(073) Pharmacometaboomics suggest a causal link between an excipient in cyclosporine A capsules and incomplete mycophenolate mofetil prodrug activation in kidney transplant recipients

Background: After transplantation, kidney transplant recipients (KTR) often receive immunosuppressive treatment with mycophenolate mofetil (MMF) and a calcineurin inhibitor to prevent graft rejection. Interestingly, coadministration of MMF with the calcineurin inhibitor cyclosporine (CsA) decreases the exposure to the active metabolite mycophenolate (MPA) by 40%, which is presumably caused by inhibited enterohepatic recirculation of MMF metabolites. Recent research utilizing the innovative pharmacometabolomics (PMx) technique, however, unveiled incomplete MMF prodrug activation in some users, suggesting an impaired conversion by the MMF converting enzymes carboxylesterases (CES). Moreover, in vitro studies previously demonstrated that the pharmaceutical excipient Kolliphor® EL, present in CsA capsules, attenuates CES enzyme activity. This presents a potential alternative explanation of the decreased exposure to MPA.

Objectives: In this work, we aimed to explore whether the pharmaceutical excipient Kolliphor® EL is responsible for the incomplete MMF prodrug activation in KTR using both MMF and CsA.

Methods: Untargeted ‘SWATH’ PMx data was used to determine relative MMF prodrug abundances (ratio of MMF and glucuronidated MMF signals over the sum of all MMF-related signals) in urine samples from 321 (derivation cohort) and 403 (validation cohort) KTR with PMx confirmed MMF use enrolled in the TransplantLines Biobank and Cohort Study and the TransplantLines Food and Nutrition Biobank and Cohort Study, respectively. A beta regression was performed to associate relative MMF prodrug abundances with clinical participant data including demographic, anthropomorphic, and laboratory measurements. Furthermore, in vitro experiments using human S9 liver extracts were performed to compare the influence of CsA on MMF activation to that of Kolliphor® EL.

Results: In beta regression analyses, CsA use was associated with relative MMF prodrug abundances in the derivation cohort (OR 1.35, 95% CI 1.21-1.50, p<0.001) as well as the validation cohort (OR 1.47, 95% CI 1.30-1.66, p<0.001). Furthermore, in vitro experiments revealed decreased MMF activation with a high Kolliphor® EL co-exposure.

Conclusions: Concomitant therapy with CsA is associated with reduced MMF prodrug activation in KTR, potentially due to attenuated CES enzyme activity caused by the pharmaceutical excipient Kolliphor® EL. This potential causal link between Kolliphor® EL and incomplete MMF prodrug activation requires further investigation. Adequate exposure to MPA is essential to avoid graft rejection, and these findings may warrant a medication switch from MMF to an enteric coated MPA tablet that circumvents conversion by CES.