The reduced function allele SLCO1B1 c.521T>C is of no practical relevance for the renal graft function over the first post-transplant year in patients treated with mycophenolic acid.

OBJECTIVE: It is unclear whether renal transplant recipients treated with mycophenolic acid (MPA) who carry the reduced-function allele at polymorphism SLCO1B1 c.521T>C differ from their wild-type peers regarding renal outcomes and tolerability. We aimed to estimate the effect of this polymorphism on the graft function (estimated glomerular filtration rate, eGFR) over the first 12 post-transplant months in patients on MPA-based maintenance immunosuppression. METHODS: In a 12-month observational cohort study, consecutive adult patients were repeatedly assessed for eGFR. The SLCO1B1 c.521C>T variant allele carriers (exposed) and wild-type subjects (controls) were balanced on a range of demographic, medical, and genetic variables at baseline, and eGFR trajectory was estimated with further adjustment for time-varying covariates. A subset of patients were assessed for exposure to MPA 5-7 days after the transplantation. RESULTS: The adjusted eGFR slopes from day 1 to day 28 (daily), and from day 28 to day 365 (monthly) were practically identical in exposed (n = 86) and control (n = 168) patients [geometric means ratios (GMR) = 0.99, 95% confidence interval (CI) = 0.92-1.06 and GMR = 0.98, 0.94-1.01, respectively]. The rates of adverse renal outcomes and possible MPA-related adverse effects were low, and similar in exposed and controls [rate ratios (RR) = 0.94, 0.49-1.84 and RR = 1.08, 0.74-1.58, respectively]. The pharmacokinetic analysis did not signal meaningful differences regarding exposure to MPA, overall (exposed n = 23, control n = 45), if cotreated with cyclosporine (n = 17 vs. n = 26) or with tacrolimus (n = 8 vs. n = 17). CONCLUSIONS: In patients treated with MPA, variant allele SLCO1B1 c.521T>C appears of no practical relevance regarding the 12-month renal graft function, MPA safety and exposure to MPA at early steady-state.

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.