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Assessment of Pharmacokinetic/Pharmacodynamic Relationships through 48 Weeks from a Study in HIV+, ART-naive Subjects Receiving Antiretroviral Regimens Containing Atazanavir 400 mg or Atazanavir/Ritonavir 300/100 mg Once Daily
Richard Bertz*1, Y Wang1, L Mahnke1, A Persson1, E Chung1, M Mathew2, S Agarwala1, D Filoramo1, J Hammond2, and D Grasela1
1Bristol-Myers Squibb Pharma Res Inst, Princeton, NJ, US and 2Bristol-Myers Squibb Pharma Res Inst, Wallingford, CT, US
Background: After 48 weeks of treatment in BMS 424-089, 2 atazanavir (ATV) regimens with or without ritonavir (RTV)
demonstrated significant antiviral activity in ART-naive subjects. Pharmacokinetic/pharmacodynamic analyses were performed to explore associations
between ATV exposure and pharmacdynamic endpoints.
Methods: We randomized 200 subjects to ATV 400 mg
(ATV400) or ATV/RTV 300/100 mg (ATV/RTV) once daily; all received stavudine and
lamivudine. As many as 9 ATV Ctrough (20
to 28 hours from dose) were measured from week 2 to 48. HIV RNA and CD4 were
quantified at baseline (BL) and 9 times through W48. Slope of HIV RNA decline (baseline
to week 8) and proportion on treatment with HIV RNA <400 and <50 copies/mL at week 48 were determined. Associations of jaundice,
diarrhea, nausea, hepatic transaminases (AST/ALT), bilirubin (TBIL), fasting
glucose (GLU), triglycerides (TG), cholesterol (TC), and HDL with ATV log Ctrough
(individual subject geometric mean of Ctrough week 2 to 48) were
explored using linear and logistic regression.
Results: ATV
geometric mean (CV) Ctrough was 125 ng/mL (105%, n = 103) for ATV400 and 663 ng/mL (62%, n = 94) for ATV/RTV. Estimated median (interquartile range) inhibitory quotient using population
wild type HIV EC90 ~14 ng/mL
was 8.9 (4.6 to 18) for ATV400 and 47 (30 to 71) for ATV/RTV. Slope of decay in
HIV RNA and increase in CD4 were not associated with ATV Ctrough (R ≤0.1). ATV Ctrough
was associated with the probability of HIV RNA <400 and <50 copies/mL at week 48 (p ≤0.001);
subjects in lowest and highest Ctrough quartile with HIV RNA <400
copies/mL were 88 and 96% and <50 copies/mL were 74 and 87%. All in the lowest Ctrough
quartile received ATV400 and 92% in the highest quartile received ATV/RTV. As
expected, TBIL (R = 0.44) and probability
of jaundice (p = 0.002) were
positively associated with ATV Ctrough. Despite
a significant regimen effect for TG (p
= 0.036) and TC (p = 0.072)
elevations, only a weak positive correlation of ATV Ctrough with TG
and TC was noted (R = 0.17 to 0.21),
suggesting association with RTV. HDL, GLU, and AST/ALT (R ≤0.08) and probability of diarrhea or nausea (p ≥0.3) were not associated with
ATV Ctrough.
Conclusions: HIV RNA <400 copies/mL
was ≥88% among ART-naive subjects in all ATV Ctrough
quartiles; however, Ctrough was associated with the probability of
HIV RNA <400 as well as <50 copies/mL at week 48.
Despite a significant regimen effect, only a weak correlation of TG and TC with
ATV Ctrough was noted; this suggests an association of these lipid
elevations with RTV administration.
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