substrates in individuals with obesity over the course of weight loss treatment.

• Fardellas, Achilleas; Barreby, Emelie; Brice, Madara; Nock, Sebastian; Russick, Jules & Vankova, Ana [Show all 21 contributors for this article] (2026). ADAR1 Controls Macrophage Scavenging and Lipid‐Buffering Programs in Metabolic Tissues. European Journal of Immunology. ISSN 0014-2980. 56(4). doi: 10.1002/eji.70189. Full text in Research Archive Show summary

  Adenosine deaminase acting on RNA 1 (ADAR1) regulates mRNA fate and function through adenosine‐to‐inosine (A‐to‐I) RNA editing and RNA‐binding activities. While its role in innate immunity is established, the broader regulatory functions of ADAR1 in macrophages remain poorly defined. Here, we systematically profiled ADAR1 expression across human immune cells and identified marked enrichment in macrophages, driven by selective usage of an alternative transcription start site during monocyte‐to‐macrophage differentiation. ADAR1 binds, edits, and modulates key macrophage targets involved in efferocytosis, endocytosis, lysosomal processing, lipid metabolism, and proliferation in an isoform‐specific manner. We further demonstrate that ADAR1 levels and activity are dynamically regulated in adipose tissue and liver during the progression of metabolic disease. Linked to this, macrophage‐specific ablation of ADAR1 co‐cultured in organotypic 3D primary human liver spheroids and exposed to metabolic stress resulted in an exacerbated lipid accumulation phenotype. Finally, we identify a lipid‐associated macrophage‐specific upregulation of ADAR1 in adipose tissue following weight loss interventions, mechanistically driven by free fatty acids. These findings uncover a previously unrecognized role for ADAR1 in lipid‐buffering, scavenging, and proliferative macrophage functions, extending its biological relevance beyond canonical interferon‐mediated immunity and establishing ADAR1 as a key regulator of macrophage adaptation in metabolic disease.

• Kangne, Haribhau; Izat, Nihan; Chen, Gong; Ogungbenro, Kayode; Jansson-Löfmark, Rasmus & Hertel, Jens Kristoffer [Show all 8 contributors for this article] (2026). Virtual Twin-PBPK Modelling: A Step Toward Precision Dosing in Patients with Obesity. AAPS Journal. 28(1). doi: 10.1208/s12248-025-01195-7. Full text in Research Archive Show summary

  Abstract Obesity significantly alters drug disposition and contributes to large inter-individual variability in pharmacokinetics (PK). The virtual-twin concept is increasingly used to support model-informed precision dosing in specific populations. In this study, physiologically-based pharmacokinetic models linked with virtual twins (VT-PBPK) have been developed and applied to predict the PK of midazolam and digoxin in patients with obesity (n = 15) and severe obesity (n = 22). The first step of the individualization included basic demographic data with lean liver volume. In the second step, individual serum creatinine, albumin, and hepatic CYP3A4/5, UGT1A4 and P-gp abundance quantified from liver biopsies in the same individuals, were integrated within models. Substrate specific improvements were presented via the stepwise individualization. The final (Step 2) VT-PBPK models predicted midazolam AUC 0-inf,iv within 2-fold for 86% of the individuals (geometric mean fold error, GMFE = 1.5; 95% confidence interval (CI95) = 1.36–1.78), with 36% within the 0.8 to 1.25-fold of the observed values. For digoxin, 97% of C max and AUC 0-24 values were predicted within 2-fold of the observed data (GMFE = 1.25; CI95 = 1.19–1.33), with 59% of predicted values within the 0.8–1.25-fold range. In the case of digoxin, the prediction accuracy was higher for patients with severe obesity (60% of C max and AUC 0-24 values within the 1.25-fold range); no clear trends were evident for midazolam. This is the first study that applied the VT-PBPK modelling approach in patients with obesity. It highlights the potential of this approach to predict the PK of other CYP3A and P-gp substrates to support individual dose optimization in this population. Graphical Abstract

• Risnes, Louise Fremgaard; Brottveit, Margit; Robertsen, Ida; Ibsen, Jostein Holen; Aabakken, Lars & Johannesen, Marie Kongshaug [Show all 12 contributors for this article] (2025). Research Communication: Teriflunomide Does Not Affect Gluten-Specific T-Cell Activity in Coeliac Disease—A Randomised, Placebo-Controlled Trial. Alimentary Pharmacology and Therapeutics. ISSN 0269-2813. 62(10), p. 1027–1031. doi: 10.1111/apt.70301. Full text in Research Archive Show summary

  Coeliac disease is an autoimmune disorder driven by gluten and managed through a strict gluten-free diet. We tested teriflunomide, a drug known for its ability to alter T-cell activity, in a phase 2a trial of 15 patients with coeliac disease. Participants received teriflunomide or placebo including a loading dose, followed by a 3-day oral gluten challenge to monitor T-cell responses. The main aim was to observe attenuation of gluten-specific T-cell activation markers after gluten exposure. We found no significant differences in T-cell activity between groups, concluding that teriflunomide is ineffective as a non-dietary treatment for coeliac disease

• Drevland, Ole Martin; Skadberg, Eline Supannee Setu; Tran, Lan Anh; Åsberg, Anders; Midtvedt, Karsten & Robertsen, Ida (2025). Development and Clinical Validation of a Volumetric Absorptive Capillary Microsampling Method for Quantification of Mycophenolic Acid and Mycophenolic Acid Glucuronide in Kidney Transplant Recipients. Therapeutic Drug Monitoring. ISSN 0163-4356. 47(6), p. 790–798. doi: 10.1097/FTD.0000000000001330. Full text in Research Archive
• Gopalakrishnan, Vancheswaran; Kumar, Chanchal; Robertsen, Ida; Morehouse, Christopher; Sparklin, Ben & Khader, Shameer [Show all 19 contributors for this article] (2025). A multi-omics microbiome signature is associated with the benefits of gastric bypass surgery and is differentiated from diet induced weight loss through 2 years of follow-up. Mucosal Immunology. ISSN 1933-0219. 18(4), p. 825–835. doi: 10.1016/j.mucimm.2025.04.002. Full text in Research Archive Show summary

  Roux-en-Y gastric bypass (GBP) surgery is an effective treatment for reducing body weight and correcting metabolic dysfunction in individuals with severe obesity. Herein, we characterize the differences between very low energy diet (VLED) and GBP induced weight loss by multi-omic analyses of microbiome and host features in a non-randomized, controlled, single-center study. Eighty-eight participants with severe obesity were recruited into two arms – GBP versus VLED with matching weight loss for 6 weeks and 2-years of follow-up. A dramatic shift in the distribution of gut microbial taxa and their functional capacity was seen in the GBP group at Week 2 after surgery and was sustained through 2 years. Multi-omic analyses were performed after 6 weeks of matching weight loss between the GBP and VLED groups, which pointed to microbiome derived metabolites such as indoxyl sulphate as characterizing the GBP group. We also identified an inverse association between Streptococcus parasanguinis (an oral commensal) and plasma levels of tryptophan and tyrosine. These data have important implications, as they reveal a significant robust restructuring of the microbiome away from a baseline dysbiotic state in the GBP group. Furthermore, multi-omics modelling points to potentially novel mechanistic insights at the intersection of the microbiome and host.

