Development of an Original Theoretical Framework for Personalised Drug Dosing in Sickle Cell Disease Patients in Nigeria

Sickle cell disease is characterised by pharmacokinetic variability driven by disease-related organ dysfunction, haematological disturbances, and genetic polymorphisms that collectively render standard dosing regimens suboptimal for Nigerian SCD patients. This study developed an original theoretical framework for personalised drug dosing in sickle cell disease, using hydroxyurea as the primary drug model. The framework development employed a multi-stage methodology: systematic review of existing pharmacokinetic and pharmacogenomic data in SCD populations; primary pharmacokinetic study in 60 adult SCD patients at Lagos and Ibadan teaching hospitals measuring hydroxyurea pharmacokinetic parameters by validated HPLC; genotyping of key pharmacogenomic variants including CYP2B6 and ABCG2 transporter polymorphisms; and population pharmacokinetic modelling using nonlinear mixed effects approaches in NONMEM. Significant covariate effects on hydroxyurea clearance were identified for weight, haemoglobin F percentage, renal function, and CYP2B6 polymorphisms. The original Personalised SCD Dosing Framework integrates population pharmacokinetic model predictions with patient-specific covariate data and pharmacogenomic markers to generate individualised dose recommendations and monitoring intervals. Framework validation was conducted in an independent cohort of 30 patients. The model demonstrated superior dose prediction accuracy over standard flat dosing (42 percent reduction in under-treatment events). The framework constitutes an original contribution to SCD pharmacotherapy science in Nigeria, providing the theoretical foundation for an adaptive dosing tool implementable in Nigerian SCD clinics.

Keywords: sickle cell disease, personalised dosing, pharmacokinetics, hydroxyurea, population pharmacokinetic model