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Antimicrobial Agents and Chemotherapy, December 2007, p. 4297-4302, Vol. 51, No. 12
0066-4804/07/$08.00+0     doi:10.1128/AAC.00332-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Population Pharmacokinetics of Lamivudine in Human Immunodeficiency Virus-Exposed and -Infected Infants

Adriana H. Tremoulet,^1* Edmund V. Capparelli,¹ Parul Patel,^1, Edward P. Acosta,² Katherine Luzuriaga,³ Yvonne Bryson,⁴ Diane Wara,⁵ Carmen Zorrilla,⁶ Diane Holland,¹ Mark Mirochnick,⁷ and the Pediatric AIDS Clinical Trials Group

Pediatric Pharmacology Research Unit, University of California San Diego, San Diego,¹ Pediatric Infectious Disease, University of California Los Angeles, Los Angeles,⁴ Pediatrics, University of California San Francisco, San Francisco, California,⁵ Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, Alabama,² Pediatrics, University of Massachusetts, Worcester,³ Neonatology, Boston University School of Medicine/Boston Medical Center, Boston, Massachusetts,⁷ Obstetrics/Gynecology, University of Puerto Rico School of Medicine, San Juan, Puerto Rico⁶

Received 11 March 2007/ Returned for modification 27 April 2007/ Accepted 11 September 2007

This study aimed to determine lamivudine disposition in infants and to construct an appropriate dose adjustment for age, given the widespread use of lamivudine for both the prevention of mother-to-child transmission of human immunodeficiency virus (HIV) and the treatment of HIV-infected infants. Using a pooled-population approach, the pharmacokinetics of lamivudine in HIV-exposed or -infected infants from four Pediatric AIDS Clinical Trials Group studies were assessed. Ninety-nine infants provided 559 plasma samples for measurement of lamivudine concentrations. All infants received combination antiretroviral therapy including lamivudine dosed at 2 mg/kg of body weight every 12 h (q12h) for the first 4 to 6 weeks of life and at 4 mg/kg q12h thereafter. Lamivudine's apparent clearance was 0.25 liter/h/kg at birth, doubling by 28 days. In the final model, age and weight were the only significant covariates for lamivudine clearance. While lamivudine is predominantly renally eliminated, the serum creatinine level was not an independent covariate in the final model, possibly because it was confounded by age. Inclusion of interoccasion variability for bioavailability improved the individual subject clearance prediction over the age range studies. Simulations based on the final model predicted that by the age of 4 weeks, 90% of infant lamivudine concentrations with the standard 2 mg/kg dose of lamivudine fell below the adult median concentration. This population pharmacokinetic analysis affirms that adjusting the dose of lamivudine from 2 mg/kg to 4 mg/kg q12 h at the age of 4 weeks for infants with normal maturation of renal function will provide optimal lamivudine exposure, potentially contributing to more successful therapy.

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* Corresponding author. Mailing address: Division of Pharmacology and Drug Discovery, Pediatric Pharmacology Research Unit (PPRU), University of California San Diego, 200 West Arbor Drive, MC 8214, San Diego, CA 92103-8214. Phone: (619) 497-2102. Fax: (619) 497-2101. E-mail: atremoul{at}ucsd.edu

Published ahead of print on 24 September 2007.

Present address: GlaxoSmithKline Pharmaceuticals, Research Triangle Park, North Carolina.

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Antimicrobial Agents and Chemotherapy, December 2007, p. 4297-4302, Vol. 51, No. 12
0066-4804/07/$08.00+0     doi:10.1128/AAC.00332-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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