Atazanavir pharmacokinetics in genetically determined CYP3A5 expressors versus non-expressors

Abstract

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 enrollment 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 genotypes. 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; P = 0.045) and the C(min) was half (87 versus 171 ng/mL; P = 0.044) in CYP3A5 expressors versus non-expressors. Non-African-American CYP3A5 expressor males had 2.1-fold faster CL/F (P = 0.003) and <20% the C(min) (P = 0.0001) 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 bilirubin increased 1.6- to 2.8-fold more in subjects with UGT1A1 *28/*28 versus *1/*28 or *1/*1.

Conclusions: CYP3A5 expressors had faster atazanavir CL/F and lower C(min) than non-expressors. The effect was most pronounced in non-African-American men. Ritonavir lessened CYP3A5 expressor effects. The wild-type ABCB1 CGC haplotype was associated with slower CL/F and the UGT1A1 *28 genotype was associated with increased bilirubin. Thus, CYP3A5, ABCB1 and UGT1A1 polymorphisms are associated with atazanavir pharmacokinetics and pharmacodynamics in vivo.

Figure 1

Atazanavir CL/F on day 7 sorted by race and gender. Solid lines show cell mean estimates. AA, African-American; non-AA, non-African-American. Atazanavir CL/F differences were most pronounced in non-African-American men.

Figure 2

Atazanavir CL/F on day 7 according to number of CGC copies in the ABCB1 gene (1236C, 2677G, 3435C). Lines show cell mean estimates; solid lines are for CYP3A5 expressors and dashed lines are for non-expressors (see text). Atazanavir CL/F was significantly faster in those with zero CGC copies versus those with one or two CGC copies. CYP3A5 expressors had a faster CL/F than non-expressors in each CGC category. NS, non-significant.

Figure 3

Geometric mean atazanavir plasma concentrations for genetically determined CYP3A5 expressors and non-expressors during the atazanavir alone (day 7) and atazanavir plus ritonavir (day 14) phases.

Figure 4

Atazanavir CL/F on day 14 according to number of CGC copies in the ABCB1 gene (1236C, 2677G, 3435C). Solid lines show cell mean estimates. Atazanavir CL/F was significantly faster in those with zero CGC copies versus those with one or two CGC copies, but CYP3A5 expressor status was not predictive of CL/F in this analysis.

Figure 5

Change in indirect bilirubin observed in the atazanavir alone and atazanavir plus ritonavir phases sorted by UGT1A1 genotypes.