• Drevland, Ole Martin; Muinck, Eric de; Trosvik, Pål; Hammerstad, Marta; Kvitne, Kine Eide & Midtvedt, Karsten [Show all 8 contributors for this article] (2025). Microbiome-derived reactivation of mycophenolate explains variations in enterohepatic recirculation in kidney transplant recipients. Microbiome. 13(1). doi: 10.1186/s40168-025-02142-6. Full text in Research Archive Show summary

  Background The pivotal role of microbes in drug metabolism is increasingly recognized, as variation in the gut microbiome composition between individuals has been shown to impact systemic drug exposure, efficacy and toxicity. Mycophenolate mofetil (MMF) is a cornerstone in immunosuppressive therapy following solid organ transplantation. However, dosing and tolerance are challenged by significant pharmacokinetic variability among patients, largely due to variable degrees of enterohepatic recirculation of mycophenolic acid (MPA), the active moiety of MMF. It is hypothesized that the variability in MPA recirculation is driven by gut microbiome-derived β-glucuronidase (β-GUS) mediated cleavage of MPA-glucuronide (MPAG) excreted in the bile. Here, we investigated the bidirectional interaction between MPA and the gut microbiome in kidney transplant recipients, using a combination of in vivo and in vitro data. Results We compared the fecal microbiomes of kidney transplant recipients (n = 21) both pre- and post-transplantation to healthy individuals (n = 15) using shotgun metagenomic sequencing. We also determined the individual microbiome-derived reactivation rate of MPAG to MPA and show a strong positive correlation between this reactivation rate and the degree of MPA enterohepatic recirculation in vivo. Through metagenomic analysis, the reactivation rate of MPA was linked to specific gut microbial species. In particular, specific β-GUS gene variants associated with Faecalibacterium prausnitzii showed a strong impact on the conversion of MPAG to MPA. Furthermore, our study confirmed a significant shift in microbial composition post-transplantation and revealed notable fluctuations in species such as F. prausnitzii and Akkermansia muciniphila across different time points after transplantation. Lastly, we provide evidence that the microbiome-derived reactivation rate of MPA is linked to specific beta-glucuronidase alleles. Conclusions We highlight for the first time that the ex vivo determined reactivation rate of MPA explains the variation of enterohepatic recirculation, emphasizing the important role of F. prausnitzii in this process. More broadly, our findings suggest that the gut microbiome significantly influences the degree of enterohepatic recirculation of MPA, providing valuable insights that could be relevant for optimizing individualized immunosuppressive drug dosing in transplant patients.

• 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.

• Karlsson, Cecilia; Johnsen, Line Kristin; Greasley, Peter; Retterstøl, Kjetil; Hedberg, Jonatan & Hall, Martin [Show all 18 contributors for this article] (2024). Gastric Bypass vs Diet and Cardiovascular Risk Factors: A Nonrandomized Controlled Trial. JAMA Surgery. ISSN 2168-6254. 159(9), p. 971–980. doi: 10.1001/jamasurg.2024.2162. Full text in Research Archive Show summary

  Importance Roux-en-Y gastric bypass (RYGB) is associated with reduced cardiovascular (CV) risk factors, morbidity, and mortality. Whether these effects are specifically induced by the surgical procedure or the weight loss is unclear. Objective To compare 6-week changes in CV risk factors in patients with obesity undergoing matching caloric restriction and weight loss by RYGB or a very low-energy diet (VLED). Design, Setting, and Participants This nonrandomized controlled study (Impact of Body Weight, Low Calorie Diet, and Gastric Bypass on Drug Bioavailability, Cardiovascular Risk Factors, and Metabolic Biomarkers [COCKTAIL]) was conducted at a tertiary care obesity center in Norway. Participants were individuals with severe obesity preparing for RYGB or a VLED. Recruitment began February 26, 2015; the first patient visit was on March 18, 2015, and the last patient visit (9-week follow-up) was on August 9, 2017. Data were analyzed from April 30, 2021, through June 29, 2023. Interventions VLED alone for 6 weeks or VLED for 6 weeks after RYGB; both interventions were preceded by 3-week LED. Main Outcomes and Measures Between-group comparisons of 6-week changes in CV risk factors. Results Among 78 patients included in the analyses, the mean (SD) age was 47.5 (9.7) years; 51 (65%) were women, and 27 (35%) were men. Except for a slightly higher mean (SD) body mass index of 44.5 (6.2) in the RYGB group (n = 41) vs 41.9 (5.4) in the VLED group (n = 37), baseline demographic and clinical characteristics were similar between groups. Major atherogenic blood lipids (low-density lipoprotein cholesterol, non–high-density lipoprotein cholesterol, apolipoprotein B, lipoprotein[a]) were reduced after RYGB in comparison with VLED despite a similar fat mass loss. Mean between-group differences were −17.7 mg/dL (95% CI, −27.9 to −7.5), −17.4 mg/dL (95% CI, −29.8 to −5.0) mg/dL, −9.94 mg/dL (95% CI, −15.75 to −4.14), and geometric mean ratio was 0.55 U/L (95% CI, 0.42 to 0.72), respectively. Changes in glycemic control and blood pressure were similar between groups. Conclusions and Relevance This study found that clinically meaningful reductions in major atherogenic blood lipids were demonstrated after RYGB, indicating that RYGB may reduce CV risk independent of weight loss. Trial Registration ClinicalTrials.gov Identifier: NCT02386917

• Kvitne, Kine Eide; Hjelmesæth, Jøran Sture; Hovd, Markus; Sandbu, Rune; Johnson, Line Kristin & Andersson, Shalini [Show all 11 contributors for this article] (2024). Oral Drug Dosing After Gastric Bypass and Diet-Induced Weight Loss: Simpler Than We Think? Lessons Learned From the COCKTAIL Study. Clinical Pharmacology and Therapeutics. ISSN 0009-9236. 16(3), p. 647–652. doi: 10.1002/cpt.3307. Full text in Research Archive Show summary

  This article summarizes the lessons learned from the COCKTAIL study: an open, three-armed, single-center study including patients with obesity scheduled for treatment with Roux-en-Y gastric bypass (RYGB) or nonsurgical calorie restriction, and a normal- to overweight control group. The clinical implications of the results from multiple peer-reviewed articles describing the effects of RYGB, severe caloric restriction, weight loss, and type 2 diabetes on the in vivo activity and protein expression of drug-metabolizing enzymes (cytochrome P450 (CYP) 1A2, 2C9, 2C19, and 3A) and transporters (DMETs; organic anion-transporting polypeptide (OATP) 1B1 and P-glycoprotein (P-gp)) are discussed in the perspective of three clinically relevant questions: (1) How should clinicians get the dose right in patients after RYGB? (2) Will drug disposition in patients with obesity be normalized after successful weight loss? (3) Are dose adjustments needed according to obesity and diabetes status? Overall, RYGB seems to have a lower impact on drug disposition than previously assumed, but clinicians should pay close attention to drugs with a narrow therapeutic range or where a high maximum drug concentration may be problematic. Whether obesity-related alterations of DMETs normalize with substantial weight loss depends on the DMET in question. Obesity and diabetes downregulate the in vivo activity of CYP2C19 and CYP3A (only obesity) but whether substrate drugs should be dose adjusted is also dependent on other factors that influence clearance, that is, liver blood flow and protein binding. Finally, we recommend frequent and individualized follow-up due to high inter- and intraindividual variability in these patients, particularly following RYGB.

