Development and Validation of a Physiologically Based Pharmacokinetic (PBPK) Model for Hydroxyurea Dose Evaluation in Nigerian Adult Sickle Cell Disease Patients

Background

Hydroxyurea is the approved disease-modifying first-line therapy for sickle cell disease (SCD). Despite its clinical benefits, significant challenges in dose optimisation for a more effective and personalised therapy persist [1,2]. Also, although physiologically based pharmacokinetic (PBPK) modelling can mechanistically predict drug disposition with integrated patient-specific variables, validated adult models for SCD on hydroxyurea are scarce [3]. This study, therefore, developed a PBPK model for hydroxyurea in adults, and thereafter, with simulations, explored the differences in hydroxyurea disposition across different doses.

Methods

A physiologically based pharmacokinetic (PBPK) model for hydroxyurea in adult sickle cell disease (SCD) patients was developed using PK-Sim (v12.0). Physicochemical properties and pharmacokinetic parameters were sourced from published literature and clinical datasets and incorporated into the model along with relevant SCD-specific physiological changes. Model structure included 18 compartments, incorporating oral absorption, hepatic metabolism, and renal excretion. Model validation was carried out using observed clinical pharmacokinetic data, and the model performance was evaluated by comparing predicted and observed PK parameters with a fold error <2. The validated model was then applied to simulate hydroxyurea pharmacokinetics across various doses (12–20 mg/kg/day) with the reference AUC of 115 mg*h/L [4,5].

Results

The PBPK model successfully predicted hydroxyurea plasma concentrations in adult SCD patients. Simulations showed that standard fixed dosing of 15-35 mg/kg/day may result in overexposure in the patients as a dose of 12mg/kg/day provided the closest area under the concentration-time curve (AUC) of 116 mg*h/L, to the target AUC of 115 mg*h/L, opposed to 15mg/kg/day which had an AUC of 145 mg*h/L.

Conclusion

This validated PBPK model of hydroxyurea is a promising tool for optimizing individualized therapy in adult SCD patients. It demonstrates potential for guiding dose optimization based on patient-specific factors. Further model expansion may include the integration of pharmacogenetic data, as well as additional specific pharmacokinetic and pharmacodynamic data.

References

1. Di Grazia D, Mirabella C, Chiara F, Caudana M, Shelton Agar FMA, Zanatta M, et al. Hydroxyurea pharmacokinetic evaluation in patients with sickle cell disease. Pharmaceuticals (Basel). 2024;17(10):1386. doi:10.3390/ph17101386
2. Power-Hays A, Dong M, Punt N, Mizuno T, Smart LR, Vinks AA, et al. Rationale, development, and validation of HdxSim, a clinical decision support tool for model-informed precision dosing of hydroxyurea for children with sickle cell anemia. Clin Pharmacol Ther. 2024;116(3):670–7. doi:10.1002/cpt.3119
3. Dong M, Ware RE, Dallmann A, Vinks AA. Hydroxyurea treatment for sickle cell anemia during pregnancy and lactation: current evidence and knowledge gaps. Pharmacotherapy. 2023;43(5):419–29. doi:10.1002/phar.2793
4. McGann PT, Ware RE. Hydroxyurea therapy for sickle cell anemia. Expert Opin Drug Saf. 2015;14(11):1749–58. doi:10.1517/14740338.2015.1088827
5. Dong M, McGann PT, Mizuno T, Ware RE, Vinks AA. Development of a pharmacokinetic-guided dose individualization strategy for hydroxyurea treatment in children with sickle cell anaemia. Br J Clin Pharmacol. 2016;81(4):742–52. doi:10.1111/bcp.12851