Middle-Out Physiologically Based Pharmacokinetic Modeling to Support Pediatric Dosing Recommendation for Alectinib.

Adult patients with anaplastic lymphoma kinase positive (ALK+) advanced non-small-cell lung cancer (NSCLC) are treated with 600 mg alectinib twice daily (BID) as first-line treatment. ALK positive solid and central nervous system (CNS) tumors are described in the pediatric population, with limited clinical data due to the rarity of the disease and challenges to determine the right dosing. This study aims to inform pediatric dose recommendations for alectinib by performing a middle-out physiologically based pharmacokinetic (PBPK) modeling approach, accounting for differences in absorption and enzyme maturation. The developed adult PBPK model is leveraging insights from two previously developed PBPK models (focusing on absorption and drug-drug interactions) and is complemented with newly generated data. The adult PBPK model is validated with pharmacokinetic data from two clinical studies in the adult population. The ratios between the predicted and observed steady-state AUC after 600 mg BID for 28 days are within the acceptable range in three different adult body weight categories (from 0.81 to 1.02). Initial pediatric dose recommendations are informed by population PK model predictions (assuming no maturation of enzymes) and aim to have similar exposure to the adult population. Intrinsic clearance values for all contributing CYP enzymes are included in the pediatric PBPK model to account for changes in enzyme maturation. The current PBPK model confirmed that the recommended alectinib doses by population PK predictions were accurate for the pediatric age range, with one exception: patients younger than 3.5 years are suggested to receive 100 mg BID, instead of 190 mg BID.