Entrectinib dose confirmation in pediatric oncology patients: pharmacokinetic considerations

Area of Science:

• Pharmacology
• Oncology
• Pediatric Medicine

Background:

• Entrectinib is a potent tropomyosin receptor kinase (TRK) inhibitor with demonstrated anti-tumor activity.
• It is effective against neurotrophic NTRK gene fusion-positive tumors.
• Understanding its pharmacokinetic profile in pediatric patients is crucial for optimizing treatment.

Purpose of the Study:

• To investigate the pharmacokinetics of entrectinib and its active metabolite (M5) in pediatric patients.
• To determine if the pediatric dose of 300 mg/m² once daily (QD) achieves systemic exposure comparable to the approved adult dose (600 mg QD).

Main Methods:

• Forty-three pediatric patients (birth to 22 years) received oral entrectinib (250-750 mg/m² QD) with food.
• Different entrectinib formulations were used: capsules without acidulant (F1) and capsules with acidulant (F2B and F06).

Main Results:

• Entrectinib and M5 exposures increased dose-dependently in pediatric patients, though F1 formulation showed interpatient variability.
• Pediatric patients receiving 400 mg/m² QD entrectinib (F1) had lower systemic exposure than adults on similar doses or the recommended adult dose.
• Pediatric exposures with 300 mg/m² QD entrectinib (F06) were comparable to adult exposures at 600 mg QD.

Conclusions:

• The F1 entrectinib formulation resulted in lower systemic exposure in pediatric patients compared to the commercial F06 formulation.
• The recommended pediatric dose of 300 mg/m² with the F06 formulation achieved systemic exposures within the efficacious range observed in adults.
• This confirms the adequacy of the recommended pediatric dose and commercial formulation for treating NTRK gene fusion-positive tumors.