title: Population pharmacokinetics of motexafin gadolinium in adults with brain metastases or glioblastoma multiforme.
abstract: The purpose of this study was to determine clinical variables affecting motexafin gadolinium (MGd) pharmacokinetics. Motexafin gadolinium (4-5.3 mg/kg/d) was administered intravenously for 2 to 6.5 weeks. Plasma samples from 3 clinical trials were analyzed for MGd using liquid chromatography/mass spectroscopy. The pooled data were analyzed using population pharmacokinetic (POP-PK) methods. The POP-PK model included 243 patients (1575 samples). Clearance (CL) was 14% lower in women, but weight-normalized clearance was only 5% lower in women. Clearance decreased with increasing alkaline phosphatase, increasing age, and decreasing hemoglobin. Administration of phenytoin increased CL by approximately 30%. Central compartment volume (V1) was 21% lower in women and increased with increasing serum creatinine. For all covariates, except sex and phenytoin, the predicted change in CL or V1 (5th and 95th percentiles) varied < or =13% from the population mean CL or V1 estimate. It was concluded that a 3-compartment, open, POP-PK model predicts small but significant effects of age, sex, alkaline phosphatase, hemoglobin, serum creatinine, and phenytoin on MGd pharmacokinetics.
authors.affiliation: Pharmacyclics Inc, 995 E. Arques Avenue, Sunnyvale, CA 94085, USA.
authors.forename: Dale R
authors.initials: DR
authors.lastname: Miles
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Smith
authors.forename: See-Chun
authors.initials: SC
authors.lastname: Phan
authors.forename: Sammy J
authors.initials: SJ
authors.lastname: Hutcheson
authors.forename: Markus F
authors.initials: MF
authors.lastname: Renschler
authors.forename: Judith M
authors.initials: JM
authors.lastname: Ford
authors.forename: Garry W
authors.initials: GW
authors.lastname: Boswell
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase / Q000378:metabolism; D000927:Anticonvulsants / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D001932:Brain Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D002986:Clinical Trials as Topic; D003404:Creatinine / Q000097:blood; D003627:Data Interpretation, Statistical; D005260:Female; D005500:Follow-Up Studies; D005909:Glioblastoma / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008665:Metalloporphyrins / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D008954:Models, Biological; D009362:Neoplasm Metastasis; D010672:Phenytoin / Q000494:pharmacology; D012737:Sex Factors; D012984:Software
chemical_list: D000927:Anticonvulsants; D000970:Antineoplastic Agents; D008665:Metalloporphyrins; D010672:Phenytoin; C437683:motexafin gadolinium; D003404:Creatinine; D000469:Alkaline Phosphatase