Background:  Indinavir (IDV) plasma concentrations are highly variable among patients and this contributes to undesirable drug responses. IDV is a substrate for CYP3A5 and P-gp, which exhibit functional genetic polymorphisms in humans. Our objective was to investigate relationships between genetic variation in CYP3A5 and P-gp with IDV concentrations and antiviral effects among HIV-infected persons.

Methods:   Antiretroviral naïve adults were participating in a study of zidovudine, lamivudine, and IDV. Plasma pharmacokinetic studies were performed 3 times over 18 months of possible follow-up.  A one-compartment, first-order model was fit to the data and pharmacokinetic parameters were determined and averaged for each individual. HIV-RNA was collected monthly. Genetic sequence data for CYP3A5*1/*3 and *1/*6 and MDR1 G2677T and C3435T were obtained by PCR-direct sequencing with PolyPhred analysis. Oral clearance (CL/F) was log transformed and analyzed with parametric and regression approaches. 

Results:  We evaluated 33 subjects, 7 of whom were African American (AA). Although linked, MDR1 2677G>T was more predictive of IDV pharmacokinetics than 3435C>T. 12 (36%) subjects were 2677GG (6 AA), 17 (52%) GT (1 AA), and 4 (12%) TT. In univariate models, IDV CL/F (L/h/kg) was higher in the GG (0.82) vs TT (0.48) subjects; p = 0.02, and also in AA vs non-AA subjects, 0.97 vs 0.83; p = 0.02;  11 (33%) subjects expressed CYP3A5 including all 7 AA. 2 were *1/*1 and 9 had one *1 allele. IDV CL/F was higher in CYP3A5 expressers than non-expressers: 1.01 (*1/*1) and 0.94 (*1/*3 or *6) vs 0.67 (*3/*3); p = 0.002.  Only CYP3A5 expression was associated with IDV CL/F when adjusted for AA and 2677GG (p <0.05). At 1 year or study exit, 2677 GT or TT subjects had a larger reduction in log HIV-RNA compared with GG subjects, -3.3 vs -2.2; p = 0.002, and this was independent of baseline log HIV-RNA (univariate p = 0.003), IDV CL/F (p = 0.04), AA (p = 0.11), and CYP3A5 expression (p = 0.17) in a stepwise regression model.

Conclusions:  Expression of CYP3A5 was associated with higher IDV CL/F independent of AA and G2677T.  Larger reductions in HIV-RNA at 1 year were related with 2677 GT or TT vs GG. This was independent of baseline HIV-RNA, CYP3A5, and IDV CL/F suggesting a specific influence of P-gp on antiviral pharmacodynamics.  In the future, genetic polymorphism relationships with antiretroviral pharmacokinetics and pharmacodynamics may provide a clinical tool to design individualized drug regimens prior to initiating therapy.

Keywords: Clinical Pharmacology; pharmacogenetics; pharmacokinetics