• 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
• Hovd, Markus Herberg; Robertsen, Ida; Woillard, Jean-Baptiste & Åsberg, Anders (2023). A Method for Evaluating Robustness of Limited Sampling Strategies—Exemplified by Serum Iohexol Clearance for Determination of Measured Glomerular Filtration Rate. Pharmaceutics. 15(4). doi: 10.3390/pharmaceutics15041073. Full text in Research Archive Show summary

  In combination with Bayesian estimates based on a population pharmacokinetic model, limited sampling strategies (LSS) may reduce the number of samples required for individual pharmacokinetic parameter estimations. Such strategies reduce the burden when assessing the area under the concentration versus time curves (AUC) in therapeutic drug monitoring. However, it is not uncommon for the actual sample time to deviate from the optimal one. In this work, we evaluate the robustness of parameter estimations to such deviations in an LSS. A previously developed 4-point LSS for estimation of serum iohexol clearance (i.e., dose/AUC) was used to exemplify the effect of sample time deviations. Two parallel strategies were used: (a) shifting the exact sampling time by an empirical amount of time for each of the four individual sample points, and (b) introducing a random error across all sample points. The investigated iohexol LSS appeared robust to deviations from optimal sample times, both across individual and multiple sample points. The proportion of individuals with a relative error greater than 15% (P15) was 5.3% in the reference run with optimally timed sampling, which increased to a maximum of 8.3% following the introduction of random error in sample time across all four time points. We propose to apply the present method for the validation of LSS developed for clinical use.

• Kvitne, Kine Eide; Drevland, Ole Martin; Haugli, Nora; Skadberg, Eline Supannee Setu; Zare, Hasse Khiabani & Åsberg, Anders [Show all 7 contributors for this article] (2023). Intraindividual Variability in Absolute Bioavailability and Clearance of Midazolam in Healthy Individuals. Clinical Pharmacokinetics. ISSN 0312-5963. 62(7), p. 981–987. doi: 10.1007/s40262-023-01257-z. Full text in Research Archive Show summary

  Background and Objective Midazolam is the preferred clinical probe drug for assessing CYP3A activity. We have previously shown substantial intraindividual variability in midazolam absolute bioavailability and clearance in patients with obesity before and after weight loss induced by gastric bypass or a strict diet. The objective was to describe intraindividual variability in absolute bioavailability and clearance of midazolam in healthy individuals without obesity. Methods This study included 33 healthy volunteers [28 ± 8 years, 21% males, body mass index (BMI) 23 ± 2.5 kg/m2] subjected to four pharmacokinetic investigations over a 2-month period (weeks 0, 2, 4, and 8). Semi-simultaneous oral (0 h) and intravenous (2 h later) midazolam dosing was used to assess absolute bioavailability and clearance of midazolam. Results At baseline, mean absolute bioavailability and clearance were 46 ± 18% and 31 ± 10 L/h, respectively. The mean coefficient of variation (CV, %) for absolute bioavailability and clearance of midazolam was 26 ± 15% and 20 ± 10%, respectively. Approximately one-third had a CV > 30% for absolute bioavailability, while 13% had a CV > 30% for clearance. Conclusions On average, intraindividual variability in absolute bioavailability and clearance of midazolam was low to moderate; however, especially absolute bioavailability showed considerable variability in a relatively large proportion of the individuals.

• Hovd, Markus Herberg; Robertsen, Ida; Johnson, Line Kristin; Krogstad, Veronica; Wegler, Christine & Kvitne, Kine Eide [Show all 16 contributors for this article] (2023). Neither Gastric Bypass Surgery Nor Diet-Induced Weight-Loss Affect OATP1B1 Activity as Measured by Rosuvastatin Oral Clearance. Clinical Pharmacokinetics. ISSN 0312-5963. 62(5), p. 725–735. doi: 10.1007/s40262-023-01235-5. Full text in Research Archive Show summary

  Introduction Rosuvastatin pharmacokinetics is mainly dependent on the activity of hepatic uptake transporter OATP1B1. In this study, we aimed to investigate and disentangle the effect of Roux-en-Y gastric bypass (RYGB) and weight loss on oral clearance (CL/F) of rosuvastatin as a measure of OATP1B1-activity. Methods Patients with severe obesity preparing for RYGB (n = 40) or diet-induced weight loss (n = 40) were included and followed for 2 years, with four 24-hour pharmacokinetic investigations. Both groups underwent a 3-week low-energy diet (LED; < 1200 kcal/day), followed by RYGB or a 6-week very-low-energy diet (VLED; < 800 kcal/day). Results A total of 80 patients were included in the RYGB group (40 patients) and diet-group (40 patients). The weight loss was similar between the groups following LED and RYGB. The LED induced a similar (mean [95% CI]) decrease in CL/F in both intervention groups (RYGB: 16% [0, 31], diet: 23% [8, 38]), but neither induced VLED resulted in any further changes in CL/F. At Year 2, CL/F had increased by 21% from baseline in the RYGB group, while it was unaltered in the diet group. Patients expressing the reduced function SLCO1B1 variants (c.521TC/CC) showed similar changes in CL/F over time compared with patients expressing the wild-type variant. Conclusions Neither body weight, weight loss nor RYGB per se seem to affect OATP1B1 activity to a clinically relevant degree. Overall, the observed changes in rosuvastatin pharmacokinetics were minor, and unlikely to be of clinical relevance.

• Drevland, Ole Martin; Robertsen, Ida; Gustavsen, Marte Theie; Kveim, Hanne Kamilla; Hovd, Markus Herberg & Midtvedt, Karsten [Show all 7 contributors for this article] (2023). Impact of Fasting Status and Circadian Variation on the Pharmacokinetics of Mycophenolate Mofetil and the Glucuronide Metabolite in Renal Transplant Recipients. Transplantation direct. 9(3). doi: 10.1097/TXD.0000000000001448. Full text in Research Archive Show summary

  Background. Mycophenolate mofetil (MMF) is an immunosuppressive prodrug often used to prevent allograft rejection following solid organ transplantation. After oral administration, MMF is rapidly hydrolyzed to the active metabolite mycophenolate acid (MPA), which is inactivated by glucuronosyltransferase to the mycophenolic acid glucuronide metabolite (MPAG). The aim was 2-fold: to investigate the impact of circadian variation and fasting versus nonfasting status on MPA and MPAG pharmacokinetics in renal transplant recipients (RTRs). Methods. RTRs with stable graft function treated with tacrolimus, prednisolone, and MMF (750 mg BID) were included in this open, nonrandomized study. Two 12-h pharmacokinetic investigations were conducted in succession following morning and evening doses, both in a fasting and in a real-life nonfasting condition. Results. A total of 30 (22 men) RTRs performed one 24-h investigation, and 16 repeated the investigation within 1 mo. In a real-life nonfasting state, MPA area under the curve (AUC)0–12 and C0 failed to meet the bioequivalence criteria. Following the evening dose, mean MPA AUC12–24 was 16% lower (P < 0.001) compared with AUC0–12, and a shorter Tmax was observed (P = 0.09). Under fasting conditions, MPA AUC12–24 was 13% lower than AUC0–12, and the absorption rate was slower after the evening dose (P < 0.05). MPAG displayed circadian variation only under real-life conditions with lower AUC0–12 following the evening dose (P < 0.001). Conclusions. Both MPA and MPAG showed circadian variation with somewhat lower systemic exposures following the evening dose with limited clinical relevance in the dosing of MMF in RTRs. Fasting status affects MMF absorption rate differently, but with similar results in systemic exposure.

