Purpose: To study the human pharmacokinetics and in vitro cytotoxicity of Apomine, an p.o. administered, nonmyelosuppressive agent that selectively inhibits cell proliferation and induces tumor cell apoptosis through the farnesoid X receptor. Experimental Design: Seven solid cancer patients who participated in an ongoing Phase I study of Apomine and received the starting dose level of 125 mg/m2/day × 14 days every 3 weeks underwent a pharmacokinetic study on day 14 of the first course. Plasma concentrations of Apomine were assayed with a Hewlett Packard gas chromatograph using a nitrogen phosphorus detector and HP-5 15m × 0.32-mm column. Fresh human ovarian cancer tumor samples were obtained during initial exploratory laparotomy from 35 chemotherapy-naive, advanced stage epithelial ovarian cancer patients. Tumor samples were tested for sensitivity to Apomine, carboplatin, cisplatin, paclitaxel, and topotecan using an in vitro clonogenic [3H]thymidine end point assay. Results: Pharmacokinetic analysis revealed a mean Apomine plasma Cmax, of 16.4 ± 9.1 μg/ml (29.1 μM), a mean plasma AUC0-12 h of 173.4 ± 105 μg · h/ml (308 μM · h), and a mean t1/2 (24-192 h) of 156.2 ± 42.9 h. In vitro assay results showed that 63 and 91% of the ovarian cancers were sensitive (i.e., >70% inhibition of tumor cell growth) to Apomine at concentrations of 10 and 20 μM. The sensitivity rates were 91% for carboplatin (270 μM), 88% for cisplatin (33 μM), 41% for paclitaxel (5.9 μM), and 85% for topotecan (2.2 μM). Conclusions: These in vitro assay results, taken together with our preliminary plasma pharmacokinetic data, suggest that Apomine should be clinically active at the 125 mg/m2 dose level.
|Original language||English (US)|
|Number of pages||5|
|Journal||Clinical Cancer Research|
|State||Published - 2001|
ASJC Scopus subject areas
- Cancer Research