A Mycophenolate Pharmacokinetic Study with New Insights into Enterohepatic Recirculation in Kidney Transplant Recipients

Background: Mycophenolic acid (MPA) has complex pharmacokinetics in part due to enterohepatic recirculation (EHR). A deeper understanding of MPA pharmacokinetics and specifically how EHR and patterns of EHR affect exposure will improve immunosuppression outcomes. This study provides a contemporary and comprehensive assessment of MPA and metabolites in the blood and urine with a focus on EHR characteristics. Methods: Kidney transplant recipients (n = 84) receiving mycophenolate mofetil (MMF) and tacrolimus underwent an intensive MPA pharmacokinetic assessment. Pharmacokinetics of MPA and its metabolites, EHR%, and number of secondary peaks were determined. The associations between EHR, the number of secondary peaks, and achievement of MPA therapeutic range were studied. MMF dose proportionality with MPA exposure was evaluated. Results: MPA exhibited high pharmacokinetic variability, with 5.5-fold differences in AUC_0–12, 18.4-fold differences in trough concentrations, and a 3.4-fold difference in EHR%. Median MPA EHR% was 40.5%. There were no significant associations between EHR% and MPA AUC_0–12 or trough. MPA AUC_0–12 and trough were significantly associated with the number of MPA secondary peaks (0, 1, or ≥ 2 peaks). Participants without secondary peaks showed the highest percentage of subtherapeutic MPA AUC_0–12 and troughs, while participants with ≥ 2 peaks were more likely to be supratherapeutic. Conclusions: There was no association between the EHR% and MPA AUC_0–12 or trough. We identified three distinct patterns of MPA secondary peaks (0, 1, or ≥ 2 peaks), which were significantly associated with MPA AUC_0–12 and trough. Studies to evaluate the relationship of MPA EHR measures and clinical outcomes are needed. Trial Registry: Clinical Trial Notation: clinicaltrials.gov, NCT04953715.