• Kvitne, Kine Eide; Hovd, Markus; Johnsen, Line Kristin; Wegler, Christine; Karlsson, Cecilia & Artursson, Per [Show all 14 contributors for this article] (2023). Digoxin Pharmacokinetics in Patients with Obesity Before and After a Gastric Bypass or a Strict Diet Compared with Normal Weight Individuals. Clinical Pharmacokinetics. ISSN 0312-5963. 63(1), p. 103–120. doi: 10.1007/s40262-023-01320-9. Full text in Research Archive Show summary

  Background and Objective Several drugs on the market are substrates for P-glycoprotein (P-gp), an efflux transporter highly expressed in barrier tissues such as the intestine. Body weight, weight loss, and a Roux-en-Y gastric bypass (RYGB) may influence P-gp expression and activity, leading to variability in the drug response. The objective of this study was therefore to investigate digoxin pharmacokinetics as a measure of the P-gp phenotype in patients with obesity before and after weight loss induced by an RYGB or a strict diet and in normal weight individuals. Methods This study included patients with severe obesity preparing for an RYGB (n = 40) or diet-induced weight loss (n = 40) and mainly normal weight individuals scheduled for a cholecystectomy (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day) followed by an additional 6 weeks of <800 kcal/day induced by an RYGB (performed at week 3) or a very-low-energy diet. Follow-up time was 2 years, with four digoxin pharmacokinetic investigations at weeks 0, 3, and 9, and year 2. Hepatic and jejunal P-gp levels were determined in biopsies obtained from the patients undergoing surgery. Results The RYGB group and the diet group had a comparable weight loss in the first 9 weeks (13 ± 2.3% and 11 ± 3.6%, respectively). During this period, we observed a minor increase (16%) in the digoxin area under the concentration–time curve from zero to infinity in both groups: RYGB: 2.7 µg h/L [95% confidence interval (CI) 0.67, 4.7], diet: 2.5 µg h/L [95% CI 0.49, 4.4]. In the RYGB group, we also observed that the time to reach maximum concentration decreased after surgery: from 1.0 ± 0.33 hours at week 3 to 0.77 ± 0.08 hours at week 9 (−0.26 hours [95% CI −0.47, −0.05]), corresponding to a 25% reduction. Area under the concentration–time curve from zero to infinity did not change long term (week 0 to year 2) in either the RYGB (1.1 µg h/L [−0.94, 3.2]) or the diet group (0.94 µg h/L [−1.2, 3.0]), despite a considerable difference in weight loss from baseline (RYGB: 30 ± 7%, diet: 3 ± 6%). At baseline, the area under the concentration–time curve from zero to infinity was −5.5 µg h/L [95% CI −8.5, −2.5] (−26%) lower in patients with obesity (RYGB plus diet) than in normal weight individuals scheduled for a cholecystectomy. Further, patients undergoing an RYGB had a 0.05 fmol/µg [95% CI 0.00, 0.10] (29%) higher hepatic P-gp level than the normal weight individuals. Conclusions Changes in digoxin pharmacokinetics following weight loss induced by a pre-operative low-energy diet and an RYGB or a strict diet (a low-energy diet plus a very-low-energy diet) were minor and unlikely to be clinically relevant. The lower systemic exposure of digoxin in patients with obesity suggests that these patients may have increased biliary excretion of digoxin possibly owing to a higher expression of P-gp in the liver.

• Kvitne, Kine Eide; Hole, Kristine; Krogstad, Veronica; Wollmann, Birgit Malene Tovik; Wegler, Christine & Johnson, Line Kristin [Show all 19 contributors for this article] (2022). Correlations between 4β-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range. European Journal of Clinical Pharmacology. ISSN 0031-6970. 78(8), p. 1289–1299. doi: 10.1007/s00228-022-03336-9. Full text in Research Archive Show summary

  Purpose Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4β-hydroxycholesterol (4βOHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4βOHC concentrations and hepatic and intestinal CYP3A4 protein expression and ex vivo microsomal activity in paired liver and jejunum samples, as well as in vivo CYP3A4 phenotyping (midazolam) in patients with a wide body weight range. Methods The patients (n = 96; 78 with obesity and 18 normal or overweight individuals) were included from the COCKTAIL-study (NCT02386917). Plasma samples for analysis of 4βOHC and midazolam concentrations, and liver (n = 56) and jejunal (n = 38) biopsies were obtained. The biopsies for determination of CYP3A4 protein concentration and microsomal activity were obtained during gastric bypass or cholecystectomy. In vivo CYP3A4 phenotyping was performed using semi-simultaneous oral (1.5 mg) and intravenous (1.0 mg) midazolam. Results 4βOHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity (ρ = 0.53, p < 0.001), and hepatic CYP3A4 concentrations (ρ = 0.30, p = 0.027), but not with intestinal CYP3A4 concentrations (ρ = 0.18, p = 0.28) or intestinal microsomal CYP3A4 activity (ρ = 0.15, p = 0.53). 4βOHC concentrations correlated weakly with midazolam absolute bioavailability (ρ =  − 0.23, p = 0.027) and apparent oral clearance (ρ = 0.28, p = 0.008), but not with systemic clearance (ρ =  − 0.03, p = 0.81). Conclusion These findings suggest that 4βOHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4βOHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs.

• Kvitne, Kine Eide; Krogstad, Veronica; Wegler, Christine; Johnson, Line Kristin; Kringen, Marianne K. & Hovd, Markus Herberg [Show all 19 contributors for this article] (2022). Short- and long-term effects of body weight, calorie restriction and gastric bypass on CYP1A2, CYP2C19 and CYP2C9 activity. British Journal of Clinical Pharmacology. ISSN 0306-5251. 88(9), p. 4121–4133. doi: 10.1111/bcp.15349. Full text in Research Archive Show summary

  Roux-en-Y gastric bypass (RYGB) may influence drug disposition due to surgery-induced gastrointestinal alterations and/or subsequent weight loss. The objective was to compare short- and long-term effects of RYGB and diet on the metabolic ratios of paraxanthine/caffeine (cytochrome P450 [CYP] 1A2 activity), 5-hydroxyomeprazole/omeprazole (CYP2C19 activity) and losartan/losartan carboxylic acid (CYP2C9 activity), and cross-sectionally compare these CYP-activities with normal-to-overweight controls. Methods This trial included patients with severe obesity preparing for RYGB (n = 40) or diet-induced (n = 41) weight loss, and controls (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day, weeks 0-3) followed by a 6-week very-low-energy diet or RYGB (both <800 kcal/day, weeks 3-9). Follow-up time was 2 years, with four pharmacokinetic investigations. Results Mean ± SD weight loss from baseline was similar in the RYGB-group (13 ± 2.4%) and the diet group (10.5 ± 3.9%) at week 9, but differed at year 2 (RYGB −30 ± 6.9%, diet −3.1 ± 6.3%). From weeks 0 to 3, mean (95% confidence interval [CI]) CYP2C19 activity similarly increased in both groups (RYGB 43% [16, 55], diet 48% [22, 60]). Mean CYP2C19 activity increased by 30% (2.6, 43) after RYGB (weeks 3-9), but not in the diet-group (between-group difference −0.30 [−0.63, 0.03]). CYP2C19 activity remained elevated in the RYGB group at year 2. Baseline CYP2C19 activity was 2.7-fold higher in controls compared with patients with obesity, whereas no difference was observed in CYP1A2 and CYP2C9 activities. Conclusion Our findings suggest that CYP2C19 activity is lower in patients with obesity and increases following weight loss. This may be clinically relevant for drug dosing. No clinically significant effect on CYP1A2 and CYP2C9 activities was observed.

