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Antimicrobial Agents and Chemotherapy, January 2005, p. 336-341, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.336-341.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Single-Dose Safety and Pharmacokinetics of Amprenavir (141W94), a Human Immunodeficiency Virus Type 1 (HIV-1) Protease Inhibitor, in HIV-Infected Children

Ram Yogev,1* Andrea Kovacs,2 Ellen G. Chadwick,1 James D. Homans,2 Yu Lou,3 and William T. Symonds3

Children's Memorial Hospital, Division of Infectious Diseases, Chicago, Illinois,1 Maternal, Child, and Adolescent Center for Infectious Diseases and Virology, Los Angeles County and University of Southern California Medical Center, University of Southern California Keck School of Medicine, Los Angeles, California,2 Glaxo Wellcome, Inc., Research Triangle Park, North Carolina3

Received 23 April 2004/ Returned for modification 23 June 2004/ Accepted 8 September 2004

A phase I, open-label, dose-escalating trial was conducted to evaluate the safety, tolerability, and pharmacokinetics of single, oral doses of amprenavir (141W94), a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) protease, in 20 HIV-infected children 4 to 12 years of age. The doses of amprenavir evaluated, 5, 10, 15, and 20 mg/kg of body weight, were comparable to those evaluated in adult phase I and II studies. The most common clinical adverse event associated with amprenavir, administered as soft gelatin capsules, was nausea. Amprenavir was rapidly absorbed, with a mean time to maximum concentration (Tmax) occurring 0.95 to 1.58 h after dosing. The area under the concentration-time curve (AUC0->{infty}) was dose proportional, and the mean maximum plasma concentration (Cmax) increased linearly in a less than dose-proportional manner. Amprenavir was eliminated relatively slowly, with a mean terminal-phase half-life (t1/2) of 6.17 to 8.28 h. The t1/2, apparent total clearance, and apparent volume of distribution during the elimination phase were dose independent. Considerable interpatient variability was seen for all pharmacokinetic parameters of amprenavir. The results of this study suggest that 20 mg of amprenavir/kg administered twice a day should be used in future pediatric studies.

* Corresponding author. Mailing address: Division of Infectious Diseases, Children's Memorial Hospital, 2300 Children's Plaza, Box 155, Chicago, IL 60614. Phone: (773) 880-4757. Fax: (773) 880-3208. E-mail: ryogev{at}childrensmemorial.org.

Antimicrobial Agents and Chemotherapy, January 2005, p. 336-341, Vol. 49, No. 1
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.1.336-341.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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