Pharmacokinetics of nilotinib in pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia or acute lymphoblastic leukemia
Mené sur 15 patients âgés de 1 à 18 ans et atteints d'une leucémie myéloïde chronique ou d'une leucémie lymphoblastique aiguë Ph+ réfractaire ou récidivante, cet essai de phase I analyse les caractéristiques pharmacocinétiques et la toxicité du nilotinib après l'échec d'une thérapie standard ou d'une thérapie par imatinib et/ou dasatinib
Purpose: We investigated nilotinib exposure in pediatric patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) resistant to, relapsed on, refractory to, or intolerant of previous treatment. Experimental Design: Fifteen patients (aged 1 to < 18 years) with CML resistant to or intolerant of imatinib and/or dasatinib (n = 11) or Ph+ ALL relapsed on or refractory to standard therapy (n = 4) enrolled in this phase 1 study. Nilotinib (230 mg/m2 twice daily; equivalent to the adult 400-mg twice-daily dose) was administered orally in 12 or 24 cycles of 28 days. The primary objective was to characterize the pharmacokinetics (PK) of nilotinib in pediatric patients. Results: The area under the concentration-time curve at steady state was slightly lower in pediatric patients vs adults (14,751.4 vs 17,102.9 ng·h/mL); the geometric mean ratio (GMR; pediatric:adult) was 0.86 (90% CI, 0.70-1.06). Body surface area-adjusted systemic clearance was slightly higher in pediatric vs adult patients (GMR, 1.30; 90% CI, 1.04-1.62). Nilotinib was generally well tolerated. The most common adverse events were headache, vomiting, increased blood bilirubin, and rash. Three patients with CML achieved major molecular response, and 3 with Ph+ ALL achieved complete remission. Conclusion: Nilotinib 230 mg/m2 twice daily in pediatric patients provided a PK and safety profile comparable to the adult reference dose; clinical activity was demonstrated in both CML and Ph+ ALL. This dose is recommended for further evaluation in pediatric patients. The safety profile was consistent with that in adults.