Neville Mwesigwa 1, Henry Enzama 1
1 Department of Pharmacology and therapeutics, Makerere University (Kampala, Uganda)
Background
Hydroxyurea is the cornerstone disease-modifying therapy for sickle cell disease (SCD) in pediatric populations. Kidney involvement is a recognized complication of SCD beginning in childhood, with reported prevalence of renal abnormalities,defined by albuminuria and/or reduced estimated glomerular filtration rate (eGFR), ranging from approximately 20–40% in pediatric cohorts, depending on diagnostic criteria and study setting (1,2).
Renal dysfunction is clinically relevant for hydroxyurea therapy because the drug is partially eliminated unchanged in urine (approximately 30–40% in adults) (3), and systemic exposure increases as renal function declines (4). Adult pharmacokinetic studies and regulatory guidance indicate that renal impairment is associated with elevated hydroxyurea area under the concentration–time curve (AUC), with product labeling recommending dose reduction in patients with creatinine clearance <60 mL/min.(5) However, quantitative data describing exposure changes across graded renal impairment (mild, moderate, severe) in pediatric SCD remain limited. Given developmental differences in renal physiology and maturation, direct extrapolation from adults may be insufficient.
Physiologically based pharmacokinetic (PBPK) modeling provides a mechanistic framework to predict drug exposure across varying levels of renal function and age groups and can support rational, exposure-guided dose adjustment in children where prospective clinical studies are difficult to conduct.
Methods
A whole-body physiologically based pharmacokinetic (PBPK) model for hydroxyurea was implemented using GastroPlus® version 10.2 (Simulations Plus, Lancaster, CA, USA). Drug-specific parameters, including physicochemical properties, plasma protein binding (fu), permeability, and systemic clearance values, were obtained from published literature and regulatory sources. Renal clearance was implemented mechanistically as glomerular filtration (fu × GFR), assuming passive filtration as the primary renal elimination pathway.
A published adult reference model representing subjects with normal renal function (6) was extended to incorporate graded renal impairment.(6) Renal dysfunction was implemented by scaling glomerular filtration rate according to creatinine clearance–based regulatory classifications. Non-renal clearance pathways were assumed unchanged. Model performance was evaluated by comparing simulated plasma concentration–time profiles, AUC, and Cmax with published adult data using fold-error criteria, with acceptance limits of 0.8–1.25.
The extended adult models were subsequently extrapolated to pediatric populations aged 5–11 and 12–17 years using age-dependent physiological scaling embedded within GastroPlus®, incorporating developmental changes in organ size, blood flow, and renal maturation. Virtual populations were simulated to quantify changes in systemic exposure (AUC and Cmax) relative to children with normal renal function. Iterative dose-reduction scenarios were explored to identify dose reduction regimens restoring exposure within ±20% of reference pediatric exposure.
Results
The extended adult PBPK model successfully incorporated graded renal impairment and served as the basis for pediatric extrapolation. Pediatric simulations demonstrated progressive increases in systemic exposure with worsening renal dysfunction.
In adolescents aged 12–17 years receiving the reference dose, predicted AUC increased from 120 µg·h/mL under normal renal function to 148.4 µg·h/mL in mild renal impairment (approximately 1.2-fold increase), 200.7 µg·h/mL in moderate renal impairment (approximately 1.6-fold increase), and 276.5 µg·h/mL in severe renal impairment (approximately 2.3-fold increase). Children aged 5–11 years demonstrated similar proportional increases in exposure across renal impairment categories.
Dose-adjustment simulations indicated that reductions of approximately 10% (mild), 30% (moderate), and 50% (severe) restored predicted AUC values to within ±20% of exposure observed under normal renal function.(7)
Conclusions
Renal impairment substantially increases hydroxyurea exposure in pediatric sickle cell disease, with predicted AUC increases of approximately 1.2-, 1.6-, and 2.3-fold in mild, moderate, and severe impairment, respectively. PBPK-guided simulations suggest that dose reductions of approximately 10%, 30%, and 50% may restore exposure to levels comparable to normal renal function. These findings support model-informed, exposure-based dose optimization of hydroxyurea in children with renal dysfunction.
References:
[1] Anto EO et al. PLoS One (2019) 14:e0225310.
[2] Kimaro FD et al. PLoS One (2019) 14:e0218024.
[3] Rodriguez GI et al. Blood (1998) 91:1533–1541.
[4] Yan JH et al. J Clin Pharmacol (2005) 45:434–445.
[5] U.S. Food and Drug Administration. Hydroxyurea prescribing information (2016). https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/016295Orig1s047,s048Lbl.pdf
[6] Enzama H et al. J Pharm Sci (2025) 114:104004.
[7] Power-Hays A et al. Blood Adv (2026) 10:418–427
Reference: PAGE 34 (2026) Abstr 12263 [www.page-meeting.org/?abstract=12263]
Poster: Drug/Disease Modelling - Absorption & PBPK