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Pharmacokinetics of docetaxel and ritonavir after oral administration of ModraDoc006/r in patients with prostate cancer versus patients with other advanced solid tumours

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Abstract

Purpose

ModraDoc006 is a novel oral formulation of docetaxel. The clearance of intravenous docetaxel is higher in medically castrated prostate cancer patients as compared to patients with other types of solid tumours. Oral docetaxel requires co-administration ritonavir (r), which might further impact the pharmacokinetics (PK). We now compare the PK of docetaxel and ritonavir between patients with Hormone Sensitive Prostate Cancer (HSPC), metastatic Castration-Resistant Prostate Cancer (mCRPC) and other metastatic solid tumours, treated on the same dose and weekly schedule of ModraDoc006/r.

Methods

The docetaxel and ritonavir PK were compared between four patient groups from three clinical phase I trials, including eight male and eight female patients with different types of solid tumours (study 1), seven patients with HSPC (study 2) and five patients with mCRPC (study 3). All patients were treated with ModraDoc006 30 mg and ritonavir 100 mg in the morning, followed by ModraDoc006 20 mg and ritonavir 100 mg in the evening (ModraDoc006/r 30–20/100–100). For comparative purposes, the PK of six mCRPC patients that received 30–20/200–100 in study 3 were also evaluated.

Results

The maximum plasma concentration (Cmax) was significantly lower for both docetaxel and ritonavir in the prostate cancer patients as compared to the patients with other types of solid tumours treated at ModraDoc006/r 30–20/100–100. The docetaxel area under the plasma concentration versus time curve (AUC) was significantly different at this dose, with a mean AUC0-48 of 1359 ± 374 ng/mL*h (N = 8) in female patients and 894 ± 223 ng/mL*h (N = 8) in male patients with different solid tumours (study 1), 321 ± 81 (N = 7) in HSPC (study 2) and 367 ± 182 ng/mL*h (N = 5) in mCRPC (study 3). A similar pattern was observed for ritonavir. ModraDoc006/r 30–20/200–100 in six mCRPC patients led to a comparable ritonavir exposure as compared to the patients at 30–20/100–100 in study 1 and increased the docetaxel AUC0–48 to 1266 ± 473 ng/mL*h (N = 6).

Conclusion

The exposure to docetaxel and ritonavir was significantly lower in prostate cancer patients as compared to patients with other types of solid tumours, treated on ModraDoc006/r 30–20/100–100. An increase of the ritonavir dose increased the docetaxel exposure in mCRPC patients. Therefore, a different RP2D of ModraDoc006/r is pursued in castrated prostate cancer patients as compared to patients with other types of solid tumours.

Trial registration

Study 1: ClinicalTrials.gov Identifier NCT01173913, date of registration August 2, 2010. Study 2: ClinicalTrials.gov Identifier NCT03066154, date of registration February 28, 2017. Study 3: ClinicalTrials.gov Identifier NCT03136640, date of registration May 2, 2017.

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Availability of data and material

Additional data are available upon reasonable request to the authors.

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Funding

Study 1 and 2 are investigator initiated trials funded by the Netherlands Cancer Institute. Jos H Beijnen has received a grand for translational research (ZonMw code 40-41200-98-004). Study 3 was funded by Modra Pharmaceuticals BV, a spin-off company from the Netherlands Cancer Institute. For this manuscript, no additional funding was obtained.

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Authors and Affiliations

  1. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands

    Marit A. C. Vermunt, Lisa T. van der Heijden, Jeroen J. M. A. Hendrikx, Alfred H. Schinkel, Vincent A. de Weger & Jos H. Beijnen

  2. Department of Nuclear Medicine, The Netherlands Cancer Institute, Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands

    Jeroen J. M. A. Hendrikx

  3. Modra Pharmaceuticals BV, Barbara Strozzilaan 201, Amsterdam, 1083HN, The Netherlands

    Eric van der Putten & Jos H. Beijnen

  4. Department of Radiotherapy, The Netherlands Cancer Institute, Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands

    Baukelien van Triest

  5. Department of Medical Oncology and Oncogenomics, The Netherlands Cancer Institute, Antoni van Leeuwenhoek, Plesmanlaan 121, Amsterdam, 1066CX, The Netherlands

    Andries M. Bergman

  6. Department of Pharmaceutical Sciences, Utrecht University, Heidelberglaan 100, Utrecht, 3584CX, The Netherlands

    Jos H. Beijnen

Authors
  1. Marit A. C. Vermunt
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Corresponding author

Correspondence to Marit A. C. Vermunt.

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Conflict of interest

Jos H Beijnen is a part time employee and shareholder of Modra Pharmaceuticals BV and is a patent holder on oral taxane formulations. Eric van der Putten is a part-time employee and director of Modra Pharmaceuticals BV and is a partner at Aglaia Oncology Funds, which has investments in Modra Pharmaceuticals BV. The other authors declare that they have no conflict of interest.

Ethics approval

The three studies were approved by the Medical Ethical Committee of the Netherlands Cancer Institute. The studies were performed in line with the principles of the Declaration of Helsinki.

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All patients provided written informed consent before start of any study procedures according to Good Clinical Practice.

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Vermunt, M.A.C., van der Heijden, L.T., Hendrikx, J.J.M.A. et al. Pharmacokinetics of docetaxel and ritonavir after oral administration of ModraDoc006/r in patients with prostate cancer versus patients with other advanced solid tumours. Cancer Chemother Pharmacol 87, 855–869 (2021). https://doi.org/10.1007/s00280-021-04259-5

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