• Wegler, Christine; Wisniewski, Jacek R.; Robertsen, Ida; Christensen, Hege; Hertel, Jens Kristoffer & Hjelmesæth, Jøran Sture [Show all 10 contributors for this article] (2022). Drug disposition protein quantification in matched human jejunum and liver from donors with obesity. Clinical Pharmacology and Therapeutics. ISSN 0009-9236. 111(5), p. 1142–1154. doi: 10.1002/cpt.2558. Full text in Research Archive Show summary

  Mathematical models, such as physiologically based pharmacokinetic (PBPK) models, are used to predict e.g., drug disposition and toxicity. However, populations differ in the abundance of proteins involved in these processes. To improve the building and refinement of such models, they must take into account these inter-individual variabilities. In this study, we used global proteomics to characterize the protein composition of jejunum and liver from 37 donors with obesity enrolled in the COCKTAIL study. Liver protein levels from the 37 donors were further compared with those from donors without obesity. We quantified thousands of proteins and could present the expression of several drug-metabolizing enzymes, for the first time, in jejunum, many of which belong to the cytochrome P450 (e.g., CYP2U1) and the amine oxidase [flavin-containing] (e.g., MAOA) families. Although we show that many metabolizing enzymes had greater expression in liver, others had higher expression in jejunum (such as, MAOA and CES2), indicating the role of the small intestine in extrahepatic drug metabolism. We further show that proteins involved in drug disposition are not correlated in the two donor-matched tissues. These proteins also do not correlate with physiological factors such as BMI, age, and inflammation status in either tissue. Furthermore, the majority of these proteins are not differently expressed in donors with or without obesity. Nonetheless, inter-individual differences were considerable, with implications for personalized prediction models and systems pharmacology.

• Kvitne, Kine Eide; Åsberg, Anders; Johnson, Line Kristin; Wegler, Christine; Hertel, Jens Kristoffer & Artursson, Per [Show all 14 contributors for this article] (2022). Impact of type 2 diabetes on in vivo activities and protein expressions of cytochrome P450 in patients with obesity. Clinical and Translational Science (CTS). ISSN 1752-8054. 15(11), p. 2685–2696. doi: 10.1111/cts.13394. Full text in Research Archive Show summary

  Previous studies have not accounted for the close link between type 2 diabetes mellitus (T2DM) and obesity when investigating the impact of T2DM on cytochrome P450 (CYP) activities. The aim was to investigate the effect of T2DM on in vivo activities and protein expressions of CYP2C19, CYP3A, CYP1A2, and CYP2C9 in patients with obesity. A total of 99 patients from the COCKTAIL study (NCT02386917) were included in this cross-sectional analysis; 29 with T2DM and obesity (T2DM-obesity), 53 with obesity without T2DM (obesity), and 17 controls without T2DM and obesity (controls). CYP activities were assessed after the administration of a cocktail of probe drugs including omeprazole (CYP2C19), midazolam (CYP3A), caffeine (CYP1A2), and losartan (CYP2C9). Jejunal and liver biopsies were also obtained to determine protein concentrations of the respective CYPs. CYP2C19 activity and jejunal CYP2C19 concentration were 63% (−0.39 [95% CI: −0.82, −0.09]) and 40% (−0.09 fmol/μg protein [95% CI: −0.18, −0.003]) lower in T2DM-obesity compared with the obesity group, respectively. By contrast, there were no differences in the in vivo activities and protein concentrations of CYP3A, CYP1A2, and CYP2C9. Multivariable regression analyses also indicated that T2DM was associated with interindividual variability in CYP2C19 activity, but not CYP3A, CYP1A2, and CYP2C9 activities. The findings indicate that T2DM has a significant downregulating impact on CYP2C19 activity, but not on CYP3A, CYP1A2, and CYP2C9 activities and protein concentrations in patients with obesity. Hence, the effect of T2DM seems to be isoform-specific.

• Kvitne, Kine Eide; Robertsen, Ida; Skovlund, Eva; Christensen, Hege Staaland; Krogstad, Veronica & Wegler, Christine [Show all 18 contributors for this article] (2021). Short- and long-term effects of body weight loss following calorie restriction and gastric bypass on CYP3A-activity – a non-randomized three-armed controlled trial. Clinical and Translational Science (CTS). ISSN 1752-8054. doi: 10.1111/cts.13142. Full text in Research Archive Show summary

  It remains uncertain whether pharmacokinetic changes following Roux-en-Y gastric bypass (RYGB) can be attributed to surgery-induced gastrointestinal alterations per se and/or the subsequent weight loss. The aim was to compare short- and long-term effects of RYGB and calorie restriction on CYP3A-activity, and cross-sectionally compare CYP3A-activity with normal weight to overweight controls using midazolam as probe drug. This three-armed controlled trial included patients with severe obesity preparing for RYGB (n = 41) or diet-induced (n = 41) weight-loss, and controls (n = 18). Both weight-loss groups underwent a 3-week low-energy-diet (<1200 kcal/day) followed by a 6-week very-low-energy-diet or RYGB (both <800 kcal/day). Patients were followed for 2 years, with four pharmacokinetic investigations using semisimultaneous oral and intravenous dosing to determine changes in midazolam absolute bioavailability and clearance, within and between groups. The RYGB and diet groups showed similar weight-loss at week 9 (13 ± 2.4% vs. 11 ± 3.6%), but differed substantially after 2 years (−30 ± 7.0% vs. −3.1 ± 6.3%). At baseline, mean absolute bioavailability and clearance of midazolam were similar in the RYGB and diet groups, but higher compared with controls. On average, absolute bioavailability was unaltered at week 9, but decreased by 40 ± 7.5% in the RYGB group and 32 ± 6.1% in the diet group at year 2 compared with baseline, with no between-group difference. No difference in clearance was observed over time, nor between groups. In conclusion, neither RYGB per se nor weight loss impacted absolute bioavailability or clearance of midazolam short term. Long term, absolute bioavailability was similarly decreased in both groups despite different weight loss, suggesting that the recovered CYP3A-activity is not only dependent on weight-loss through RYGB.

• Krogstad, Veronica; Peric, Alexandra; Robertsen, Ida; Kringen, Marianne K.; Vistnes, Maria & Hjelmesæth, Jøran [Show all 15 contributors for this article] (2020). Correlation of body weight and composition with hepatic activities of cytochrome P450 enzymes. Journal of Pharmaceutical Sciences. ISSN 0022-3549. 110(1), p. 432–437. doi: 10.1016/j.xphs.2020.10.027. Full text in Research Archive Show summary

  Obesity is associated with comorbidities of which pharmacological treatment is needed. Physiological changes associated with obesity may influence the pharmacokinetics of drugs, but the effect of body weight on drug metabolism capacity remains uncertain. The aim of this study was to investigate ex vivo activities of hepatic drug metabolizing CYP enzymes in patients covering a wide range of body weight. Liver biopsies from 36 individuals with a body mass index (BMI) ranging from 18 to 63 kg/m2 were obtained. Individual hepatic microsomes were prepared and activities of CYP3A, CYP2B6, CYP2C8, CYP2D6, CYP2C9, CYP2C19 and CYP1A2 were determined. The unbound intrinsic clearance (CLint,u) values for CYP3A correlated negatively with body weight (r = −0.43, p < 0.01), waist circumference (r = −0.47, p < 0.01), hip circumference (r = −0.51, p < 0.01), fat percent (r = −0.41, p < 0.05), fat mass (r = −0.48, p < 0.01) and BMI (r = −0.46, p < 0.01). Linear regression analysis showed that CLint,u values for CYP3A decreased with 5% with each 10% increase in body weight (r2 = 0.12, β = −0.558, p < 0.05). There were no correlations between body weight measures and CLint,u values for the other CYP enzymes investigated. These results indicate reduced hepatic metabolizing capacity of CYP3A substrates in patients with increasing body weight.

