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.
Tran
Jonathan Q
JQ
Agouron Pharmaceuticals, Inc., A Pfizer Company, La Jolla, California, USA. jonathan.tran@pfizer.com
Petersen
Carolyn
C
Garrett
May
M
Hee
Brian
B
Kerr
Bradley M
BM
D000284:Administration, Oral; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D023241:Antiretroviral Therapy, Highly Active; D019540:Area Under Curve; D002219:Carbamates; D020008:Delavirdine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005663:Furans; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D012016:Reference Values; D013449:Sulfonamides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D019380:Anti-HIV Agents; D002219:Carbamates; D005663:Furans; D013449:Sulfonamides; C095108:amprenavir; D020008:Delavirdine