Physiologically based pharmacokinetic modeling to supplement nilotinib pharmacokinetics and confirm dose selection in pediatric patients.

In adult patients nilotinib is indicated for chronic myeloid leukemia at an approved oral dose of 300 or 400 mg BID. Physiologically based pharmacokinetic (PBPK) model was developed to describe and supplement limited PK data in the pediatric population ranging from 2 to less than 6 years of age and ultimately inform dosing regimen. An adult Simcyp PBPK model was established and verified with clinical pharmacokinetic data after a single or multiple oral doses of 400 mg nilotinib (230 mg/m2 ). The model was then applied to a pediatric PBPK model taking account of ontogeny profiles of metabolizing enzymes and pediatric physiological parameters. The model was further verified using observed pediatric PK data in 12 to < 18 year old and from 6 to < 12 year old patients. The PBPK models were able to recover, describe and supplement the limited nilotinib concentration-time data profile in 2 to < 6 year old patients after a single dose and Cmin,ss after BID dosing. The exposure (Cmax,ss , Cmin,ss and AUCtau,ss ) was predicted to be similar across age groups. PBPK model simulations confirmed that BSA-normalized dosing regimen of 230 mg/m2 is considered appropriate for pediatric patients > 2 to < 18 years of age.