Mycophenolic Acid and Its Pharmacokinetic Drug‐Drug Interactions in Humans: Review of the Evidence and Clinical Implications

Abstract

Mycophenolic acid (MPA) is an immunosuppressive agent commonly prescribed during posttransplant periods for the prevention of acute and chronic rejection following organ transplantation. Compelling evidence has demonstrated a pivotal role of the exposure level of MPA in determining the rate of allograft rejection as well as the incidence of adverse outcomes, such as gastrointestinal complaints and myelosuppression. Because MPA has wide interindividual pharmacokinetic (PK) variability, the importance of maintaining the MPA concentration levels within its therapeutic range is clear. In addition, due to its complex PKs, MPA is prone to inadvertently develop PK drug-drug interactions (DDIs) with many agents, some of which are commonly used in organ transplant recipients. Failure to acknowledge such clinically significant PK DDIs between MPA and other coadministered drugs could potentially lead to devastating outcomes, ie, the occurrence of acute and chronic allograft rejection or the development of severe adverse events. The rationale to avoid concomitant use of certain drugs with MPA has been established; however, there is a lack of comprehensive literature to guide clinicians and medical professionals on the recognition and monitoring of potential PK DDIs when MPA is prescribed. In this article we comprehensively review, summarize, and discuss previous clinical studies that investigated the impact of coadministered drugs on the PK of MPA, with a major focus on the PK DDIs between MPA and commonly coadministered drugs.

Pharmacologic Treatment of Transplant Recipients Infected With SARS-CoV-2: Considerations Regarding Therapeutic Drug Monitoring and Drug–Drug Interactions

“…The metabolism of MPA mainly involves glucuronidation by the uridine 5 0 -diphosphate-glucuronosyltransferase (UGT) enzyme superfamily. 9 MPA is subjected to entero-hepatic recirculation, which extends its terminal half-life. Hepatic excretion of MPA glucuronide (MPAG) is driven by uptake from the portal vein through OATP1B3 and, to a lesser extent, OATP1B1.…”

Phase II, multi-center, open-label, single-arm clinical trial evaluating the efficacy and safety of Mycophenolate Mofetil in patients with high-grade locally advanced or metastatic osteosarcoma (ESMMO): rationale and design of the ESMMO trial

“…There are three drug regimens to be used for prophylaxis of possible infection during study participation: (1) ivermectin (12 mg/day) for 2 days before Cycle 1, Week 0 [28], (2) trimethoprim-sulfamethoxazole (160/800 mg/ day) once daily from Cycle 1, Week 1, until discontinuation of mycophenolate mofetil [29], and (3) acyclovir (400 mg/day) twice daily from Cycle 1, Week 1, until discontinuation of mycophenolate mofetil [30]. No evidence of PK drug-drug interactions between any of these regimens and mycophenolate mofetil is reported [31].…”

Mycophenolate mofetil for systemic sclerosis: drug exposure exhibits considerable inter-individual variation—a prospective, observational study

“…The pharmacokinetics of MMF is complex [6,7]. Briefly, ingested MMF is hydrolised to the active metabolite mycophenolic acid (MPA) in the stomach and then rapidly absorbed.…”

“…MPA is converted to the inactive metabolite MPA-7-O-glucoronide (MPAG) in the liver and kidney and excreted in the bile and urine. MPAG that reaches the intestine is deconjugated to MPA by anaerobe bacteria and readily reabsorbed [7].…”

“…Individual MPA exposure is difficult to estimate based on a single analysis of plasma MPA. A good estimation of MPA exposure can be made by measuring plasma MPA multiple times during a 3-6-h period and calculating MPA area under the concentration-time curve 0-12 h (MPA_AUC 0-12 ) [6][7][8].…”