Developing a Predictive Pharmacological Model for Dosing High-Alert Medications in Critically Ill Paediatric Patients in Nigerian ICUs Using Physiologically Based Pharmacokinetic Modelling

Background: Critically ill paediatric patients exhibit profound physiological alterations that dramatically alter drug pharmacokinetics, making standard dosing regimens unreliable. Physiologically based pharmacokinetic (PBPK) modelling allows integration of patient-specific physiological parameters to predict drug exposure and guide individualised dosing. In Nigeria, no PBPK dosing framework exists for paediatric ICUs despite significant unmet need. This study develops a PBPK-based dosing model for high-alert medications in Nigerian critically ill children. Methods: Clinical data including body weight, organ function parameters, haemodynamic indices, and therapeutic drug monitoring concentrations were prospectively collected from 90 paediatric ICU patients aged 1 month to 12 years at teaching hospitals in Lagos and Kano. PBPK models for vancomycin, gentamicin, and midazolam were constructed using PK-Sim software with Nigerian paediatric physiological parameters. Model performance was validated against observed drug concentration data. Dosing simulations targeted therapeutic exposure ranges from published paediatric PK/PD targets. Results: Nigerian paediatric ICU patients showed significant deviations from published physiological parameters, particularly in renal clearance and protein binding. PBPK models predicted concentrations within acceptable error margins after local parameter integration. Simulated dosing regimens differed substantially from standard formulary recommendations for 73 percent of simulated cases. Conclusion: PBPK modelling informed by locally collected physiological data reveals the inadequacy of standard dosing in Nigerian paediatric ICU settings. This modelling framework provides a precision dosing tool for pharmacists and clinicians in high-risk paediatric care. Keywords: PBPK modelling, paediatric pharmacokinetics, ICU, high-alert medications, precision dosing