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Combining fosamprenavir with lopinavir/ritonavir substantially reduces amprenavir and lopinavir exposure: ACTG protocol A5143 results

Kashuba, Angela DMa; Tierney, Camlinb; Downey, Gerald Fb; Acosta, Edward Pc; Vergis, Emanuel Nd; Klingman, Karine; Mellors, John Wd; Eshleman, Susan Hf; Scott, Trevor Rg; Collier, Ann Ch

Clinical Science

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: akashuba@unc.edu

© 2005 Lippincott Williams & Wilkins, Inc.