Population Pharmacokinetics of Abacavir in HIV-infected African children
Tjokosela Tikiso (1), Andrzej Bienczak (1), Diana Gibb (2), David Burger (3), Helen McIlleron (1), Paolo Denti (1)
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa; (2) MRC Clinical Trials Unit at University College London, London, United Kingdom; (3) Department of Pharmacy, Radboud University Medical Centre, Nijmegen, the Netherlands.
Objectives: Abacavir is a potent nucleoside reverse transcriptase inhibitor (NRTI), recommended by WHO as a component of 1st line antiretroviral treatment (ART) for infants and children
Methods: Data from the studies ARROW [2] and CHAPAS-3 [3] have been collected for a pooled modelling analysis. Both studies recruited HIV-infected African children, who were dosed either once or twice daily based on weight bands as recommended by WHO[4], [5]. Samples were collected immediately before administration and at 1, 2, 3, 4, 6, 8 and 12 hours after dosing (and 24 hours for the once daily regimen), at steady state. Allometric scaling was used to account for the effect of body size [6]. Data below the limit of quantification (LLOQ) was included as LLOQ/2. NONMEM 7.3 was used to analyse PK data.
Results: Abacavir Pharmacokinetics was best described by a two-compartment model with first-order absorption with lag time and first-order elimination. The typical value of clearance was 23.1 L/h for a 20 kg child. No maturation processes were observed in this population group. There was no difference in PK parameters between once and twice daily dosing.
Conclusions: The PK estimates are consistent with literature [7]. The disposition of abacavir in children within the age range from 4 to 12 years appears to be affected only by differences in size, and not age. This model is the first step for a pooled analysis including datasets from younger children and infants < 3 months, and on different ART regimens.
References:
[1] World Health Organisation, “Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection,” November, 2015.
[2] V. Musiime, L. Kendall, S. Bakeera-Kitaka, W. B. Snowden, F. Odongo, M. Thomason, P. Musoke, K. Adkison, D. Burger, P. Mugyenyi, A. Kekitiinwa, D. M. Gibb, and a S. Walker, “Pharmacokinetics and acceptability of once- versus twice-daily lamivudine and abacavir in HIV type-1-infected Ugandan children in the ARROW Trial.,” Antivir. Ther., vol. 15, no. 8, pp. 1115–24, Jan. 2010.
[3] V. Mulenga, V. Musiime, A. Kekitiinwa, A. D. Cook, G. Abongomera, J. Kenny, C. Chabala, and G. Mirembe, “Abacavir , zidovudine , or stavudine as paediatric tablets for African HIV-infected children ( CHAPAS-3 ): an open-label , parallel-group , randomised controlled trial,” Lancet Infect. Dis., vol. 16, no. 2, pp. 169–179, 2016.
[4] World Health Organisation, “WHO recommendations on ARV medicines for treating and preventing HIV infections in younger children, technical summary. 30 Nov 2006,” November, 2006.
[5] World Health Organisation, “Antiretroviral therapy for HIV infection in infants and children: Towards universal access,” 2010.
[6] B. J. Anderson and N. H. G. Holford, “Mechanism-Based Concepts of Size and Maturity in Pharmacokinetics,” Annu. Rev. Pharmacol. Toxicol., vol. 48, no. 1, pp. 303–332, Feb. 2008.
[7] W. Zhao, C. Piana, M. Danhof, D. Burger, O. Della Pasqua, and E. Jacqz-Aigrain, “Population pharmacokinetics of abacavir in infants, toddlers and children,” Br. J. Clin. Pharmacol., vol. 75, no. 6, pp. 1525–1535, Jun. 2013.