• 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
• Egeland, Erlend Johannessen; Witczak, Bartlomiej J; Zare, Hasse Khiabani; Christensen, Hege Staaland; Åsberg, Anders & Robertsen, Ida (2020). Chronic Inhibition of CYP3A is Temporarily Reduced by Each Hemodialysis Session in Patients With End‐Stage Renal Disease. Clinical Pharmacology and Therapeutics. ISSN 0009-9236. 108(4), p. 866–873. doi: 10.1002/cpt.1875. Full text in Research Archive
• 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
• Wegler, Christine; Garcia, Luna Prieto; Klinting, Signe; Robertsen, Ida; Wisniewski, Jacek R. & Hjelmesæth, Jøran [Show all 10 contributors for this article] (2020). Proteomics‐informed prediction of rosuvastatin plasma profiles in patients with a wide range of body weight. Clinical Pharmacology and Therapeutics. ISSN 0009-9236. 109(3), p. 762–771. doi: 10.1002/cpt.2056. Full text in Research Archive
• Åsberg, Anders; Bjerre, Anna Kristina; Almaas, Runar; Luis-Lima, Sergio; Robertsen, Ida & Salvador, Cathrin Lytomt [Show all 10 contributors for this article] (2019). Measured GFR by Utilizing Population Pharmacokinetic Methods to Determine Iohexol Clearance. Kidney International Reports. 5(2), p. 189–198. doi: 10.1016/j.ekir.2019.11.012. Full text in Research Archive Show summary

  Introduction There is an increasing demand for accurately measured glomerular filtration rate (GFR). Iohexol serum clearance has become a new gold standard, but it is challenging when GFR is low and 24-hour sampling is required for accurate results. The primary aim of this study was to develop an iohexol pharmacokinetic population model for accurate determination of individual GFR using limited sampling for up to 5 hours also when renal function is <40 ml/min. Methods A nonparametric iohexol population pharmacokinetic model was developed with rich data from 176 patients. In a validation cohort of 43 patients, a model-determined GFR (iohexol clearance) using different limited sampling strategies for up to 5 hours was compared with the strategy currently used in routine care, a log-linear 2-point method. In all, 1526 iohexol concentrations were used, from patients ranging in age from 1 to 82 years and GFR from 14 to 149 ml/min. Results The clinical 2-point method showed insufficient agreement compared with reference values; 15% of GFR values had an error of greater than ±10% even when sampling for 24 hours when estimating GFR <40 ml/min per 1.73 m2 (standard procedure). Restricted sampling the first 5 hours with the population model required 4 samples to determine GFR accurately. This strategy showed excellent agreement with the reference; <3% of GFR values had an error greater than ±10 %. Conclusion Using an iohexol population pharmacokinetic model allows for accurate determination of GFR within 5 hours when applying 4 optimally timed samples, even in patients with GFR <40 ml/min.

• Halden, Thea Anine Strøm; Kvitne, Kine Eide; Midtvedt, Karsten; Rajakumar, Laavanyaah; Robertsen, Ida & Brox, Jan [Show all 10 contributors for this article] (2019). Efficacy and Safety of Empagliflozin in Renal Transplant Recipients With Posttransplant Diabetes Mellitus. Diabetes Care. ISSN 0149-5992. 42(6), p. 1067–1074. doi: 10.2337/dc19-0093. Full text in Research Archive Show summary

  OBJECTIVE Sodium–glucose cotransporter 2 (SGLT2) inhibitors have lately become the recommended treatment in patients with type 2 diabetes and high cardiovascular risk. Patients with posttransplant diabetes mellitus (PTDM) also have high cardiovascular risk. The aim of this study was to investigate the safety and efficacy of empagliflozin in renal transplant recipients with PTDM. RESEARCH DESIGN AND METHODS Forty-nine renal transplant recipients were included in an investigator-initiated, single-center, prospective, double-blind study and randomized to receive either 10 mg empagliflozin or placebo once daily for 24 weeks. Patients transplanted >1 year ago, diagnosed with PTDM, with stable renal function (estimated glomerular filtration rate [eGFR] >30 mL/min/1.73 m2), and with stable immunosuppressive therapy were studied. RESULTS Forty-four renal transplant recipients (22 empagliflozin/22 placebo, 34 males) completed the study. Median (interquartile range) change in glycated hemoglobin (HbA1c) was significantly reduced with empagliflozin compared with placebo: −0.2% (−0.6, −0.1) (−2.0 mmol/mol [−6.5, −1.0]) vs. 0.1% (−0.1, 0.4) (1.0 mmol/mol [−0.75, 3.8]) (P = 0.025). The magnitude of glucose reduction was dependent on GFR and baseline HbA1c. The treatment also resulted in a significant reduction in body weight of −2.5 kg (−4.0, −0.05) compared with an increase of 1.0 kg (0.0, 2.0) in the placebo group (P = 0.014). There were no significant differences between the groups in adverse events, immunosuppressive drug levels, or eGFR. CONCLUSIONS Empagliflozin appeared safe and improved glycemic control in renal transplant recipients with PTDM compared with placebo. A concomitant reduction in body weight was seen.

• Krogstad, Veronica; Peric, Alexandra; Robertsen, Ida; Kringen, Marianne K.; Wegler, Christine & Angeles, Philip Carlo Soriano [Show all 13 contributors for this article] (2019). A Comparative Analysis of Cytochrome P450 Activities in Paired Liver and Small Intestinal Samples from Patients with Obesity. Drug Metabolism And Disposition. ISSN 0090-9556. 48(1), p. 8–17. doi: 10.1124/DMD.119.087940. Full text in Research Archive
• Angeles, Philip Carlo Soriano; Robertsen, Ida; Seeberg, Lars Thomas; Krogstad, Veronica; Skattebu, Julie & Sandbu, Rune [Show all 8 contributors for this article] (2019). The influence of bariatric surgery on oral drug bioavailability in patients with obesity: A systematic review. Obesity Reviews. ISSN 1467-7881. 20(9), p. 1299–1311. doi: 10.1111/obr.12869. Full text in Research Archive Show summary

  Anatomical changes in the gastrointestinal tract and subsequent weight loss may influence drug disposition and thus drug dosing following bariatric surgery. This review systematically examines the effects of bariatric surgery on drug pharmacokinetics, focusing especially on the mechanisms involved in restricting oral bioavailability. Studies with a longitudinal before‐after design investigating the pharmacokinetics of at least one drug were reviewed. The need for dose adjustment following bariatric surgery was examined, as well as the potential for extrapolation to other drugs subjected to coinciding pharmacokinetic mechanisms. A total of 22 original articles and 32 different drugs were assessed. The majority of available data is based on Roux‐en‐Y gastric bypass (RYGBP) (18 of 22 studies), and hence, the overall interpretation is more or less limited to RYGBP. In the case of the majority of studied drugs, an increased absorption rate was observed early after RYGBP. The effect on systemic exposure allows for a low degree of extrapolation, including between drugs subjected to the same major metabolic and transporter pathways. On the basis of current understanding, predicting the pharmacokinetic change for a specific drug following RYGBP is challenging. Close monitoring of each individual drug is therefore recommended in the early postsurgical phase. Future studies should focus on the long‐term effects of bariatric surgery on drug disposition, and they should also aim to disentangle the effects of the surgery itself and the subsequent weight loss.

