Model-Informed Population Pharmacokinetic Simulation of Osimertinib and Az5104 in a Virtual Indian Nsclc Cohort: Exposure Variability, QTCF Tail-Risk Quantification, and Risk-Stratified ECG Monitoring

Abstract

Objective: Osimertinib is a third generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that has concentration-dependent QTc prolongation. Pivotal trials are under-representing Indian patients and they could differ in specific baseline characteristics (covariates) that are important for drug exposure. This simulation informed by this model was used to characterize exposure variability and tail risk of QTcF in a virtual Indian non-small cell lung cancer (NSCLC) cohort of patients. Methods: The published joint Osimertinib–AZ5104 population pharmacokinetic (PopPK) model by Brown et al. was implemented in Pumas. A virtual Indian NSCLC cohort (N = 1000) was simulated under 40, 80, and 160 mg once-daily regimens to steady state. QTcF effects were projected using the published linear concentration–ΔQTcF relationship. Sensitivity analyses incorporated baseline QTcF variability and residual electrocardiogram (ECG) noise to estimate exceedance probabilities for QTcF>500 ms and ΔQTcF>60 ms. Drug–drug interaction (DDI) proxy scenarios and a risk-stratified ECG monitoring framework were evaluated. Results: At 80 mg, median Osimertinib AUC0–24,ss was 5426 ng·h/ml (p05–p95: 2804–10,606) and median ΔQTcF at Cmax,ss was 13.4 ms (7.4–25.3). P(ΔQTcF>20 ms) was 15.1% at 80 mg and 79.5% at 160 mg. QTcF>500 ms exceedance remained low at 80 mg (~0.1%) but rose to 1.9% at 160 mg. The DDI proxy scenario (80 mg+strong CYP3A4 inhibitor) produced QTc profiles comparable to 160 mg. Conclusion: Osimertinib 80 mg produced exposure and ΔQTcF projections consistent with published benchmarks, suggesting consistency with established safety profiles for Indian patients. Higher-exposure scenarios substantially increased QTcF tail risk, motivating risk-stratified ECG monitoring. A post hoc sensitivity analysis evaluated the impact of AZ5104 metabolite QTc potency (0.5×, 1×, 2× parent) on total ΔQTcF, demonstrating that even under conservative assumptions the safety profile at 80 mg remained within regulatory bounds. Prospective Indian PK and ECG validation is required.