title: Influence of SLCO1B1 polymorphisms on the drug-drug interaction between darunavir/ritonavir and pravastatin.
abstract: The authors investigated whether SLCO1B1 polymorphisms contribute to variability in pravastatin pharmacokinetics when pravastatin is administered alone versus with darunavir/ritonavir. HIV-negative healthy participants were prospectively enrolled on the basis of SLCO1B1 diplotype: group 1 (*1A/*1A, n = 9); group 2 (*1A/*1B, n = 10; or *1B/*1B, n = 2); and group 3 (*1A/*15, n = 1; *1B/*15, n = 5; or *1B/*17, n = 1). Participants received pravastatin (40 mg) daily on days 1 through 4, washout on days 5 through 11, darunavir/ritonavir (600/100 mg) twice daily on days 12 through 18, with pravastatin 40 mg added back on days 15 through 18. Pharmacokinetic studies were conducted on day 4 (pravastatin alone) and day 18 (pravastatin + darunavir/ritonavir). Pravastatin area under the plasma concentration-time curve (AUC(tau)) was 21% higher during administration with darunavir/ritonavir compared with pravastatin alone; however, this difference was not statistically significant (P = .11). Group 3 variants had 96% higher pravastatin AUC(tau) on day 4 and 113% higher pravastatin AUC(tau) on day 18 compared with group 1. The relative change in pravastatin pharmacokinetics was largest in group 3 but did not differ significantly between diplotype groups. In sum, the influence of SLCO1B1*15 and *17 haplotypes on pravastatin pharmacokinetics was maintained in the presence of darunavir/ritonavir. Because OATP1B1 inhibition would be expected to be greater in carriers of normal or high-functioning SLCO1B1 haplotypes, these findings suggest that darunavir/ritonavir is not a potent inhibitor of OATP1B1-mediated pravastatin transport in vivo.
authors.affiliation: PharmD, Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, 12850 East Montview Blvd, Mail Stop C238, Room V20-4103, Aurora, CO 80045, USA. Christina.aquilante@ucdenver.edu
authors.forename: Christina L
authors.initials: CL
authors.lastname: Aquilante
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Kiser
authors.forename: Peter L
authors.initials: PL
authors.lastname: Anderson
authors.forename: Uwe
authors.initials: U
authors.lastname: Christians
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Kosmiski
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Daily
authors.forename: Keith L
authors.initials: KL
authors.lastname: Hoffman
authors.forename: Charles W
authors.initials: CW
authors.lastname: Hopley
authors.forename: Julie A
authors.initials: JA
authors.lastname: Predhomme
authors.forename: Bjorn
authors.initials: B
authors.lastname: Schniedewind
authors.forename: Maha S
authors.initials: MS
authors.lastname: Sidhom
mesh_terms: D000328:Adult; D002784:Cholesterol / Q000097:blood; D000069454:Darunavir; D004347:Drug Interactions; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage*; D006239:Haplotypes; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000235:genetics*; D011110:Polymorphism, Genetic; D017035:Pravastatin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D014280:Triglycerides / Q000097:blood
chemical_list: D017320:HIV Protease Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D013449:Sulfonamides; D014280:Triglycerides; D002784:Cholesterol; D017035:Pravastatin; D019438:Ritonavir; D000069454:Darunavir