Trial lecture - time and place
20.06.2025, 10.15, Gydas vei 8, auditoriet
Hypothesis, method of investigation and clinical perspective on gut microbiota’s impact on drug disposition and response in solid organ transplantation
Conferral summary
En av de største utfordringene innen moderne legemiddelbehandling er den store variasjonen i legemiddelrespons både innad og mellom individer. For mykofenolat, en hjørnestein i den immunsuppresive behandlingen etter organtransplantasjon, er denne variasjonen særlig uttalt. Dette doktorgradsarbeidet bidrar med viktig kunnskap om faktorer som påvirker farmakokinetikken til mykofenolat, og fremhever tarmmikrobiomet som en sentral bidragsyter til variasjonen i legemiddelrespons.
Main research findings
Mycophenolic acid (MPA), the prodrug of mycophenolate mofetil (MMF), is a cornerstone in immunosuppressive therapy following solid organ transplantation. Correct dosing of MMF remains challenging due to large variations between and within patients, with MPA systemic exposure shown to differ by more than 10-fold. Individualization of MMF therapy holds significant unrealized potential, as much of the variability in MPA exposure remains unexplained and unpredictable. In this thesis, three studies were conducted to investigate the variability in MPA pharmacokinetics and to improve its measurement techniques, to improve long-term patient and graft outcomes following kidney transplantation.
First, circadian variation and fasting status were shown not to influence drug exposure to a clinically relevant extent, suggesting that real-life data can be utilized in future clinical studies. Second, the bidirectional interaction between MPA and the gut microbiome was investigated. The gut microbiome was identified as an important contributor to interindividual variability, with specific bacterial species, particularly Faecalibacterium prausnitzii, linked to microbial reactivation of MPA. These findings provide novel insights into how the gut microbiome modulates MPA exposure, offering a potential avenue for more personalized immunosuppressive therapy. Finally, a microsampling method using capillary blood was developed and clinically validated. Implementing this technique will facilitate therapeutic drug monitoring of MPA and support future clinical investigations.