Population pharmacokinetics of motexafin gadolinium in adults with brain metastases or glioblastoma multiforme.
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.
Miles
Dale R
DR
Pharmacyclics Inc, 995 E. Arques Avenue, Sunnyvale, CA 94085, USA.
Smith
Jennifer A
JA
Phan
See-Chun
SC
Hutcheson
Sammy J
SJ
Renschler
Markus F
MF
Ford
Judith M
JM
Boswell
Garry W
GW
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
D000927:Anticonvulsants; D000970:Antineoplastic Agents; D008665:Metalloporphyrins; D010672:Phenytoin; C437683:motexafin gadolinium; D003404:Creatinine; D000469:Alkaline Phosphatase