title: Pharmacokinetics and acceptability of once- versus twice-daily lamivudine and abacavir in HIV type-1-infected Ugandan children in the ARROW Trial.
abstract: BACKGROUND
  No data on once-daily dosing of nucleoside analogues in African children currently exist. We compared the pharmacokinetics (PK) of once- versus twice-daily lamivudine and abacavir treatment using the World Health Organization recommended weight band dosing of scored adult tablets.
  
  
  METHODS
  HIV type-1 (HIV-1)-infected Ugandan children aged 3-12 years receiving antiretroviral therapy that included lamivudine and abacavir twice daily (total 150+300 mg, 225+450 mg and 225/300+600 mg daily for 12-<20, 20-<25 and ≥25 kg, respectively) were enrolled in a crossover study. Plasma PK sampling (at 0, 1, 2, 4, 6, 8 and 12 h after observed morning intake) was performed for the twice-daily regimen at steady-state. Children were then switched to once-daily treatment with PK sampling repeated 4 weeks later (with an additional 24 h sample). Acceptability questionnaires were completed at both time points. Daily area under the curve (AUC(0-24)) and maximum concentrations (C(max)) were compared by geometric mean ratios (GMRs).
  
  
  RESULTS
  A total of 41 HIV-1-infected children (median age of 7 years) and n=23, n=14 and n=4 in 12-<20, 20-<25 and ≥25 kg weight bands, respectively, were enrolled. Mean AUC(0-24) was 13.0 and 12.0 mg•h/l for once- and twice-daily lamivudine (GMR 1.09, 90% confidence intervals [CI] 0.98-1.20) and 15.3 and 15.6 mg•h/l for once- and twice-daily abacavir (GMR 0.98, 90% CI 0.89-1.08), respectively, with no difference in 3-6 versus 7-12 year olds. C(max) was 76% (lamivudine) and 64% (abacavir) higher on once-daily regimens. For both children and caregivers, once-daily dosing of lamivudine plus abacavir was highly acceptable and strongly preferred over twice-daily.
  
  
  CONCLUSIONS
  In children aged 3-12 years, AUC(0-24) of lamivudine and abacavir were bioequivalent on once- and twice-daily regimens. Once-daily dosing of abacavir and lamivudine could provide an alternative dosing strategy for HIV-1-infected children, with high acceptability and strong preference suggesting the potential for improved adherence.
authors.affiliation: Joint Clinical Research Centre, Kampala, Uganda.
authors.forename: Victor
authors.initials: V
authors.lastname: Musiime
authors.forename: Lindsay
authors.initials: L
authors.lastname: Kendall
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bakeera-Kitaka
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Snowden
authors.forename: Florence
authors.initials: F
authors.lastname: Odongo
authors.forename: Margaret
authors.initials: M
authors.lastname: Thomason
authors.forename: Philippa
authors.initials: P
authors.lastname: Musoke
authors.forename: Kimberly
authors.initials: K
authors.lastname: Adkison
authors.forename: David
authors.initials: D
authors.lastname: Burger
authors.forename: Peter
authors.initials: P
authors.lastname: Mugyenyi
authors.forename: Adeodata
authors.initials: A
authors.lastname: Kekitiinwa
authors.forename: Diana M
authors.initials: DM
authors.lastname: Gibb
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D016001:Confidence Intervals; D018592:Cross-Over Studies; D003521:Cyclopropanes; D015224:Dideoxynucleosides / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D014454:Uganda; D000099227:Abacavir
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D015224:Dideoxynucleosides; D019259:Lamivudine; D000099227:Abacavir; C098320:efavirenz