Clinical pharmacology and pharmacokinetics of amprenavir

To review the pharmacokinetics, pharmacodynamics, drug interactions, and dosage and administration information of amprenavir.

An extensive review of the literature (MEDLINE search from 1994 to April 2001) relating to the clinical pharmacology of the HIV protease inhibitors was conducted. Meeting abstracts or full presentations and data submitted to the Food and Drug Administration were also reviewed.

The data on pharmacokinetics, pharmacodynamics, drug interactions, and drug resistance were obtained from in vitro studies and open-label and controlled clinical trials.

Like all HIV protease inhibitors, amprenavir interrupts the maturation phase of the HIV replicative cycle by forming an inhibitor-enzyme complex, which prevents HIV protease from binding with its normal substrates (biologically inactive viral polyproteins). Amprenavir has an enzyme inhibition constant (Ki = 0.6 nM) that falls within the Ki range of the other protease inhibitors. Amprenavir's in vitro 50% inhibitory concentration (IC50) against wild-type clinical HIV isolates is 14.6 +/- 12.5 ng/mL (mean +/- SD). Pharmacodynamic modeling indicates that, as is the case with other protease inhibitors, the concentration-response curve for amprenavir plateaus at amprenavir trough values above the IC50 for these isolates. This exposure-activity relationship, plus such favorable pharmacokinetic parameters as a long terminal elimination half-life (7-10 h), makes amprenavir an attractive drug of choice when considering potent antiretrovirals. The higher trough exposure obtained with amprenavir coadministered with ritonavir may allow effective treatment of patients with decreased susceptibility viral isolates and once-daily dosing. Amprenavir has been approved for adults and children; the recommended capsule doses are 1200 mg twice daily for adults and 20 mg/kg twice daily or 15 mg/kg 3 times daily for children < 13 years of age or adolescents < 50 kg. The recommended dose for amprenavir oral solution is 1.5 mL/kg twice daily or 1.1 mL/kg 3 times daily.

The clinical pharmacology, exposure-activity relationship, and drug resistance profile of amprenavir support the use of this potent HIV protease inhibitor in combination antiretroviral regimens, especially for persons who have experienced virologic failure while on protease inhibitor-containing regimens.