Population pharmacokinetic and dynamic analysis of the topoisomerase I inhibitor lurtotecan in phase II studies.

Population pharmacokinetic-dynamic analysiswas prospectively integrated in a broadphase II program of lurtotecan (GI147211),a novel camptothecin derived topoisomeraseI inhibitor, to determine the populationpharmacokinetic profile in a largerpopulation, to estimate individualpharmacokinetic parameters and toinvestigate relationships with clinicaloutcome. A sparse sampling method wasapplied during course one, which involvedtwo sampling time-points. A Bayesianalgorithm was used to estimate individualpharmacokinetic parameters, in particulartotal plasma clearance (CL) and volume ofdistribution. In total, samples werecollected of 109 (63%) of 173 patients.Pharmacokinetic-dynamic evaluation could becarried out successfully in 85 (78%) ofthe sampled patients. CL of lurtotecanshowed substantial variability (mean 87± 28 L/h) and was of the same magnitudeas in the phase I studies where fullpharmacokinetic curves were used. Residualvariability in the population estimate ofCL was 9.9%. No significant relationshipswere observed between exposure parametersand toxicity nor likelihood of tumorresponse, however the latter relationshipmay well have been obscured by theheterogeneity of the studied population.Prospective implementation of large scalepopulation pharmacokinetic-dynamic analysisis feasible and important to establishwhether interpatient variability in drugexposure is a major determinant of toxicityor activity.