Background: Although zidovudine (ZDV) is widely used in children, pharmacokinetic (PK) data, particularly on the most commonly used twice daily regimens and WHO-recommended weight-band dosing, are scarce.
Methods: Two intensive PK crossover studies were undertaken in HIV-1-infected Ugandan children in the ARROW trial with samples 0, 1, 2, 4, 6, 8, and 12 hours after observed intake of ZDV at steady-state (with other ART). Dosing followed WHO guidelines: 100-120 mg, am and pm, ZDV as syrups for 10-12 or 12-15 kg; 150-300 mg, am and pm, ZDV as Combivir (CBV) tablets for 12-20 or 30-35 kg, and 300 mg am, 150 mg pm for 20-30 kg. The original PK studies had compared twice-daily syrups vs twice daily tablets, and twice- to once-daily lamivudine+abacavir (some children also took ZDV at the first PK day). In exploratory analyses, associations between ZDV AUC0-12 and sex, age, dose (mg m2), weight- and height-for-age, and formulation were investigated using multivariable mixed models allowing for multiple AUC0-12 per child.
Results: 45 children had 1 or 2 ZDV AUC0-12: 17 (3-12 years) once on tablets and 28 (1-4 years) once on syrups and once on tablets 4 weeks later. 8 children were on tablets in the 20-30 kg split dose weight-band and 17 (38%) were boys. Median (IQR) age at the first PK day was 3.4 (2.6-6.2) years. One PK with implausible time-concentration curve was excluding, leaving 72 PK curves in analysis with median ZDV dose 242 (214-278) mg per m2. Overall median (IQR) AUC0-12 was 3.19 (2.23-4.02) h.mg per L (n=72), 32% higher than reported for adults (mean 2.4 h.mg L SPC CBV). ZDV AUC0-12 was 0.41 h.mg L higher for every 50 mg per m2 higher ZDV dose [95% CI 0.12,0.69] (p=0.005). Associations between age and ZDV AUC0-12 varied across the age range (non-linearity p=0.002). ZDV AUC0-12 was 1.05 h.mg L lower per year older up to 4 years of age [0.46,1.65] (p smaller than 0.001): over 4, there was no association with age (+0.04 h.mg per L per year older [-0.15,+0.23], p=0.72). ZDV AUC0-12 was 0.75 h.mg L lower for every unit higher weight-for-age [0.32,1.18] (p=0.001). There was no independent effect of sex (p=0.62), height-forage (p=0.49) or syrups tablets (p=0.79). 34 children had haemoglobin values within more or less 1 day of PK: there was marginal evidence for 0.31 g per dL lower haemoglobin per 1 h.mg per L higher ZDV AUC0-12 [-0.65,+0.03] (p=0.07).
Conclusions: ZDV exposure in children in Africa dosed according to WHO guidelines was on average 32% higher than in adults. Exposure appeared highest in youngest children: further studies of potential mechanisms and associations with clinically relevant toxicity are needed.
Fillekesa, Q.; Kendallb, L.; Kitakac, S.; Mugyenyid, P.; Musokec, P.; Ndigendawanid, M.; Bwakura-Dangarembizie, M.; Gibbb, D.M.; Burgera, D.; Walkerb, A.S. Pharmacoknetics of Zidovudine dosed twice-daily according to who weight-bands in African hiv-1-infected children. Presented at 18th Conference on retroviruses and opportunistic infections, 27 February – 2 March 2011, Boston, Massachusetts. (2011) 1 pp.