Atazanavir pharmacokinetics in genetically determined CYP3A5 expressors versus non-expressors

Objectives: The objective of this study was to compare atazanavir pharmacokinetics in genetically determined CYP3A5 expressors versus non-expressors. Methods: HIV-negative adult volunteers were pre-screened for CYP3A5 *3, *6 and *7 polymorphisms and enrolment was balanced for CYP3A5 expressor status, gender and race (African-American versus non-African-American). Participants received atazanavir 400 mg daily for 7 days followed by atazanavir/ ritonavir 300 mg/100 mg daily for 7 days with pharmacokinetic studies on days 7 and 14. Other measures collected were bilirubin, UGT1A1 *28, and ABCB1 1236C>T, 2677G>T/A and 3435C>T geno-types. Data analyses utilized least squares regression. Results: Fifteen CYP3A5 expressors and 16 non-expressors participated. The day 7 atazanavir oral clearance (CL/F) was 1.39-fold faster (0.25 versus 0.18 L/h/kg; P50.045) and the Cmin was half (87 versus 171 ng/mL; P50.044) in CYP3A5 expressors versus non-expressors. Non-African-American CYP3A5 expressor males had 2.1-fold faster CL/F (P50.003) and <20 % the Cmin (P50.0001) compared with non-African-American non-expressor males. No overall CYP3A5 expressor effects were observed during the ritonavir phase. One or two copies of wild-type ABCB1 haplotype (1236C/2677G/3435C) was predictive of slower atazanavir and ritonavir CL/F compared with zero copies (P<0.06). Indirect bilirubi