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

Vermunt, Marit A C; Heijden, Lisa T van der; Hendrikx, Jeroen J M A; Schinkel, Alfred H.; Weger, Vincent A. de; Putten, E. Van Der; Triest, Baukelien van; Bergman, Andries M.; Beijnen, Jos H.

doi:10.1007/s00280-021-04259-5

Cited by 13 publications

(22 citation statements)

References 38 publications

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“…The plasma AUC of docetaxel could be enhanced 7.3-fold with coadministration of ritonavir, whereas the plasma AUC of paclitaxel showed a 2.5-fold enhancement . These preclinical results have been used as a basis to develop oral administration regimens for paclitaxel and especially docetaxel, which are currently tested and optimized in humans. ,, Currently, an oral docetaxel formulation (ModraDoc006) in combination with ritonavir is tested in clinical trials. , Taking all results of the present study together, they form a good starting point to test an oral cabazitaxel formulation in combination with ritonavir in a small patient population. An oral drug formulation is more patient-friendly, and besides it allows metronomic chemotherapy .…”

Section: Discussionmentioning

confidence: 68%

“…9,36,37 Currently, an oral docetaxel formulation (ModraDoc006) in combination with ritonavir is tested in clinical trials. 19,36 Taking all results of the present study together, they form a good starting point to test an oral cabazitaxel formulation in combination with ritonavir in a small patient population. An oral drug formulation is more patientfriendly, and besides it allows metronomic chemotherapy.…”

Section: ■ Discussionmentioning

confidence: 84%

“…Interestingly, the low oral availability of paclitaxel and docetaxel could be enhanced with the pharmacological CYP3A inhibitor ritonavir . Originally, ritonavir was developed as an HIV protease inhibitor, but it is now often also used as an oral availability booster due to its CYP3A-inhibiting capacity in other therapy regimens, including Covid-19 treatment. − Of note, ritonavir itself is also metabolized by CYP3A and therefore there is likely higher exposure to ritonavir itself as well due to its CYP3A inhibition. , Currently, oral formulations of paclitaxel and docetaxel including ritonavir as a booster are tested in clinical studies. , As our research group is also interested in the development of an oral cabazitaxel formulation, the question came up whether ritonavir could be used as a booster for cabazitaxel as well.…”

Section: Introductionmentioning

confidence: 99%

“…17,18 Currently, oral formulations of paclitaxel and docetaxel including ritonavir as a booster are tested in clinical studies. 9,19 As our research group is also interested in the development of an oral cabazitaxel formulation, the question came up whether ritonavir could be used as a booster for cabazitaxel as well. Similar to the other two taxanes, cabazitaxel is extensively metabolized in the liver and intestine by CYP3A4/5, by approximately 80−90% and to a lesser extent by CYP2C8.…”

Section: ■ Introductionmentioning

confidence: 99%

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Enhancement of the Oral Availability of Cabazitaxel Using the Cytochrome P450 3A (CYP3A) Inhibitor Ritonavir in Mice

et al. 2023

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There is currently great interest in developing oral taxanes due to their lower costs and greater patient friendliness. We here wanted to test whether oral ritonavir, a cytochrome P450 3A (CYP3A) inhibitor, could boost the pharmacokinetics and tissue distribution of orally administered cabazitaxel (10 mg/kg) in male wild-type, Cyp3a –/–, and Cyp3aXAV (transgenic overexpression of human CYP3A4 in liver and intestine) mice. Ritonavir was initially administered at a dose of 25 mg/kg, but lower dosages of 10 and 1 mg/kg were also studied to assess the remaining amount of boosting, aiming to minimize possible side effects. Compared to the respective vehicle groups, plasma exposure of cabazitaxel (AUC0–24h) was enhanced 2.9-, 10.9-, and 13.9-fold in wild-type mice and 1.4-, 10.1-, and 34.3-fold in Cyp3aXAV mice by treatment with 1, 10, and 25 mg/kg ritonavir, respectively. Upon treatment with 1, 10, and 25 mg/kg of ritonavir, the peak plasma concentration (C max) was increased by 1.4-, 2.3-, and 2.8-fold in wild-type mice, while it increased by 1.7-, 4.2-, and 8.0-fold in Cyp3aXAV mice, respectively. AUC0–24h and C max remained unchanged in Cyp3a –/–. Biotransformation of cabazitaxel to its active metabolites still took place when coadministered with ritonavir, but this process was delayed due to the Cyp3a/CYP3A4 inhibition. These data indicate that CYP3A is the primary limiting factor in the plasma exposure to cabazitaxel and that cabazitaxel oral bioavailability could be dramatically enhanced by coadministration of an effective CYP3A inhibitor such as ritonavir. These findings could be a starting point for the setup of a clinical study, which would be needed to verify the boosting of cabazitaxel by ritonavir in humans.

