Naslov
Loss of function ABCG2 c.421C>A (rs2231142) polymorphism increases steady-state exposure to mycophenolic acid in stable renal transplant recipients: exploratory matched cohort study

Autori
Borić-Bilušić, Ana ; Božina, Nada ; Lalić, Zdenka ; Lovrić, Mila ; Nađ-Škegro, Sandra ; Penezić, Luka ; Barišić, Karmela ; Trkulja, Vladimir

Izvornik
Advances in therapy (0741-238X) (2022), 1235; 12325, 18

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
mycophenolic acid, renal transplant, breast cancer resistance protein, polymorphism

Sažetak
Introduction. Polymorphism ABCG2 c.421C>A (rs2231142) results in a reduced activity of the important drug efflux transporter breast cancer resistance protein (BCRP/ABCG2). One study suggested that it may affect enterohepatic recirculation of mycophenolic acid (MPA). We evaluated the effect 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 vs. wild- type (wt) patients were matched in 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 vs. 56 wt patients) indicated by 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 by 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 vs. 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 high unsusceptibility 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.

Izvorni jezik
Engleski

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