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Antimicrobial Agents and Chemotherapy, March 1999, p. 603-608, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Safety and Pharmacokinetics of Abacavir (1592U89) following Oral Administration of Escalating Single Doses in Human Immunodeficiency Virus Type 1-Infected Adults

Princy N. Kumar,1 Donna E. Sweet,2 James A. McDowell,3,* William Symonds,3 Yu Lou,3 Seth Hetherington,3 and Stephen LaFon3

Glaxo Wellcome Inc., Research Triangle Park, North Carolina 277093; Department of Medicine, Georgetown University Medical Center, Washington, D.C. 200071; and Department of Psychiatry, University of Kansas School of Medicine, Wichita, Kansas 672142

Received 1 July 1998/Returned for modification 26 October 1998/Accepted 26 December 1998

Abacavir (1592U89) is a nucleoside analog reverse transcriptase inhibitor that has been demonstrated to have selective activity against human immunodeficiency virus (HIV) in vitro and favorable safety profiles in mice and monkeys. A phase I study was conducted to evaluate the safety and pharmacokinetics of abacavir following oral administration of single escalating doses (100, 300, 600, 900, and 1,200 mg) to HIV-infected adults. In this double-blind, placebo-controlled study, subjects with baseline CD4+ cell counts ranging from <50 to 713 cells per mm3 (median, 315 cells per mm3) were randomly assigned to receive abacavir (n = 12) or placebo (n = 6). The bioavailability of the caplet formulation relative to that of the oral solution was also assessed with the 300-mg dose. Abacavir was well tolerated by all subjects; mild to moderate asthenia, abdominal pain, headache, diarrhea, and dyspepsia were the most frequently reported adverse events, and these were not dose related. No significant clinical or laboratory abnormalities were observed throughout the study. All doses resulted in mean abacavir concentrations in plasma that exceeded the mean 50% inhibitory concentration (IC50) for clinical HIV isolates in vitro (0.07 µg/ml) for almost 3 h. Abacavir was rapidly absorbed following oral administration, with the time to the peak concentration in plasma occurring at 1.0 to 1.7 h postdosing. Mean maximum concentrations in plasma (Cmax) and the area under the plasma concentration-time curve from time zero to infinity (AUC0-infinity ) increased slightly more than proportionally from 100 to 600 mg (from 0.6 to 4.7 µg/ml for Cmax; from 1.0 to 15.7 µg · h/ml for AUC0-infinity ) but increased proportionally from 600 to 1,200 mg (from 4.7 to 9.6 µg/ml for Cmax; from 15.7 to 32.8 µg · h/ml for AUC0-infinity ). The elimination of abacavir from plasma was rapid, with an apparent elimination half-life of 0.9 to 1.7 h. Abacavir was well absorbed, with a relative bioavailability of the caplet formulation of 96% versus that of an oral solution (drug substance in water). In conclusion, this study showed that abacavir is safe and is well tolerated by HIV-infected subjects and demonstrated predictable pharmacokinetic characteristics when it was administered as single oral doses ranging from 100 to 1,200 mg.

* Corresponding author. Mailing address: Worldwide Clinical Pharmacology, Glaxo Wellcome Inc., Five Moore Drive, Research Triangle Park, NC 27709. Phone: (919) 483-1102. Fax: (919) 483-6380. E-mail: JAM36914{at}glaxowellcome.com.

Antimicrobial Agents and Chemotherapy, March 1999, p. 603-608, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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