Amprenavir and lopinavir pharmacokinetics following coadministration of amprenavir or fosamprenavir with lopinavir/ritonavir, with or without efavirenz

Background: Amprenavir (APV), fosamprenavir (FPV), lopinavir (LPV), ritonavir (RTV) and efavirenz (EFV) are to varying degrees substrates, inducers and inhibitors of CYP3A4. Coadministration of these drugs might result in complex pharmacokinetic drug-drug interactions. Methods: Two prospective, open-label, non-randomized studies evaluated APV and LPV steady-state pharmacokinetics in HIV-infected patients on APV 750 mg twice daily + LPV/RTV 533/133 mg twice daily with EFV (n=7) or without EFV (n=12) + background nucleosides (Study 1) and after switching FPV 1,400 mg twice daily for APV (n=10) (Study 2). Results: In Study 1 EFV and non-EFV groups did not differ in APV minimum plasma concentration (C_min; 1.10 versus 1.06 μg/ml, P=0.89), area under the concentration-time curve (AUC; 17.46 versus 24.34 μg•h/ml, P=0.22) or maximum concentration (C_max; 2.61 versus 4.33 μg/ml, P=0.08); for LPV there was no difference in C_min (median: 3.66 versus 6.18 μg/ml, P=0.20), AUC (81.84 versus 93.75 μg•h/ml, P=0.37) or C_max (10.36 versus 10.93 μg/ml, P=0.61). In Study 2, after switching from APV to FPV, APV C_min increased by 58% (0.83 versus 1.30 μg/ml, P=0.0001), AUC by 76% (19.41 versus 34.24 μg•h/ml, P=0.0001), and C_max by 75% (3.50 versus 6.14, P=0.001). Compared with historical controls, LPV and RTV pharmacokinetics were not changed. All treatment regimens were well tolerated. Seven of eight completers (88%) maintained HIV-1 RNA <400 copies/ml 12 weeks after the switch (1 lost to follow up). Conclusions: EFV did not appear to significantly alter APV and LPV pharmacokinetic parameters in HIV-infected patients taking APV 750 mg twice daily + LPV 533/133 mg twice daily. Switching FPV 1,400 mg twice daily for APV 750 mg twice daily resulted in an increase in APV C_min, AUC, and C_max without changing LPV or RTV pharmacokinetics or overall tolerability.