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Pharmacokinetic Study of Once- vs Twice-daily Abacavir and Lamivudine as Part of Combination ART in Children with HIV-1 Infection aged 3 to 36 months: Pediatric European Network for Treatment of AIDS 15 and ANRS 133
Evelyne Jacqz-Aigrain*1, L Farrelly2, A Compagnucci3, L Harrison2, W Zhao1, D Hamadache4, S Welch5, U Wintergerst6, G Firtion7, D Burger8,9, and Penta 15 Trial Steering Committee
1Hopital Robert Debré, Paris, France; 2Med Res Council, London, UK; 3INSERM SC10, Paris, France; 4Imperial Coll Hlthcare NHS Trust, London, UK; 5Birmingham Heartlands Hosp, UK; 6Universitats-kinderliniken, Munich, Germany; 7Hosp Port-Royal, Paris, France; 8University Medical Centre Nijmengen, The Netherlands; and 9Nijmegen University Center for Infectiuos Diseases (NUCI), Nijmegen, The Nederlands
Background: In the treatment of HIV-1-infected
children, one challenge is to reduce barriers to good adherence to medication. In
adults every 24 hours (once daily) dosing of abacavir (ABC) and lamivudine
(3TC) results in equivalent AUC and efficacy to every 12 hours (twice daily)
dosing; however there are insufficient data in children. We conducted PENTA
(Pediatric European Network for Treatment of AIDS) 15, a single-arm, open-label,
crossover, multi-center pharmacokinetic study to compare pharmacokinetic parameters
of every 12 hours and every 24 hours dosing for ABC and 3TC in HIV-1-infected children
aged 3 to 36 months, and to evaluate differences between 3 age groups (≥3
to 12, ≥12 to <24 and ≥24 to <36 months).
Methods: Children who had taken ABC every 12 hours
with or without 3TC every 12 hours for at least 12 weeks as part of combination
ART, with stable CD4 percentage and HIV-1 RNA (viral load) <20,000 copies/mL
were enrolled. Intensive plasma pharmacokinetic sampling was performed while
children were on every 12 hours ABC (8 mg/kg) ±
3TC (4 mg/kg), after which children changed to every 24 hours ABC (16 mg/kg) ± 3TC (8 mg/kg) and pharmacokinetic sampling
was repeated 4 weeks later. AUC0-24 and Cmax were
calculated using non-compartment methods, and every 24- and every 12-hour
dosing compared using geometric mean ratios (GMR) of within-patient ratios. An
overall GMR with 90% confidence interval (CI) falling within 0.80 to 1.25 was
considered bioequivalent for AUC0-24.
Results: We enrolled 18 children (4, 6, and 8 in ≥3
to 12, ≥12 to <24, and ≥24 to <36 month age groups; 10 boys
and 8 girls; median (range) weight 11 (7 to 16) kg) and provided evaluable pharmacokinetic
data on ABC (n = 18) and 3TC (n = 17). The GMR of AUC0-24, every 24 hours
vs every 12 hours, was 1.07 (0.92 to 1.23) and 0.91 (0.79 to 1.06) for ABC and
3TC, respectively. Varied GMR of ABC AUC0-24 were observed among age
groups, likely due to the small sample size per group. As expected, Cmax almost
doubled on every 24 hours than every 12 hours: GMR (95%CI) 2.04 (1.67 to 2.50)
and 1.78 (1.47 to 2.16) for ABC and 3TC. respectively. At both baseline and
week 4, 16 of the 18 (89%) children had viral load <400 copies/mL.
Conclusions: In HIV-infected children aged 3 to 36
months, bioequivalence was demonstrated on AUC0-24 between every 12-hour
and every 24-hour dosing of ABC and 3TC. The geometric means of AUC0-24
and Cmax on 12- and 24-hour dosing were comparable to data in
children aged 2 to 13 years (PENTA 13) and adult data, and suggest that every 24-hour
dosing of ABC and 3TC may be an option for children. The children continue to
be followed to evaluate the efficacy and safety of every 24-hour dosing to 48
weeks.
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