Quantification of the pharmacokinetic-toxicodynamic relationship of oral docetaxel co-administered with ritonavir

Huixin Yu, Julie M. Janssen, Vincent A. de Weger, Bastiaan Nuijen, Rik E. Stuurman, Serena Marchetti, Jan H.M. Schellens, Jos H. Beijnen, Thomas P.C. Dorlo, Alwin D.R. Huitema

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1 Citaat (Scopus)


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.

Originele taal-2Engels
Pagina's (van-tot)1526-1532
Aantal pagina's7
TijdschriftInvestigational New Drugs
Nummer van het tijdschrift5
StatusGepubliceerd - 1 okt. 2020
Extern gepubliceerdJa


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