title: Population pharmacokinetic and pharmacodynamic analysis of bosutinib.
abstract: Bosutinib is an orally active, competitive inhibitor of Src/Abl tyrosine kinases. A population pharmacokinetic model was developed using data pooled from 3 studies of patients (n = 870) with solid tumors or Philadelphia chromosome-positive leukemia. Patients (aged 18-91 y, weighing 35-221 kg) who received bosutinib 50 to 600 mg orally with food each contributed 6-9 pharmacokinetic samples. The final pharmacokinetic model was a linear two-compartment model with first-order absorption, an absorption lag-time, and dose-dependent bioavailability. Oral absorption was relatively slow, with a half-time of 1.14 h and a lag-time of 0.87 h; time to peak concentration was 5-6 h. Apparent clearance was 120 L/h. The apparent volume of the peripheral compartment was large with a slow turnover; alpha and beta half-lives were 19 h and 290 days, respectively. All parameters were estimated with acceptable precision (standard error <30%). No tested covariate (protocol, baseline demographic/clinical characteristics, or laboratory results) explained the high inter-individual variability of bosutinib pharmacokinetics. Therefore, adjusting bosutinib dose for body size (weight, surface area) would not provide benefit over fixed dosing. Using this exposure model in pharmacodynamic assessment of one study, adverse event incidence was shown to be similar in overall and bosutinib-responsive populations.
authors.affiliation: Pfizer Inc.
authors.forename: Poe-Hirr
authors.initials: PH
authors.lastname: Hsyu
authors.forename: Diane R
authors.initials: DR
authors.lastname: Mould
authors.forename: Richat
authors.initials: R
authors.lastname: Abbas
authors.forename: Michael
authors.initials: M
authors.lastname: Amantea
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D054796:Drug Dosage Calculations; D005260:Female; D065569:Gastrointestinal Absorption; D006207:Half-Life; D006801:Humans; D016014:Linear Models; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D009570:Nitriles / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011804:Quinolines; C471992:bosutinib