Pharmacokinetic interaction between amprenavir and clarithromycin in healthy male volunteers

The P450 enzyme, CYP3A4, extensively metabolizes both amprenavir and clarit hromycin, To determine if an interaction exists when these two drugs are co administered, the pharmacokinetics of amprenavir and clarithromycin were in vestigated in healthy adult male volunteers. This was a Phase I, open-label , randomized, balanced, multiple-dose, three-period crossover study. Fourte en subjects received the following three regimens: amprenavir, 1,200 mg twi ce daily over 4 days (seven doses); clarithromycin, 500 mg twice daily over 4 days (seven doses); and the combination of the above regimens over 4 day s (seven doses of each drug). Twelve subjects completed all treatments and the follow-up period. The erythromycin breath test (ERMBT) was administered at baseline, 2 h after the final dose of each of the three regimens and at the first follow-up visit. Coadministration of clarithromycin and amprenav ir significantly increased the mean amprenavir AUC(ss), C-max,C-ss, and C-m in,C-ss by 18, 15, and 39%, respectively. Amprenavir had no significant eff ect on the AUG,, of clarithromycin, but the median T-max,T-ss for clarithro mycin increased by 2.0 h, renal clearance increased by 34%, and the AUC(ss) for 14-(R)-hydroxyclarithromycin decreased by 35% when it was given with a mprenavir. Amprenavir and clarithromycin reduced the ERMBT result by 85 and 67%, respectively, and by 87% when the two drugs were coadministered. The baseline ERMBT value did not correlate with clearance of amprenavir or clar ithromycin. A pharmacokinetic interaction occurs when amprenavir and clarit hromycin are coadministered, but the effects are not likely to be clinicall y important, and coadministration does not require a dosage adjustment for either drug.