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

Angela D.M. Kashuba, Camlin Tierney, Gerald F. Downey, Edward P. Acosta, Emanuel N. Vergis, Karin Klingman, John W. Mellors, Susan H. Eshleman, Trevor R. Scott, Ann C. Collier

Research output: Contribution to journalArticle

Abstract

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 (AUC 0-12 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 C 12 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.

Original languageEnglish (US)
Pages (from-to)145-152
Number of pages8
JournalAIDS
Volume19
Issue number2
DOIs
StatePublished - Jan 28 2005

Keywords

  • Amprenavir
  • Drug interactions
  • Fosamprenavir
  • Lopinavir
  • Pharmacokinetics
  • Protease inhibitors
  • Ritonavir
  • Salvage treatment

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Kashuba, A. D. M., Tierney, C., Downey, G. F., Acosta, E. P., Vergis, E. N., Klingman, K., Mellors, J. W., Eshleman, S. H., Scott, T. R., & Collier, A. C. (2005). Combining fosamprenavir with lopinavir/ritonavir substantially reduces amprenavir and lopinavir exposure: ACTG protocol A5143 results. AIDS, 19(2), 145-152. https://doi.org/10.1097/00002030-200501280-00006