title: Pharmacokinetics of antiretroviral drug varies with formulation in the target population of children with HIV-1.
abstract: The bioequivalence of formulations is usually evaluated in healthy adult volunteers. In our study in 19 HIV-1-infected Ugandan children (1.8-4 years of age, weight 12 to <15 kg) receiving zidovudine, lamivudine, and abacavir solutions twice a day for ≥24 weeks, the use of scored tablets allowed comparison of plasma pharmacokinetics of oral solutions vs. tablets. Samples were collected 0, 1, 2, 4, 6, 8, and 12 h after each child's last morning dose of oral solution before changing to scored tablets of Combivir (coformulated zidovudine + lamivudine) and abacavir; this was repeated 4 weeks later. Dose-normalized area under curve (AUC)(0-12) and peak concentration (C(max)) for the tablet formulation were bioequivalent with those of the oral solution with respect to zidovudine and abacavir (e.g., dose-normalized geometric mean ratio (dnGMR) (tablet:solution) for zidovudine and abacavir AUC(0-12) were 1.01 (90% confidence interval (CI) 0.87-1.18) and 0.96 (0.83-1.12), respectively). However, lamivudine exposure was ~55% higher with the tablet formulation (AUC(0-12) dnGMR = 1.58 (1.37-1.81), C(max) dnGMR = 1.55 (1.33-1.81)). Although the clinical relevance of this finding is unclear, it highlights the impact of the formulation and the importance of conducting bioequivalence studies in target pediatric populations.
authors.affiliation: Paediatric Infectious Diseases Clinic, Baylor-Uganda, Mulago Hospital, Kampala, Uganda.
authors.forename: P
authors.initials: P
authors.lastname: Kasirye
authors.forename: L
authors.initials: L
authors.lastname: Kendall
authors.forename: K K
authors.initials: KK
authors.lastname: Adkison
authors.forename: C
authors.initials: C
authors.lastname: Tumusiime
authors.forename: M
authors.initials: M
authors.lastname: Ssenyonga
authors.forename: S
authors.initials: S
authors.lastname: Bakeera-Kitaka
authors.forename: P
authors.initials: P
authors.lastname: Nahirya-Ntege
authors.forename: T
authors.initials: T
authors.lastname: Mhute
authors.forename: A
authors.initials: A
authors.lastname: Kekitiinwa
authors.forename: W
authors.initials: W
authors.lastname: Snowden
authors.forename: D M
authors.initials: DM
authors.lastname: Burger
authors.forename: D M
authors.initials: DM
authors.lastname: Gibb
authors.forename: A S
authors.initials: AS
authors.lastname: Walker
mesh_terms: D000284:Administration, Oral; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002626:Chemistry, Pharmaceutical / Q000706:statistics & numerical data*; D002675:Child, Preschool; D015224:Dideoxynucleosides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007223:Infant; D019259:Lamivudine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D012996:Solutions / Q000493:pharmacokinetics; D013607:Tablets / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency; D015215:Zidovudine / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000099227:Abacavir
chemical_list: D018501:Antirheumatic Agents; D015224:Dideoxynucleosides; D004338:Drug Combinations; D019259:Lamivudine; D012996:Solutions; D013607:Tablets; D015215:Zidovudine; D000099227:Abacavir; C109078:lamivudine, zidovudine drug combination