Quantification of the pharmacokinetic-toxicodynamic relationship of oral docetaxel co-administered with ritonavir
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PHASE I STUDIES
Quantification of the pharmacokinetic-toxicodynamic relationship of oral docetaxel co-administered with ritonavir Huixin Yu 1 & Julie M. Janssen 1 & Vincent A. de Weger 2 & Bastiaan Nuijen 1 & Rik E. Stuurman 1,3 & Serena Marchetti 2 & Jan H. M. Schellens 2,4,5 & Jos H. Beijnen 1,4,5 & Thomas P. C. Dorlo 1 & Alwin D. R. Huitema 1,6 Received: 22 January 2020 / Accepted: 7 April 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Introduction Oral formulations of docetaxel have successfully been developed as an alternative for intravenous administration. Co-administration with the enzyme inhibitor ritonavir boosts the docetaxel plasma exposure. In dose-escalation trials, the maximum tolerated doses for two different dosing regimens were established and dose-limiting toxicities (DLTs) were recorded. The aim of current analysis was to develop a pharmacokinetic (PK)-toxicodynamic (TOX) model to quantify the relationship between docetaxel plasma exposure and DLTs. Methods A total of 85 patients was included in the current analysis, 18 patients showed a DLT in the four-week observation period. A PK-TOX model was developed and simulations based on the PK-TOX model were performed. Results The final PK-TOX model was characterized by an effect compartment representing the toxic effect of docetaxel, which was linked to the probability of developing a DLT. Simulations of once-weekly, once-daily 60 mg and once-weekly, twice-daily 30 mg followed by 20 mg of oral docetaxel suggested that 14% and 34% of patients, respectively, would have a probability >25% to develop a DLT in a four-week period. Conclusions A PK-TOX model was successfully developed. This model can be used to evaluate the probability of developing a DLT following treatment with oral docetaxel and ritonavir in different dosing regimens. Keywords Docetaxel . Oral formulation . Ritonavir . Pharmacokinetics . Toxicodynamics
Introduction Oral administration of docetaxel is currently in clinical development as a convenient alternative for intravenous administration [1]. Firstly, a solid dispersion capsule formulation
* Julie M. Janssen [email protected] 1
Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX Amsterdam, The Netherlands
2
Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
3
Centre for Human Drug Research, Leiden, The Netherlands
4
Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
5
Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
6
Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
(ModraDoc001) was developed which showed improved dissolution characteristics compared to crystalline docetaxel. Secondly, a further improved solid dispersion tablet formulation (ModraDoc006) was developed [2–4]. A major limitation for oral administration of docetaxel is low bioavaila
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