Background:  Amprenavir (APV) and lopinavir (LPV) exposure are significantly reduced when 908 and LPV/RTV are combined (Adult ACTG Protocol A5143, ICAAC 2003). Since lower drug exposure may put patients at risk of virologic failure, enrollment in A5143 was ended. We determined whether physical separation of 908 and LPV/RTV doses could overcome this interaction.

Methods:  A prospective, non-blinded, randomized, 3 treatment, 3-way crossover study in seronegative subjects was designed. To ensure maximal CYP450 induction, subjects were given 908+LPV/RTV 700 mg+400/100 mg twice daily simultaneously for 10 days, then randomized to receive 3 treatments (7 days each) followed by pharmacokinetic sampling: 908+LPV/RTV 700 mg+400/100 mg twice daily simultaneously (0HR); 908/RTV 700 mg/100 mg twice daily + LPV/RTV 400/100 mg twice daily, separated by 4 hours (4HR); 908/RTV 1400/200 QAM+LPV/RTV 800/200 QPM (12HR). Samples were analyzed for 908, APV, and LPV by HPLC/MS/MS. Noncompartmental pharmacokinetic parameters were calculated by WinNonLin and analyzed using a mixed model with compound covariance (p <0.02*).

Results:  Of 11 subjects, 10 were male, 9 Caucasian, with median age 22 years, and body mass index of 24 kg/m². The geometric mean pharmacokinetic parameters are summarized in the table below.

Compared with the 0HR treatment, a significant overall decrease in APV exposure, and a significant increase in LPV exposures were seen with 4HR and 12HR treatments. RTV exposures increased with the 4- and 12-hour separation as expected with the additional RTV dosing.

Conclusions:  Similar to A5143, APV and LPV were substantially reduced with the combination of 908+LPV/RTV. Separating by 4 or 12 hours did not improve APV exposure (as compared to 0HR), but corrected LPV exposure (although increased RTV doses may have contributed). Further investigation is needed to determine an optimal dosing strategy when combining 908 and LPV/RTV.

Keywords: fosamprenavir; lopinavir; pharmacokinetics