Loss of Function ABCG2 c.421C>A (rs2231142) Polymorphism Increases Steady-State Exposure to Mycophenolic Acid in Stable Renal Transplant Recipients: An Exploratory Matched Cohort Study

Introduction Polymorphism ABCG2 c.421C > A (rs2231142) results in reduced activity of the important drug efflux transporter breast cancer-resistance protein (BCRP/ABCG2). One study has suggested that it may affect enterohepatic recirculation of mycophenolic acid (MPA). We evaluated the effect of rs2231142 on steady-state exposure to MPA in renal transplant recipients. Methods Consecutive, stable adult (age ≥ 16 years) renal transplant recipients on standard MPA-based immunosuppressant protocols ( N = 68; 43 co-treated with cyclosporine, 25 with tacrolimus) underwent routine therapeutic drug monitoring after a week of initial treatment, and were genotyped for ABCG2 c.421C > A and 11 polymorphisms in genes encoding enzymes and transporters implicated in MPA pharmacokinetics. ABCG2 c.421C > A variant versus wild-type (wt) patients were matched with respect to demographic, biopharmaceutic, and genetic variables (full optimal combined with exact matching) and compared for dose-adjusted steady-state MPA pharmacokinetics [frequentist and Bayes (skeptical neutral prior) estimates of geometric means ratios, GMR]. Results Raw data (12 variant versus 56 wt patients) indicated around 40% higher total exposure (frequentist GMR = 1.45, 95% CI 1.10–1.91; Bayes = 1.38, 95% CrI 1.07–1.81) and around 30% lower total body clearance (frequentist GMR = 0.66, 0.58–0.90; Bayes = 0.71, 0.53–0.95) in variant carriers than in wt controls. The estimates were similar in matched data (11 variant versus 43 wt patients): exposure GMR = 1.41 (1.11–1.79) frequentist, 1.39 (1.15–1.81) Bayes, with 90.7% and 85.5% probability of GMR > 1.20, respectively; clearance GMR = 0.73 (0.58–0.93) frequentist, 0.71 (0.54–0.95) Bayes. Sensitivity analysis indicated low susceptibility of the estimates to unmeasured confounding. Conclusions Loss-off-function polymorphism ABCG2 c.421C > A increases steady-state exposure to MPA in stable renal transplant patients.