Abstract:
: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 body surface area-normalized dosing regimen of 230 mg/m2 is considered appropriate for pediatric patients >2 to <18 years of age.
journal_name
J Pharm Scijournal_title
Journal of pharmaceutical sciencesauthors
Heimbach T,Lin W,Hourcade-Potelleret F,Tian X,Combes FP,Horvath N,He Hdoi
10.1016/j.xphs.2019.01.028subject
Has Abstractpub_date
2019-06-01 00:00:00pages
2191-2198issue
6eissn
0022-3549issn
1520-6017pii
S0022-3549(19)30078-4journal_volume
108pub_type
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