Population pharmacokinetics of tipifarnib in healthy subjects and adult cancer patients

Abstract

To characterize the population pharmacokinetics of tipifarnib. A total of 1083 subjects treated orally with a solution, capsule or tablet formulations of tipifarnib, given as a single dose or as multiple twice-daily doses (range 25-1300 mg) were combined with data from 1, 2 and 24 h intravenous infusions. A total of 3445 concentrations in the index data set were fitted by an open three-compartment linear disposition model with sequential zero-order input into the depot compartment, followed by a first-order absorption process, and lag time, using NONMEM V. The effect of patient covariates on tipifarnib pharmacokinetics was explored. The model was evaluated using goodness of fit plots and relative error measurements for 3894 concentrations in the test data set. Computer simulations were undertaken to evaluate the effect of covariates on tipifarnib pharmacokinetics. Tipifarnib oral bioavailability (26.7%) did not differ between the formulations. The absorption rate from the solution was faster than from the solid forms. Whereas the absorption rate and systemic clearance were more rapid in healthy subjects, the extent of absorption and the steady-state volume of distribution were comparable in cancer patients and healthy subjects. Systemic clearance in cancer patients (21.9 l h-1) exhibited a statistically significant relationship with total bilirubin. The typical volume of the central compartment in cancer patients (54.6 l 70 kg-1) was directly proportional to body weight. The clinical relevance of these covariates in cancer patients is questionable as there was a substantial overlap in simulated concentration-time profiles across a wide range of covariate values. A population PK approach has been used to integrate data gathered during clinical development and to characterize the pharmacokinetics of tipifarnib. Individualization of dose based on body weight or total bilirubin concentration in adult cancer patients is not warranted.