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Antimicrobial Agents and Chemotherapy, March 1999, p. 609-615, Vol. 43, No. 3
Department of Infectious Diseases, St. Jude
Children's Research Hospital, Memphis, Tennessee
38105-27941; Glaxo Wellcome Inc.,
Research Triangle Park, North Carolina 277092;
Department of Pediatrics, Baylor College of Medicine and
Texas Children's Hospital, Houston, Texas
770303; and Department of
Pediatrics, Children's Memorial Hospital, Chicago, Illinois
606144
Received 1 July 1998/Returned for modification 26 October
1998/Accepted 26 December 1998
Abacavir (formerly 1592U89) is a potent 2'-deoxyguanosine analog
reverse transcriptase inhibitor that has been demonstrated to have a
favorable safety profile in initial clinical trials with adults with
human immunodeficiency virus (HIV) type 1 infection. A phase I study
was conducted to evaluate the pharmacokinetics and safety of abacavir
following the administration of two single oral doses (4 and 8 mg/kg of
body weight) to 22 HIV-infected children ages 3 months to 13 years.
Plasma was collected for analysis at predose and at 0.5, 1, 1.5, 2, 2.5, 3, 5, and 8 h after the administration of each dose. Plasma
abacavir concentrations were determined by high-performance liquid
chromatography, and data were analyzed by noncompartmental methods.
Abacavir was well tolerated by all subjects. The single
abacavir-related adverse event was rash, which occurred in 2 of 22 subjects. After administration of the oral solution, abacavir was
rapidly absorbed, with the time to the peak concentration in plasma
occurring within 1.5 h postdosing. Pharmacokinetic parameter
estimates were comparable among the different age groups for each dose
level. The mean maximum concentration in plasma
(Cmax) and the mean area under the curve from
time zero to infinity (AUC0-
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Safety and Single-Dose Pharmacokinetics of Abacavir (1592U89) in
Human Immunodeficiency Virus Type 1-Infected Children
) increased by 16 and 45%
more than predicted, respectively, as the abacavir dose was doubled from 4 to 8 mg/kg (Cmax increased from 1.69 to
3.94 µg/ml, and AUC0- increased from 2.82 to 8.09 µg · h/ml). Abacavir was rapidly eliminated, with a mean
elimination half-life of 0.98 to 1.13 h. The mean apparent
clearance from plasma decreased from 27.35 to 18.88 ml/min/kg as the
dose increased. Neither body surface area nor creatinine clearance were
correlated with pharmacokinetic estimates at either dose. The extent of
exposure to abacavir appears to be slightly lower in children than in
adults, with the comparable unit doses being based on body weight. In
conclusion, this study showed that abacavir is safe and well tolerated
in children when it is administered as a single oral dose of 4 or 8 mg/kg.
*
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. 609-615, Vol. 43, No. 3
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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