From Clinical Trials to Real-World Patients: Population Pharmacokinetics and Precision Dosing Simulations of Lorlatinib

Résumé fourni par la source

BACKGROUND AND OBJECTIVE: The pharmacokinetics of lorlatinib have been characterized in a population pharmacokinetic (PK) model by the license holder, but external validation with real-world data is lacking. As higher trough concentrations are linked to increased toxicity, there may be a role for model-informed precision dosing (MIPD). METHODS: The published lorlatinib population PK model was externally validated using data from 150 patients with non-small cell lung cancer (NSCLC) treated in France and the Netherlands. Model performance was assessed using mean percentage error (MPE) and mean absolute percentage error (MAPE). Suboptimal validation results led to development of a refined population PK model, which was subsequently used to simulate lorlatinib exposure across different doses. A MIPD strategy targeting trough concentrations of 75-125 ng/mL was assessed. RESULTS: External validation revealed significant bias (MPE: -6.1%, 95% CI -11.1 to -0.5%), with the original population PK model systematically underestimating trough concentrations. The refined model included a lower clearance (13.7 versus 14.5 L/h). Simulations with the refined model predicted a median steady state trough level of 127.0 ng/mL (IQR: 96.1-162.0 ng/mL) versus 106.0 ng/mL with the original model for standard 100 mg once-daily (QD) regimen. MIPD increased the proportion of patients within target range from 35 to 62% after one cycle of dose adjustment. CONCLUSIONS: The published population PK model underestimates real-world trough concentrations, underscoring the importance of external validation of clinical trial-derived models. The refined model reflects lorlatinib pharmacokinetics in clinical practice better. Simulations suggest that lower lorlatinib doses may be feasible and MIPD may reduce toxicity.

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