Two single-center, double-blind, randomized, placebo-controlled, phase I studies to investigate the tolerability and pharmacokinetics of CH-1504, an antifolate, in healthy male subjects.

ABSTRACT

BACKGROUND: Several studies have suggested that a significant proportion of the toxicity profile of the antifolate methotrexate can be attributed to its hydroxylated and polyglutamylated metabolites. CH-1504 is an investigational antifolate, which is neither hydroxylated or polyglutamylated. OBJECTIVE: The purpose of this study was to test the tolerability and pharmacokinetics of single and multiple ascending doses of CH-1504. METHODS: Two single-center, double-blind, randomized, placebo-controlled, Phase I studies were conducted in single and multiple ascending-dose designs in healthy male adult volunteers. In the single ascending-dose study, subjects were randomized to receive the study drug (1, 5, 7.5, 10, 15, or 20 mg) or placebo in a 41 ratio. Subjects were under clinical supervision for 48 hours following a single oral administration. Follow-up occurred on days 10 and 30. In the multiple ascending-dose study, subjects were randomized to receive the study drug (7.5, 10, or 15 mg) or placebo at a 31 ratio. Subjects received a single oral administration of CH-1504 once daily on days 1 through 7, during which time they remained under clinical supervision. Follow-up was conducted on days 16 and 30. Tolerability was determined through echocardiogram and clinical laboratory tests (eg, hematology, serum biochemistry, urinalysis). RESULTS: No clinically significant abnormalities were observed in any of the tolerability evaluations. No adverse events were attributed to treatment and those that were possibly related (eg, rash, headache, dizziness) were all considered mild. Peak plasma concentrations occurred between 1 to 2.5 hours after administration and the apparent t(1/2) was approximately 3 hours. On average, <3.1% of the administered dose was recovered as CH-1504 in the urine in the single-dose study and <1.5% in the multiple-dose study. CONCLUSIONS: CH-1504 appeared to be well tolerated in single administered doses up to 20 mg and daily administrations for 7 days up to 15 mg in healthy male volunteers in these studies. However, the results of the pharmacokinetic analysis support the development of a new formulation to improve the bioavailability before further clinical studies are warranted.