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Population Pharmacokinetics of Motexafin Gadolinium in Adults With Brain Metastases or Glioblastoma Multiforme

From Pharmacyclics Inc, Sunnyvale, California (Dr Miles, Dr Smith, Dr Phan, Dr Renschler, Dr Boswell); Quintiles Inc, Kansas City, Missouri (Dr Hutcheson); and UCLA Medical Center, Radiation Oncology, Los Angeles, California (Dr Ford).

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 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.

Key Words: Motexafin gadolinium • population pharmacokinetics • brain metastases • glioblastoma multiforme

Address for reprints: Dale R. Miles, Pharmacyclics Inc, 995 E. Arques Avenue, Sunnyvale, CA 94085.

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