A Roadmap to Individualized Irinotecan Dosing

Ever since its introduction to the drug-market in the late eighties, early nineties of the last century, irinotecan is fighting its image. Particularly, the unpredictable occurrence and severity of delayed-type diarrhea, its main dose-limiting adverse effect, remains a serious concern for medical oncologists. In this perspective, reliable a priori knowledge of the toxicity profile of irinotecan therapy in the individual patient is of utmost importance, since it would guide physician’s choice and enable adaptive drug administration. In this thesis, different pharmacological aspects of irinotecan therapy have been investigated. Using pharmacokinetic, pharmacogenetic, and phenotyping strategies, as well as pharmacological prophylactic interventions, ways to improve irinotecan tolerability have been investigated. To truly individualize irinotecan treatment, efforts to develop and implement patient-friendly, simple, and feasible limited sampling models and phenotyping and genotyping strategies on a routine basis should be strongly encouraged. Additionally, relations between genotype (UGT1A1*28) and the incidence and severity of adverse effects and therapeutic outcome should be confirmed in large trials, resulting in evidence-based dosing recommendations. Ultimately, lowering the incidence and severity of delayed-type diarrhea will make irinotecan therapy better tolerable and may give this classical topoisomerase I inhibitor the image it deserves in the rapidly changing field of anticancer agents.

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