title: Population pharmacokinetic modeling of motesanib and its active metabolite, M4, in cancer patients.
abstract: Motesanib is a small molecule and potent multikinase inhibitor with antiangiogenic and antitumor activity. Population pharmacokinetic (POPPK) modeling of motesanib and M4, an active metabolite, was performed to assess sources of variability in cancer patients. The analysis included data collected from 451 patients from 8 clinical trials with oral doses of motesanib ranging from 25 to 175 mg, either once daily or twice daily. The POPPK analyses were performed using nonlinear mixed-effect models with a sequential approach. Covariate effects of demographics and other baseline characteristics were assessed with stepwise covariate modeling. A 2-compartment model with food effect on absorption parameters fitted the PK data of motesanib well. The effects albumin and sex on apparent clearance (CL/F) of motesanib were statistically significant. The albumin effect was more important but remained below a 25% difference. A 1-compartment model fitted PK data of M4 well. Effects of race (Asian vs non-Asian) and dosing frequency were identified as statistically significant covariates on the CL/F of M4. The maximum effect of albumin would result in less than 25% change in motesanib CL/F and as such would not warrant any dosing adjustment. However, faster elimination of M4 in Asian patients requires further investigation.
authors.affiliation: Pharsight - A Certara™ Company, Montreal, Quebec, Canada.
authors.forename: Nathalie H
authors.initials: NH
authors.lastname: Gosselin
authors.affiliation: Pharsight - A Certara™ Company, Montreal, Quebec, Canada.
authors.forename: Mohamad-Samer
authors.initials: MS
authors.lastname: Mouksassi
authors.affiliation: PKDM, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Jian-Feng
authors.initials: JF
authors.lastname: Lu
authors.affiliation: PKDM, Amgen Inc., Thousand Oaks, CA, USA.
authors.forename: Cheng-Pang
authors.initials: CP
authors.lastname: Hsu
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D044466:Asian People; D001711:Biotransformation; D002986:Clinical Trials as Topic; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000208:ethnology; D009536:Niacinamide / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000075462:Serum Albumin, Human / Q000378:metabolism
chemical_list: C422455:ALB protein, human; D020533:Angiogenesis Inhibitors; D007211:Indoles; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; C000625785:motesanib diphosphate; D000075462:Serum Albumin, Human
keywords: Nonmem; VEGFR inhibitor; active metabolite; motesanib; population PK model