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

Area of Science:

• Pharmacology
• Oncology
• Pediatrics

Background:

• Adults with ALK+ advanced non-small-cell lung cancer (NSCLC) receive alectinib 600 mg twice daily (BID).
• Pediatric ALK-positive tumors are rare, with limited data for optimal alectinib dosing.
• Physiologically based pharmacokinetic (PBPK) modeling is crucial for pediatric dose determination.

Purpose of the Study:

• To establish pediatric dose recommendations for alectinib using a middle-out PBPK modeling approach.
• To account for developmental differences in absorption and enzyme maturation in children.
• To ensure comparable drug exposure between pediatric and adult patients.

Main Methods:

• Developed an adult PBPK model incorporating existing data and new information.
• Validated the adult PBPK model using pharmacokinetic data from adult clinical studies.
• Integrated pediatric-specific data, including CYP enzyme maturation, into the PBPK model for dose prediction.

Main Results:

• The adult PBPK model accurately predicted alectinib exposure across different adult weight categories (predicted/observed AUC ratios 0.81-1.02).
• Initial pediatric dose recommendations were derived from population PK models.
• The PBPK model confirmed most population PK predictions but identified a need for a lower dose (100 mg BID) for children under 3.5 years.

Conclusions:

• The PBPK model provides a robust framework for pediatric alectinib dose recommendations.
• A specific dose adjustment is necessary for young children (under 3.5 years) to optimize alectinib exposure.
• This study addresses a critical need for evidence-based dosing in pediatric ALK+ cancers.