SLCO1B1 Genotype Influences the Drug-Drug Interaction between Cyclosporine and Pravastatin

Purpose Cyclosporine (CYA) increases pravastatin (PRAV) plasma exposure by inhibiting the OATP1B1 ( SLCO1B1 ) transporter. The aim of this study was to determine if the SLCO1B1 c.521 T>C polymorphism influences pharmacokinetic (PK) variability in the magnitude of the drug-drug interaction between CYA and PRAV. Methods and Materials Healthy adults were enrolled based on SLCO1B1 c.521 genotype (T/T n=23; T/C n=8; C/C n=1). In phase 1, subjects received PRAV 20 mg x 1 dose. In phase 2, subjects received CYA 1.25 mg/kg x 2 doses, with PRAV 20 mg given 1 hr after the 2 nd CYA dose. A 12-hr PK study followed each PRAV dose, with a 7-day washout between phases. PRAV (parent) and SQ31906 (metabolite) plasma concentrations were measured with LC-MS/MS. PK parameters were generated for PRAV+SQ31906 (PRAV total ). Results The study included 19 women and 13 men, with a mean age of 29 ± 5 yrs. CYA increased PRAV total AUC 0-12 by 4.7-fold (range 1.6 to 10.8-fold; P SLCO1B1 c.521 T/T genotype had a larger increase in PRAV total AUC 0-12 and C max than C allele carriers (table). Of subjects with more than a 5-fold increase in PRAV total AUC 0-12 , 11/11 had the T/T genotype. SLCO1B1 c.521 was a predictor of the relative change in PRAV total AUC 0-12 (P=0.01) and C max (p=0.03) in regression analysis. Conclusions SLCO1B1 c.521 genotype significantly influences the magnitude of the interaction between CYA and PRAV. The T/T genotype appears to be more susceptible to the inhibitory effects of CYA than C allele carriers. These data suggest that transporter genotype should be evaluated in drug-drug interaction studies, particularly those involving agents used commonly in cardiac transplantation. PRAV total Parameter Phase c.521 T/T c.521 T/C or C/C P value AUC 0-12 (ng*h/ml) PRAV 91 ± 51 106 ± 40 0.26 PRAV+CYA 425 ± 185 325 ± 114 0.13 Relative Change 5.3 (2.5–10.8) 3.2 (1.6–4.8) 0.008 C max (ng/ml) PRAV 44 ± 28 52 ± 23 0.10 PRAV+CYA 232 ± 120 182 ± 90 0.23 Relative Change 6.9 (2.4–17.0) 3.7 (1.5–6.8) 0.003 Mean±SD (range); P values, between genotype groups