Population pharmacokinetics and dynamics in phase II studies of the novel bioreductive alkylating cytotoxic indoloquinone EO9

Population pharmacokinetic-dynamic analysis was prospectively integrated in the clinical phase If programme of EO9 to determine the population pharmac okinetic profile in a larger population of patients, to estimate individual patient pharmacokinetic parameters, and to investigate relationships betwe en drug exposure and clinical outcome. A sparse sampling method was develop ed, which involved three sampling times, and was implemented during course 1. A Bayesian algorithm was used to estimate individual pharmacokinetic par ameters, In particular total plasma clearance (CL) of EO9 and area under th e curve (AUC). In total, samples were collected of 85 (65%) of the patients . Pharmacokinetic evaluation was successful in 61 (72%) of the sampled pati ents. CL of EO9 showed substantial variability (median 5.08 l/min; range 2. 67-6.42) and was of the same magnitude as in the phase I study where full p harmacokinetic profiles were used. No significant relationships were notice d between exposure parameters and safety, but overall limited toxicity was observed. No tumor responses were documented. Prospective implementation of large-scale population pharmacokinetic-dynamic analysis is feasible and ma y generate important findings, In particular when tumor responses and relev ant toxicity are observed. [(C) 2001 Lippincott Williams & Wilkins.].