Pharmacokinetics and relative bioavailability of carboxyamido-triazole with respect to food and time of administration: Use of a single model for simultaneous determination of changing parameters

Carboxyamido-triazole (CAI) is an anti-invasive, antimetastatic, antiangiog enic agent in clinical development for cancer treatment. It has been postul ated that food might enhance the oral absorption of micronized CAI based on an apparent discrepancy in steady stale maximum concentrations when taken without regard to meals vs, fasting. The purpose of this study was to deter mine if a standardized meal affects the absorption and pharmacokinetics of this agent. Twelve patients with refractory cancers and good end organ func tion were randomized to receive tno doses of CAI (250 mg/m(2)) with and wit hout a standardized high fat meal One cohort of 6 patients received these d oses at 9 AM, and the remaining 6 patients received CAI at 9 PM. Blood was obtained prior to each dose, and serially thereafter. A series of pharmacok inetic (PK) models were fit to the concentration-lime data. PK parameters w ere ultimately calculated using a model which allows simultaneous estimatio n of parameters from both test doses using nonlinear least squares analysis with ADAPT II. This model estimates independent absorption rate constants and relative fraction absorbed for each condition. AUC(0-t) was determined using the trapezoidal method extrapolated to infinity, and used to calculat e the relative bioavailability. No significant differences in PK parameters were noted between the morning and evening cohorts. However:, the relative bioavailability, as measured by AUC(0-infinity), of CAI was significantly increased when administered with a high fat meal compared to fasting (138.9 vs. 52.2 mu g * hr/ml; p = 0.0005). The magnitude of the increase in relat ive bioavailability of CAI taken with food could have profound implications for patients who may inadvertently take this medication shortly after eati ng.