1. Population Pharmacokinetic and Dynamic Analysis of the Topoisomerase I Inhibitor Lurtotecan in Phase II Studies.
- Author
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Schellens, J.H.M., Heinrich, B., Lehnert, M., Gore, M.E., Kaye, S.B., Dombernowsky, P., Paridaens, R., van Oosterom, A.T., Verweij, J., Loos, W.J., Calvert, H., Pavlidis, N., Cortes-Funes, H., Wanders, J., Roelvink, M., Sessa, C., Selinger, K., Wissel, P.S., Gamucci, T., and Hanauske, A.R.
- Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2002
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