Article révisé par les pairs
Résumé : PURPOSE: A single-agent dose-escalating phase I and pharmacokinetic study on the farnesyl transferase inhibitor SCH 66336 was performed to determine the safety profile, maximum-tolerated dose, and recommended dose for phase II studies. Plasma and urine pharmacokinetics were determined. PATIENTS AND METHODS: SCH 66336 was given orally bid without interruption to patients with histologically or cytologically confirmed solid tumors. Routine antiemetics were not prescribed. RESULTS: Twenty-four patients were enrolled onto the study. Dose levels studied were 25, 50, 100, 200, 400, and 300 mg bid. Pharmacokinetic sampling was performed on days 1 and 15. At 400 mg bid, the dose-limiting toxicity (DLT) consisted of grade 4 vomiting, grade 4 neutropenia and thrombocytopenia, and the combination of grade 3 anorexia and diarrhea with reversible grade 3 plasma creatinine elevation. After dose reduction, at 300 mg bid, the DLTs consisted of grade 4 neutropenia, grade 3 neurocortical toxicity, and the combination of grade 3 fatigue with grade 2 nausea and diarrhea. The recommended dose for phase II studies is 200 mg bid, which was found feasible for prolonged periods of time. Pharmacokinetic analysis showed a greater than dose-proportional increase in drug exposure and peak plasma concentrations, with increased parameters at day 15 compared with day 1, indicating some accumulation on multiple dosing. Plasma half-life ranged from 4 to 11 hours and seemed to increase with increasing doses. Steady-state plasma concentrations were attained at days 7 through 14. A large volume of distribution at steady-state indicated extensive distribution outside the plasma compartment. CONCLUSION: SCH 66336 can be administered safely using a continuous oral bid dosing regimen. The recommended dose for phase II studies using this regimen is 200 mg bid.

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