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Antimicrobial Agents and Chemotherapy, January 2001, p. 30-37, Vol. 45, No. 1
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.1.30-37.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Pharmacokinetic and Pharmacodynamic Study of the Human Immunodeficiency Virus Protease Inhibitor Amprenavir after Multiple Oral Dosing

Brian M. Sadler,1,* Catherine Gillotin,2 Yu Lou,1 and Daniel S. Stein1

Glaxo Wellcome Inc., Research Triangle Park, North Carolina,1 and Laboratoire Glaxo Wellcome, 781 Marly-le-Roi, France2

Received 16 February 2000/Returned for modification 4 July 2000/Accepted 28 September 2000

In a dose-ranging study of amprenavir (formerly 141W94), an inhibitor of the protease enzyme of human immunodeficiency virus (HIV) type 1, single-dose and steady-state pharmacokinetic parameters were estimated from plasma samples collected on day 1 and during week 3, respectively. Amprenavir was administered on either a twice-daily (b.i.d.) or three-times-daily dosage schedule to 62 HIV-infected adults, 59 of whom had pharmacokinetic data. Log-log regression analysis (the power model) revealed that the steady-state area under the curve (AUCss) and the maximum, minimum, and average concentrations at steady state (Cmax,ss, Cmin,ss, and Cavg,ss, respectively) increased in a dose-proportional manner over the 300- to 1,200-mg dose range. Steady-state clearance was dose independent. AUCss/AUC0right-arrow infinity decreased linearly with dose and correlated significantly with treatment-associated decreases in alpha 1-acid glycoprotein. After 3 weeks, the dose of 1,200 mg b.i.d. provided a median amprenavir Cmin,ss (0.280 µg/ml) that was higher than the median in vitro 50% inhibitory concentration for clinical HIV isolates (0.023 µg/ml), even after adjustment for protein binding. The median amprenavir Cmin,ss was also greater than the estimated in vivo trough concentration calculated to yield 90% of the maximum antiviral effect (0.228 µg/ml) over 4 weeks. A pharmacodynamic analysis of the relationship between steady-state pharmacokinetic parameters and safety revealed headache and oral numbness to be the only side effects significantly associated with Cmax. The pharmacodynamic relationship defined in this study supports the use of 1,200 mg b.i.d. as the approved dose of amprenavir.

* Corresponding author. Mailing address: Division of Clinical Pharmacology, Glaxo Wellcome Inc., Research Triangle Park, NC 27709. Phone: (919) 483-1449. Fax: (919) 483-6380. E-mail: BMS44974{at}GLAXOWELLCOME.COM.

Antimicrobial Agents and Chemotherapy, January 2001, p. 30-37, Vol. 45, No. 1
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.1.30-37.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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