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Influence of SLCO1B1 Polymorphisms on the Drug‐Drug Interaction Between Darunavir/Ritonavir and Pravastatin
Author(s) -
Aquilante Christina L.,
Kiser Jennifer J.,
Anderson Peter L.,
Christians Uwe,
Kosmiski Lisa A.,
Daily Elizabeth B.,
Hoffman Keith L.,
Hopley Charles W.,
Predhomme Julie A.,
Schniedewind Bjorn,
Sidhom Maha S.
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270011427907
Subject(s) - pravastatin , darunavir , ritonavir , pharmacokinetics , pharmacology , slco1b1 , medicine , chemistry , cholesterol , viral load , human immunodeficiency virus (hiv) , immunology , pharmacogenetics , biochemistry , antiretroviral therapy , genotype , gene
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.