Exposure Comparison of Standard Versus Alternate Hydroxyurea Dosing in Ugandan Children with Sickle Cell Disease: A Non-Compartmental Pharmacokinetic Analysis - PAGE Meeting (Population Approach Group Europe)

Nandawula Habra ¹, Henry Enzama ¹, Mukonzo Jackson ¹

1 Department of pharmacology and therapeutics- Makerere University (kampala, Uganda)

Background
Hydroxyurea (HU) is the standard disease-modifying therapy for sickle cell disease (SCD), improving survival and reducing vaso-occlusive complications through fetal hemoglobin induction (1,2). In sub-Saharan Africa, fixed capsule strengths and supply constraints frequently necessitate alternate dosing strategies derived from weekly dose calculations rather than precise daily weight-based administration. While hydroxyurea pharmacokinetics have been described in multinational pediatric cohorts (3,4), exposure implications of alternate dosing strategies in African children remain insufficiently characterized. Understanding HU’s PK profile in this population is crucial for optimizing individualized dosing, enhancing efficacy, and minimizing toxicity. This study quantified systemic hydroxyurea exposure under standard daily versus alternate dosing regimens in Ugandan children using non-compartmental pharmacokinetic analysis and evaluated comparability using geometric exposure metrics.

Methods
A prospective steady-state pharmacokinetic study was conducted in 66 Ugandan children aged 0–12 years receiving hydroxyurea at a target equivalent dose of 20–30 mg/kg/day at Mulago National Referral Hospital. Participants were stratified into two groups: standard daily weight-based dosing and alternate dosing derived from weekly 500 mg capsule totals. Serial venous plasma samples were collected over 24 hours following observed dosing. Hydroxyurea concentrations were quantified using validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) with electrospray ionization in positive mode. Non-compartmental analysis using the linear-log trapezoidal method estimated AUC₀–24 (mg·h/L), Cmax (mg/L), Cmin (mg/L), and Tmax (hours). Between-group comparisons were performed using geometric mean ratios (GMR) with 90% confidence intervals. Interindividual variability was summarized as coefficient of variation (%CV), consistent with published pediatric PK reporting standards (3,5).

Results
All 66 participants completed pharmacokinetic sampling (mean age 7.1 ± 3.2 years). Mean AUC₀–24 was 108 ± 35 mg·h/L in the standard dosing group and 102 ± 30 mg·h/L in the alternate dosing group. The geometric mean ratio for AUC was 0.95 (90% CI: 0.86–1.06), indicating comparable systemic exposure between regimens. Mean Cmax was 28.5 ± 9.8 mg/L for standard dosing and 26.2 ± 8.3 mg/L for alternate dosing, with a GMR of 0.93 (90% CI: 0.84–1.04). Median Tmax occurred at 1.4 hours (IQR 1.0–1.8) for standard dosing and 1.6 hours (IQR 1.2–2.0) for alternate dosing. Exposure variability was moderate (AUC %CV 28–32%; Cmax %CV 30–34%), consistent with previously reported pediatric hydroxyurea pharmacokinetic ranges (3–5). No statistically or clinically meaningful differences in primary exposure parameters were observed between dosing strategies.

Conclusions
Standard and alternate hydroxyurea dosing strategies achieved comparable systemic exposure in this Ugandan pediatric cohort. The absence of clinically significant differences in AUC and Cmax suggests that alternate capsule-derived dosing can maintain therapeutic exposure in settings where precise weight-based daily dosing is not feasible (3,4). However, moderate interindividual variability highlights the importance of future population pharmacokinetic modelling to identify covariates influencing clearance and distribution and to support model-informed precision dosing approaches in African children with SCD. These findings provide foundational exposure data necessary to optimize hydroxyurea dosing policies in resource-limited environments.

References:
1. Ware RE, et al. Hydroxyurea therapy for sickle cell disease. N Engl J Med. 2017.
2. McGann PT, Ware RE. Hydroxyurea for children with sickle cell disease. Blood. 2015.
3. Power-Hays A, et al. Hydroxyurea pharmacokinetics in children with sickle cell anemia across global populations. Blood Adv. 2026.
4. McGann PT, et al. Pharmacokinetics-guided dosing of hydroxyurea in children with SCA. Am J Hematol. 2019.
5. de Montalembert M, et al. Hydroxyurea pharmacokinetics in pediatric SCD. Haematologica. 2006.

Reference: PAGE 34 (2026) Abstr 12270 [www.page-meeting.org/?abstract=12270]

Poster: Clinical Applications