Objective: To evaluate fosamprenavir/lopinavir (LPV)/ritonavir (RTV), fosamprenavir/RTV, or LPV/RTV in antiretroviral treatment-experienced patients. Lack of drug interaction data prompted a pharmacokinetic substudy to minimize subject risk.
Design: Multi-center, open-label, selectively randomized, steady-state pharmacokinetic study in HIV-infected subjects.
Methods: A planned independent interim review occurred after at least eight subjects were randomized to each arm. Subjects received twice daily LPV/RTV 400/100 mg (arm A; n = 8); fosamprenavir/RTV 700/100 mg (arm B; n = 8) or LPV/RTV/fosamprenavir 400/100/700 mg (arm C; n = 17). Plasma samples were collected over 12 h between study weeks 2 and 4. Pharmacokinetic parameters were compared based on a one-sided t-test on log-transformed data with a Peto stopping boundary (P < 0.001).
Results: Amprenavir mean area under the curve over 12 h (AUC0–12 h) and concentration at 12 h (C12 h) (μg/ml) were, respectively, 42.7 μg × h/ml (range, 33.1–55.1) and 2.4 μg/ml (range, 1.4–3.2) in arm B and 17.4 μg × h/ml (range, 4.6–41.3) and 0.9 μg/ml (range, 0.2–2.7) in arm C: geometric mean ratio (GMR) arm C:B was 0.36 [99.9% upper confidence boundary (UCB), 0.64] and 0.31 (99.9% h UCB, 0.61), respectively (P ≤ 0.0001). Lopinavir AUC0–12 h and C12 h were, respectively, 95.3 μg × h/ml (range, 60.3–119.3) and 6.3 μg/ml (range, 2.2–9.2) in arm A and 54.4 μg × h/ml (range, 23.5–112.2) and 3.0 μg/ml (range, 0.4–7.9) in arm C: GMR arm C:A of 0.52 (99.9% UCB, 0.89) and 0.39 (99.9% UCB, 0.98), respectively (P ≤ 0.0008). Ritonavir exposure was not significantly different between arms.
Conclusion: APV and LPV exposures are significantly reduced using LPV/RTV/fosamprenavir, possibly increasing the risk of virologic failure. Consequently, A5143 was closed to enrollment.
From the aSchool of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
bSDAC/Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts
cDivision of Clinical Pharmacology, University of Alabama, Birmingham, Alabama
dDivision of Infectious Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania
eHIV Research Branch, TRP, DAIDS, NIAID, NIH, Bethesda, Maryland
fDepartment of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
gGlaxoSmithKline, Research Triangle Park, North Carolina
hDepartment of Medicine, University of Washington School of Medicine, Seattle, Washington, USA
Received 23 July, 2004
Revised 17 September, 2004
Accepted 14 October, 2004
Correspondence to Dr A. D. M. Kashuba, School of Pharmacy, University of North Carolina, Kerr Hall, CB 7360, Chapel Hill, North Carolina 27599, USA. Email: firstname.lastname@example.org