• 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
• Robertsen, Ida; Debord, Jean; Åsberg, Anders; Marquet, Pierre & Woillard, Jean-Baptiste (2018). A Limited Sampling Strategy to Estimate Exposure of Everolimus in Whole Blood and Peripheral Blood Mononuclear Cells in Renal Transplant Recipients Using Population Pharmacokinetic Modeling and Bayesian Estimators. Clinical Pharmacokinetics. ISSN 0312-5963. 57(11), p. 1459–1469. doi: 10.1007/s40262-018-0646-5. Full text in Research Archive
• Egeland, Erlend Johannessen; Reisæter, Anna Varberg; Robertsen, Ida; Midtvedt, Karsten; Strøm, Erik Heyerdahl & Holdaas, Hallvard [Show all 8 contributors for this article] (2018). High tacrolimus clearance ? a risk factor for development of interstitial fibrosis and tubular atrophy in the transplanted kidney: a retrospective single-center cohort study. Transplant International. ISSN 0934-0874. 32(3), p. 257–269. doi: 10.1111/tri.13356. Full text in Research Archive
• Hjelmesæth, Jøran; Åsberg, Anders; Andersson, Shalini; Sandbu, Rune; Robertsen, Ida & Johnson, Line Kristin [Show all 16 contributors for this article] (2018). Impact of body weight, low energy diet and gastric bypass on drug bioavailability, cardiovascular risk factors and metabolic biomarkers: protocol for an open, non-randomised, three-armed single centre study (COCKTAIL). BMJ Open. 8:e021878(5), p. 1–10. doi: 10.1136/bmjopen-2018-021878. Full text in Research Archive Show summary

  Introduction: Roux-en-Y gastric bypass (GBP) is associated with changes in cardiometabolic risk factors and bioavailability of drugs, but whether these changes are induced by calorie restriction, the weight loss or surgery per se, remains uncertain. The COCKTAIL study was designed to disentangle the short-term (6 weeks) metabolic and pharmacokinetic effects of GBP and a very low energy diet (VLED) by inducing a similar weight loss in the two groups. Methods and analysis: This open, non-randomised, three-armed, single-centre study is performed at a tertiary care centre in Norway. It aims to compare the short-term (6 weeks) and long-term (2 years) effects of GBP and VLED on, first, bioavailability and pharmacokinetics (24 hours) of probe drugs and biomarkers and, second, their effects on metabolism, cardiometabolic risk factors and biomarkers. The primary outcomes will be measured as changes in: (1) all six probe drugs by absolute bioavailability area under the curve (AUCoral/AUCiv) of midazolam (CYP3A4 probe), systemic exposure (AUCoral) of digoxin and rosuvastatin and drug:metabolite ratios for omeprazole, losartan and caffeine, levels of endogenous CYP3A biomarkers and genotypic variation, changes in the expression and activity data of the drug-metabolising, drug transport and drug regulatory proteins in biopsies from various organs and (2) body composition, cardiometabolic risk factors and metabolic biomarkers. Ethics and dissemination: The COCKTAIL protocol was reviewed and approved by the Regional Committee for Medical and Health Research Ethics (Ref: 2013/2379/REK sørøst A). The results will be disseminated to academic and health professional audiences and the public via presentations at conferences, publications in peer-reviewed journals and press releases and provided to all participants.

• Egeland, Erlend Johannessen; Robertsen, Ida; Hermann, Monica; Midtvedt, Karsten; Størset, Elisabet & Gustavsen, Marte Theie [Show all 12 contributors for this article] (2017). High tacrolimus clearance is a risk factor for acute rejection in the early phase after renal transplantation. Transplantation. ISSN 0041-1337. 101(8), p. e273–e279. doi: 10.1097/TP.0000000000001796. Full text in Research Archive Show summary

  Background Patients with high tacrolimus clearance eliminate more drug within a dose interval compared with those with low clearance. Delays in dosing time will result in transient periods of lower concentrations in high versus low clearance patients. Transient subtherapeutic tacrolimus concentrations may induce acute rejection episodes. Methods A retrospective study in all renal transplant patients treated with tacrolimus at our center from 2009 to 2013 was conducted. The association between individually estimated tacrolimus clearance (daily tacrolimus dose [mg]/trough concentration [μg/L]) and biopsy-proven acute rejection (BPAR) the first 90 days posttransplantation was investigated. Results In total, 638 patients treated with oral tacrolimus were included in the analysis. Eighty-five (13.3%) patients experienced BPAR. Patients were stratified into 4 groups per their estimated clearance. The patients in the high clearance group had significantly higher incidence of BPAR (20.6%) with a hazard ratio of 2.39 (95% confidence interval, 1.30-4.40) compared with the low clearance group. Clearance estimate (as a continuous variable) showed a hazard ratio of 2.25 (95% confidence interval, 1.70-2.99) after adjusting for other risk factors. There were no significant differences in neither trough concentrations the first week after transplantation nor time to target trough concentration between patients later experiencing BPAR or not. Conclusions High estimated clearance is significantly associated with increased risk of BPAR the first 90 days posttransplantation and may predict an increased risk of rejection in the early phase after renal transplantation.

• Hermann, Monica; Robertsen, Ida & Christensen, Hege Staaland (2015). Immunologisk aktivitet og biologiske legemidler påvirker legemiddelmetabolisme og -transport. Norsk Farmaceutisk Tidsskrift (NFT). ISSN 0029-1935. 123(6), p. 22–25. 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
• 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
• Robertsen, Ida; Falck, Pål; Andreassen, Arne K.; Næss, Nina Kaajal; Lunder, Niclas & Christensen, Hege Staaland [Show all 8 contributors for this article] (2013). Endomyocardial, intralymphocyte and whole blood concentrations of ciclosporin A in heart transplant recipients. Transplantation Research. 2(5). doi: 10.1186/2047-1440-2-5. Full text in Research Archive Show summary

  Background In the early phases following heart transplantation a main challenge is to reduce the impact of acute rejections. Previous studies indicate that intracellular ciclosporin A (CsA) concentration may be a sensitive acute rejection marker in renal transplant recipients. The aims of this study were to evaluate the relationships between CsA concentrations at different target sites as potential therapeutic drug monitoring (TDM) tools in heart transplant recipients. Methods Ten heart transplant recipients (8 men, 2 women) on CsA-based immunosuppression were enrolled in this prospective single-center pilot study. Blood samples were obtained once to twice weekly up to 12 weeks post-transplant. One of the routine biopsies was allocated to this study at each sampling time. Whole blood, intralymphocyte, and endomyocardial CsA concentrations were determined with validated HPLC-MS/MS-methods. Mann–Whitney U test was used when evaluating parameters between the two groups of patients. To correlate whole blood, intralymphocyte, and endomyocardial CsA concentrations linear regression analysis was used. Results Three patients experienced mild rejections. In the study period, the mean (range) intralymphocyte CsA trough concentrations were 10.1 (1.5 to 39) and 8.1 (1.3 to 25) ng/106 cells in the rejection and no-rejection group, respectively (P=0.21). Corresponding whole blood CsA concentrations were 316 (153 to 564) and 301 (152 to 513) ng/mL (P=0.33). There were no correlations between whole blood, intralymphocyte, or endomyocardial concentrations of CsA (P >0.11). Conclusions The study did not support an association between decreasing intralymphocyte CsA concentrations and acute rejections. Further, there were no association between blood concentrations and concentrations at sites of action, potentially challenging TDM in these patients.

