Pharmacokinetic interaction between amprenavir and delavirdine: Evidence of induced clearance by amprenavir

Objective: Our objective was to determine the pharmacokinetic interaction between amprenavir and delavirdine. Methods: Healthy volunteers participated in 2 open-label, 3-period, longitudinal studies. In the first study, 12 volunteers received a single dose of amprenavir, 1200 mg, alone and then again after 7 days of delavirdine, 600 mg twice daily. In the second study, another 12 subjects received amprenavir, 1200 mg twice daily, alone for 7 days. After a 7-day washout period, subjects received delavirdine, 600 mg twice daily, alone for 7 days followed by a combination with amprenavir, 600 mg twice daily, for another 7 days. Amprenavir and delavirdine pharmacokinetics when given alone and in combination were compared. Results: All 12 subjects completed the first study, and 11 subjects completed the second study. Delavirdine significantly increased the area under the curve (AUC) of single-dose amprenavir by 4-fold (P=.0001). Amprenavir, 600 mg twice daily, with delavirdine produced higher levels of amprenavir AUC, minimum concentration (C-min), and maximum concentration (C-max), by 30%, 90%, and 18%, respectively, than those of amprenavir, 1200 mg twice daily, alone (P<.05). In contrast, amprenavir decreased delavirdine AUC, C-min, and C-max by 50%, 70%, and 30%, respectively (P<.005). Conclusions: Because of the inhibitory effect of delavirdine on the cytochrome P450 3A4-mediated metabolism of amprenavir, the combination of a reduced dose of amprenavir, 600 mg twice daily, with delavirdine resulted in a higher amprenavir exposure than the standard dose of amprenavir, 1200 mg twice daily. However, amprenavir induced the clearance of delavirdine, resulting in a reduction in delavirdine exposure. Further clinical studies are needed to determine the appropriate dosing regimens for delavirdine and amprenavir during coadministration.