Original Development of a Physiologically-Based Pharmacokinetic Model for Predicting Drug Disposition in Sickle Cell Disease Patients in Nigeria

Physiologically based pharmacokinetic modelling enables mechanistic prediction of drug disposition by incorporating organ function, tissue composition, and physiological parameters into mathematical representations of drug distribution and elimination. Disease-specific PBPK models for sickle cell disease patients in Nigeria, where organ dysfunction and haematological abnormalities alter pharmacokinetics profoundly, have not been previously developed. This study developed an original PBPK model incorporating SCD-specific physiological parameters for predicting drug disposition in Nigerian SCD patients. The model development methodology encompassed systematic identification of SCD-related physiological parameter deviations including splenic sequestration, haemolysis-related protein binding changes, hepatic blood flow alterations, and renal hyperfiltration, with quantitative estimates derived from the literature and original data collection at teaching hospitals in Lagos, Ibadan, and Kano. The SCD-adapted PBPK model was built in Simcyp Simulator, incorporating customised SCD virtual populations. Model verification was performed for hydroxyurea, diclofenac, and paracetamol, with observed plasma concentration data from 60 SCD patients. The final models showed acceptable predictive performance, with geometric mean fold errors of 1.32, 1.41, and 1.28 for the three drugs respectively. Simulation studies using the model identified clinically significant dosing adjustments required for opioid analgesics and NSAIDs due to SCD-specific pharmacokinetic modifications. The study provides an original PBPK modelling contribution with direct clinical application for individualised dosing in Nigerian SCD pharmacotherapy.

Keywords: physiologically based pharmacokinetic model, sickle cell disease, drug disposition, PBPK, Nigerian patients