Phase I clinical and pharmacokinetic study of flavopiridol in children with refractory solid tumors: a Children's Oncology Group Study.

PURPOSE: To determine the dose-limiting toxicities, maximum-tolerated dose, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol (NSC 649890) when administered as a 1-hour infusion over 3 consecutive days to children with recurrent or refractory solid tumors. PATIENTS AND METHODS: Flavopiridol was administered as a 1-hour intravenous infusion daily for 3 consecutive days every 21 days, or when hematologic toxicity or any grade 2 or greater nonhematologic toxicity resolved. The starting dose was 37.5 mg/m2/d. Dose escalation was in cohorts of three patients in a standard fashion until dose-limiting toxicity and the maximum-tolerated dose were determined. Flavopiridol levels were measured on days 1, 2, and 3. RESULTS: Twenty-five children received flavopiridol at doses of 37.5 to 80 mg/m2/day over 3 consecutive days. The maximum-tolerated dose was 62.5 mg/m2/d. The primary dose-limiting toxicities were neutropenia and diarrhea. No antitumor effect was observed in this population. Mean peak plasma concentrations of 3.71 and 9.11 micromol/L were achieved at the end of the 1-hour infusion, following dose escalation from 37.5 mg/m2 to 80 mg/m2, respectively. The median flavopiridol plasma clearance was 8.0 L/h/m2 (range, 2.6 to 17.1 L/h/m2). CONCLUSION: The maximum-tolerated dose of flavopiridol in children, and the recommended phase II dose for pediatric studies, was 62.5 mg/m2/day when administered as a 1-hour infusion for 3 consecutive days. Dose-limiting toxicities of neutropenia and diarrhea were similar to those in adult studies.

Rat and human liver cytochrome P-450 isoform metabolism of ecteinascidin 743 does not predict gender-dependent toxicity in humans.

Ecteinascidin 743 (ET743, NSC648766) is a marine natural product with potent in vivo activity in human xenograft models. Hepatotoxicity was the most prominent toxicity in preclinical studies and was greater in female rats than in male rats. To assess the potential implications for human toxicities, the in vitro metabolism of ET743 was characterized using rat and human preparations. NADPH-dependent ET743 metabolism was greater with male rat liver microsomal preparations than with preparations from female rats and was induced by pretreatment of rats with phenobarbital and dexamethasone but not by pretreatment with 3-methylcholanthrene. Rat and human microsomal metabolism of ET743 was reduced in the presence of chemical CYP3A inhibitors or antirat CYP3A2 antiserum and to a much lesser extent by CYP2E, CYP2C, and CYP2A inhibitors. In human liver panel studies, ET743 disappearance was highly correlated with CYP3A activities and to a lesser extent with CYP2C activities. ET743 was metabolized by a number of cDNA-expressed rat P-450 isoforms, including male-predominant CYP2A2 and CYP3A2. ET743 was metabolized by cDNA-expressed human CYP3A4 and to a much lesser extent by CYP2C9, CYP2D6, and CYP2E1 preparations. Three oxidative metabolites were detected in cDNA-expressed isoform incubations, including the N-demethylated metabolite ET729 and two additional products characterized by laser capture-mass spectrometry analyses. The plasma pharmacokinetics and biliary excretion of ET743 were characterized in rats. There were no gender-dependent differences in half-life or total body clearance values. Although very modest, the biliary excretion of ET743 in male rats (0.48%) was greater than in female rats (0.28%). In contrast, the biliary excretion of the cytotoxic N-demethylated metabolite ET729 was 5-fold greater in the female rat (1.05% of dose) than in the male rat (0.19% of dose). Biliary excretion of ET729 may contribute to the hepatic toxicity in rats. These data are consistent with a major role for CYP3A isoforms in ET743 rat and human metabolism. Although there are conflicting data in the literature, expression of CYP3A isoforms in human tissues and elimination of CYP3A substrates have not been shown to vary substantially by gender. There are no indications that the other CYP isoforms implicated in ET743 metabolism are expressed differently in males and females. Thus, although it is not possible to rule out gender differences in ET743 human toxicities, our data do not predict major gender-dependent differences in the toxicity of ET743 based on metabolism.