• 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

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• Thoresen, G. Hege; Simonsen, terje; Christensen, Hege; Johansen, Harald Thidemann; Kase, Eili Tranheim & Robertsen, Ida [Show all 9 contributors for this article] (2021). Basal farmakologi. Fagbokforlaget. ISBN 9788245033557. 405 p. Full text in Research Archive
• Thoresen, G. Hege; Solberg, Rigmor; Johansen, Harald Thidemann; Kase, Eili Tranheim; Rustan, Arild Christian & Christensen, Hege [Show all 7 contributors for this article] (2020). Illustrert farmakologi. Fagbokforlaget. ISBN 9788245033564. 392 p. Full text in Research Archive

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• Skogvoll, Vidar; Winther-Larsen, Hanne Cecilie & Robertsen, Ida (2024). Real læring - Realistfabrikken: Hvordan lage farmasøyt. [Radio]. Podcast. Full text in Research Archive
• Kvitne, Kine Eide; Hole, Kristine; Molden, Espen & Robertsen, Ida (2022). Response to: “Utility of endogenous 4β-hydroxycholesterol as a biomarker to assess cytochrome P 450 3A (CYP3A) activity: not quite ready for prime time”. European Journal of Clinical Pharmacology. ISSN 0031-6970. doi: 10.1007/s00228-022-03387-y. 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
• Åsberg, Anders; Bergan, Stein; Bjørkto, Magnus; Mjøen, Geir; Reisæter, Anna Varberg & Robertsen, Ida [Show all 7 contributors for this article] (2020). Severe mycophenolate intoxication in a solid organ transplant recipient - No intervention actually needed. Transplantation direct. 6:e609, p. 1–4. doi: 10.1097/TXD.0000000000001058. Full text in Research Archive
• Robertsen, Ida; Woillard, Jean-Baptiste & Åsberg, Anders (2019). Why dose adjust systemic exposure when looking for associations with adverse events in tacrolimus‐treated transplant recipients? British Journal of Clinical Pharmacology. ISSN 0306-5251. 86(12), p. 2535–2535. doi: 10.1111/bcp.13984. Full text in Research Archive
• Johnson, Line Kristin; Sandbu, Rune; Robertsen, Ida; Åsberg, Anders; Andersson, Tommy & Andersson, Shalini [Show all 8 contributors for this article] (2019). Effect of gastric bypass and very-low energy diet on cardiometabolic risk factors. Surgery for Obesity and Related Diseases. ISSN 1550-7289. 15, p. S114–S114. doi: 10.1016/j.soard.2019.08.232. Full text in Research Archive
• Angeles, Philip Carlo Soriano; Robertsen, Ida; Seeberg, Lars Thomas; Krogstad, Veronica; Sandbu, Rune & Åsberg, Anders [Show all 7 contributors for this article] (2019). Reply to letter: “What about drug bioavailability in patients who had bariatric surgery and dependent on immunosuppressives?”. Obesity Reviews. ISSN 1467-7881. 21(2). doi: 10.1111/obr.12954. Full text in Research Archive
• Egeland, Erlend Johannessen; Størset, Elisabet; Robertsen, Ida; Hermann, Monica; Midtvedt, Karsten & Gustavsen, Marte Theie [Show all 10 contributors for this article] (2018). The Authors' Reply. Transplantation. ISSN 0041-1337. 102(1), p. e43–e44. doi: 10.1097/TP.0000000000001961. Full text in Research Archive
• Egeland, Erlend Johannessen; Robertsen, Ida; Hermann, Monica; Midtvedt, Karsten; Størset, Elisabet & Gustavsen, Marte Theie [Show all 12 contributors for this article] (2017). High tacrolimus clearance and acute rejection risk after renal transplantation. Full text in Research Archive
• Egeland, Erlend Johannessen; Robertsen, Ida; Hermann, Monica; Midtvedt, Karsten; Størset, Elisabet & Gustavsen, Marte Theie [Show all 12 contributors for this article] (2017). High tacrolimus clearance – a risk factor for acute rejection and fibrosis in the transplanted kidney. Full text in Research Archive
• Egeland, Erlend Johannessen; Robertsen, Ida; Hermann, Monica; Midtvedt, Karsten; Størset, Elisabet & Gustavsen, Marte Theie [Show all 12 contributors for this article] (2017). High tacrolimus clearance may predict rejection and chronic damage to the transplanted kidney. Full text in Research Archive
• Åsberg, Anders; Robertsen, Ida & Midtvedt, Karsten (2017). How to report and interpret bioequivalence data in solid organ transplant recipients. Transplantation. ISSN 0041-1337. 101(11), p. e347–e347. doi: 10.1097/TP.0000000000001894. Full text in Research Archive
• Ose, Anne M; Krogstad, Veronica; Hasvold, Grete; Robertsen, Ida; Egeland, Erlend Johannessen & Hermann, Monica [Show all 9 contributors for this article] (2017). Optimalisering av metode for kvantifisering av CYP3A5 og P_glykoprotein i små nyrebiopsier. Full text in Research Archive
• Vu, Martin; Krogstad, Veronica; Johnson, Line Kristin; Angeles, Philip Carlo S; Hasvold, Grete & Hermann, Monica [Show all 13 contributors for this article] (2017). Effect of low calorie diet on the absolute bioavailability of midazolam in patients with severe obesity. Full text in Research Archive
• Egeland, Erlend Johannessen; Hermann, Monica; Robertsen, Ida; Midtvedt, Karsten; Hartmann, Anders & Reisæter, Anna Varberg [Show all 12 contributors for this article] (2016). High tacrolimus clearance is a risk factor for acute rejection early after renal transplantation. Full text in Research Archive
• Le, Peter Huy Vo; Robertsen, Ida; Åsberg, Anders; Christensen, Hege Staaland & Hermann, Monica (2016). Utvikling av en sensitiv LC-MS/MS-metode for å kvantifisere midazolam og metabolitter i pasienter med sykelig overvekt før og etter gastrisk bypass-operasjon. Full text in Research Archive
• Ulvmoen, Anders; Robertsen, Ida; Åsberg, Anders; Christensen, Hege Staaland & Hermann, Monica (2015). Utvikling av en sensitiv LC-MS/MS-metode for å kvantifisere midazolam og metabolitter in vitro og i sykelig overvektige pasienter. Full text in Research Archive
• Ahlsen, Kathrine; Robertsen, Ida; Midtvedt, Karsten; Åsberg, Anders & Christensen, Hege Staaland (2014). Aktivitet av P-glykoprotein i mononukleære celler fra perifert blod. 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
• Robertsen, Ida; Falck, Pål; Næss, Nina Kaajal; Andreassen, Arne K.; Gullestad, Lars & Christensen, Hege Staaland [Show all 7 contributors for this article] (2012). Endomyovardial, intralymphocyte and whole blood concentrations of cyclosporine A in heart transplant recipients. Full text in Research Archive
• Jensstuen, Ågot K; Robertsen, Ida; Amundsen, Rune & Christensen, Hege Staaland (2011). CYP3A4-mediert metabolisme av cyklosporin i insektsmikrosomer. 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

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