Interaction between amprenavir and lopinavir thwarts triple PI salvage

Several studies presented at ICAAC drove home the important lesson that we cannot do without careful testing of novel antiretroviral regimens. Drug interactions on many levels are complex and unpredictable, and the “one from column A and two from column B” approach cannot be depended upon.

Adult ACTG Protocol A5143 was a carefully designed study to test the antiviral effect of combining GW433908 (Fosamprenavir or “908”, the better absorbed prodrug of amprenavir nearing FDA approval) with Lopinavir/Ritonavir (LPV/R) in patients with PI resistance. PIs were given in combination with tenofovir plus one or two other nucleoside reverse transcriptase inhibitors (NRTIs).

Kashuba presented the findings of an open-label, steady-state PK substudy, performed in the absence of clear PK data to minimise subject risk. A planned independent interim review was performed after the first eight subjects were randomised to each arm. Surprisingly, both APV and LPV exposures were substantially lower in the double PI arm (LPV 12 hr AUC 92.97 ug/hr/mL (60.3-119.3) versus 48.05 ug/hr/mL (23.5-112.2) triple PI arm, and APV 12 hr AUC double PI 41.77 ug/hr/mL (33.1-55.1) versus 15.2 ug/hr/mL (4.6-41.3) triple PI). Ritonavir exposure was similar in all arms and tenofovir did not account for the lowered PI exposure. This study was closed upon this analysis, and this combination of PIs should be avoided until further data is available.

Arm A (n=8): LPV/R 3caps BID Arm B (n=8): 908/R 700mg/100mg BID Arm C (n=17); LPV/R 3caps BID + 908 700mg BID.

Kashuba A, Tierney C, Downey G et al. Combining GW433908 (fosamprenavir; 908) with lopinavir/ritonavir (LPV/R) in HIV-1 infected adults results in substantial reductions in amprenavir (APV) and LPV concentrations: pharmacokinetic (PK) results from adult ACTG protocol A5143. 43rd ICAAC, September, 2003; Abstract H-855a.