Combining Fosamprenavir with Lopinavir/Ritonavir Substantially Reduces Amprenavir and Lopinavir Exposure: ACTG Protocol A5143 Results

The aim of the current study (ACTG protocol A5143) was to evaluate fosamprenavir(Lexiva)/ lopinavir/ritonavir (RTV)[Kaletra], fosamprenavir/RTV, or LPV/RTV in antiretroviral treatment-experienced patients. Lack of drug interaction data prompted a pharmacokinetic substudy to minimize subject risk.

This was a multicenter, open-label, selectively randomized, steady-state pharmacokinetic study in HIV-infected subjects.

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) (mug/ml) were, respectively, 42.7 mug x h/ml and 2.4 mug/ml in arm B and 17.4 mug x h/ml  and 0.9 mug/ml in arm C: geometric mean ratio (GMR) arm C:B was 0.36 and 0.31, respectively (P </= 0.0001).

Lopinavir AUC0-12 h and C12 h were, respectively, 95.3 mug x h/ml and 6.3 mug/ml in arm A and 54.4 mug x h/ml and 3.0 mug/ml in arm C: GMR arm C:A of 0.52 and 0.39, respectively (P </= 0.0008).

Ritonavir exposure was not significantly different between arms.

The authors conclude, “APV and LPV exposures are significantly reduced using LPV/RTV/fosamprenavir, possibly increasing the risk of virologic failure. Consequently, [ACTG] A5143 was closed to enrollment.”

From the School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina SDAC/Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts Division of Clinical Pharmacology, University of Alabama, Birmingham, Alabama Division of Infectious Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania HIV Research Branch, TRP, DAIDS, NIAID, NIH, Bethesda, Maryland Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland GlaxoSmithKline, Research Triangle Park, North Carolina Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.

01/31/05

Reference
A D Kashuba and others. Combining fosamprenavir with lopinavir/ritonavir substantially reduces amprenavir and lopinavir exposure: ACTG protocol A5143 results. AIDS 19(2): 145-152. January 28, 2005.