Clinical pharmacology of camptothecins: Model based population pharmacokinetic and pharmacodynamic analysis

As drug exposure has shown a direct correlation with pharmacologic response for a number of drugs, the objective of this thesis was to develop parametric models that can be used to determine drug exposure for two members of the camptothecin family of anticancer agents, irinotecan and topotecan. As toxicity can be dose limiting, the model was used to identify individual characteristics that may contribute to ineffective therapy.; Parametric models were used to describe the disposition of two members of the camptothecin family: irinotecan and topotecan. Potential sources contributing to variability in the concentration time curves of these compounds and their metabolites were tested for significance, including individual attributes, coadministration of other drugs, and timing of dose administrations. Logistic regression was used to determine the relationship between exposure and response for both topotecan and the active metabolite of irinotecan, SN-38.; Two distinct populations of the active metabolite of irinooecan, SN-38, disposition were found and may be attributed to differences in the formation of SN-38. Sex and biliary excretion may account for the different subpopulations of SN-38 disposition in this population. The influence of impaired biliary function on SN-38 disposition was validated in a population with impaired hepatic function. The importance of biliary excretion of irinotecan was highlighted in a drug interaction study. The disposition of SN-38 was modulated by cyclosporine A and phenobarbital as they appeared to tip the balance between biliary excretion and metabolism of irinotecan as a means of irinotecan elimination.; Oral topotecan was best described by a one compartment open model with first order absorption in patients with myelodysplastic syndrome. Topotecan toxicity was related to maximum steady state concentrations and area under the concentration time curve (AUC). While twice a day treatment led to higher steady state maximum concentrations it also led to sustained concentrations of topotecan above 1 ng/ml and may be proven to be more effective in a larger population. Topotecan compliance, while contributing to variability in the concentration time curve appeared to have little effect on the response to treatment.