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.
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BN, JB and JS are inventors and hold a patent on oral ModraDoc formulations. JB and JS are part-time employees and shareholders in Modra Pharmaceuticals, a spinout company developing oral taxane formulations. HY, JJ, VW, RS, SM, TD and AH declare that they have no conflict of interest.
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Yu, H., Janssen, J.M., de Weger, V.A. et al. Quantification of the pharmacokinetic-toxicodynamic relationship of oral docetaxel co-administered with ritonavir. Invest New Drugs 38, 1526–1532 (2020). https://doi.org/10.1007/s10637-020-00935-0
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DOI: https://doi.org/10.1007/s10637-020-00935-0