Quantification of the difference in oral docetaxel pharmacokinetics in patients with prostate cancer compared to patients with other solid tumours

Lisa T. van der Heijden (1), Marit A.C. Vermunt (1), Thomas P.C. Dorlo (1,2), Jos H. Beijnen (1,3,4), Alwin D.R. Huitema (1,5,6)

Antoni van Leeuwenhoek/The Netherlands Cancer Institute

Introduction: Oral docetaxel in combination with ritonavir boosting has been investigated for the treatment of solid tumours including prostate cancer [1-4]. Patients with prostate cancer have a significantly lower docetaxel and ritonavir exposure compared to patients with other solid tumours [5,6]. A lower exposure could potentially be clinically relevant since a lower docetaxel exposure after intravenous (IV) administration was associated with a significantly lower odds of neutropenia [6]. Furthermore, a lower exposure might also lead to decreased efficacy of the treatment. The observed differences in docetaxel and ritonavir pharmacokinetics might be caused by an altered metabolism via Cytochrome P450 3A (CYP3A) or an upregulated hepatic uptake, resulting in a higher clearance and lower exposure [10]. The aim of the current study is to describe the observed difference in docetaxel and ritonavir pharmacokinetics using a population pharmacokinetic model. This model will enable dose-simulations for the docetaxel-ritonavir combination to identify an effective and safe dose for patients with prostate cancer.

Objective:

Quantify the difference in ritonavir and docetaxel pharmacokinetics between patients with prostate cancer and patient with other solid tumours.

Methods: A previously published semi-physiological population pharmacokinetic model for oral docetaxel and oral ritonavir in patients with other solid tumours was used [8]. The integrated model consisted of separate models for ritonavir and docetaxel. The boosting effects of ritonavir on the pharmacokinetics of docetaxel was incorporated as a well-stirred liver model with concentration dependent inhibition of docetaxel intrinsic clearance by ritonavir. The model was updated with data from two dose-escalation studies with ModraDoc006/r [3,9]. The first study included 23 patients with metastatic castration resistant prostate cancer [3] while the second study included 25 newly diagnosed prostate cancer patients who received radiotherapy and androgen deprivation therapy next to ModraDoc006/r [9]. All patients were medically castrated. Prostate cancer was investigated as a binary covariate on ritonavir clearance and docetaxel intrinsic clearance.

Results:  Inclusion of prostate cancer as a binary covariate on ritonavir clearance resulted in a significant decrease in objective function value (dOFV) of -1450 with a decrease in IIV of 13.5%. The estimated fold-difference in ritonavir clearance for patients with prostate cancer was 2.0 (RSE: 7.2%). However, the model structurally underestimated the higher ritonavir concentrations related to the higher ritonavir doses. Peak ritonavir concentrations increased more than dose-proportionally. Since ritonavir is both a substrate and an inhibitor of CYP3A and P-glycoprotein, cumulative ritonavir dose was included as a continuous covariate in a power function on oral bioavailability. The model fit improved significantly with a dOFV of -65. The oral bioavailability of ritonavir increased exponentially with a power exponent of 0.88, resulting in a relative bioavailability of 1.4 and 1.8 for the most commonly administered cumulative doses of 300 and 400 mg ritonavir, respectively. The visual predictive check demonstrated adequate predictive performance with the median, 2.5^th and 95^th percentiles of the observations falling inside the respective confidence intervals. For docetaxel, inclusion of prostate cancer as binary covariate on intrinsic clearance resulted in a dOFV of -9 and a decrease of IIV of 3.6%. The estimated fold-difference in intrinsic clearance was 1.6.

Conclusions Patients with prostate cancer had a 2.0-fold higher ritonavir clearance and 1.6-fold higher docetaxel intrinsic clearance compared with patients with other solid tumours. These results are consistent with the hypothesis of an altered clearance in patients with prostate cancer, either due to increased CYP3A activity or upregulated hepatic transporters [10]. The final ritonavir and docetaxel models will be used for dose simulations to find a dose reaching a similar exposure to IV docetaxel.

References:

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Reference: PAGE 31 (2023) Abstr 10442 [www.page-meeting.org/?abstract=10442]

Poster: Drug/Disease Modelling - Oncology