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Section: Discussionmentioning

confidence: 68%

Section: ■ Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Enhancement of the Oral Availability of Cabazitaxel Using the Cytochrome P450 3A (CYP3A) Inhibitor Ritonavir in Mice

et al. 2023

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“…We have previously described the importance of hypoxia in treatment response. Several studies have explored the effect of hypoxic radiosensitizer to overcome the radioresistence mechanisms induced by low oxygen levels inside the tumour mass [ 53 , 54 , 55 , 56 , 57 ]. Among them, the DAHANCA 5 trial tested the hypoxia modifier nimorazole in combination with radiotherapy on HNSCC patients [ 58 , 59 ].…”

Section: Hncs Clinical Approachesmentioning

confidence: 99%

Precision Medicine in Head and Neck Cancers: Genomic and Preclinical Approaches

Miserocchi

Spadazzi

Calpona

et al. 2022

JPM

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Head and neck cancers (HNCs) represent the sixth most widespread malignancy worldwide. Surgery, radiotherapy, chemotherapeutic and immunotherapeutic drugs represent the main clinical approaches for HNC patients. Moreover, HNCs are characterised by an elevated mutational load; however, specific genetic mutations or biomarkers have not yet been found. In this scenario, personalised medicine is showing its efficacy. To study the reliability and the effects of personalised treatments, preclinical research can take advantage of next-generation sequencing and innovative technologies that have been developed to obtain genomic and multi-omic profiles to drive personalised treatments. The crosstalk between malignant and healthy components, as well as interactions with extracellular matrices, are important features which are responsible for treatment failure. Preclinical research has constantly implemented in vitro and in vivo models to mimic the natural tumour microenvironment. Among them, 3D systems have been developed to reproduce the tumour mass architecture, such as biomimetic scaffolds and organoids. In addition, in vivo models have been changed over the last decades to overcome problems such as animal management complexity and time-consuming experiments. In this review, we will explore the new approaches aimed to improve preclinical tools to study and apply precision medicine as a therapeutic option for patients affected by HNCs.

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Is Higher Docetaxel Clearance in Prostate Cancer Patients Explained by Higher CYP3A? An In Vivo Phenotyping Study with Midazolam

van der Heijden,

Ribbers,

Vermunt

et al. 2023

The Journal of Clinical Pharma

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Patients with Prostate Cancer (PCa) have a lower docetaxel exposure for both intravenous (1.8‐fold) and oral administration (2.4‐fold) than patients with other solid cancers, which could influence efficacy and toxicity. An altered metabolism by Cytochrome P450 3A (CYP3A) due to castration status might explain the observed difference in docetaxel pharmacokinetics. In this in vivo phenotyping, pharmacokinetic study CYP3A activity defined by midazolam clearance (Cl) was compared between patients with PCa and male patients with other solid tumors. All patients with solid tumors who did not use CYP3A modulating drugs were eligible for participation. Patients received 2 mg midazolam orally and 1 mg midazolam intravenously (IV) on two consecutive days. Plasma concentrations were measured with a validated liquid chromatography tandem mass‐spectrometry method (LC‐MS/MS). Genotyping was performed for CYP3A4 and CYP3A5. Nine patients were included in each group. Oral midazolam Cl was 1.26‐fold higher in patients with PCa compared to patients with other solid tumors (geometric mean (CV%): 94.1 (33.5%) L/h vs. 74.4 (39.1%) L/h, respectively; p = 0.08). IV midazolam Cl did not significantly differ between the two groups (p = 0.93). Moreover, the metabolic ratio of midazolam to 1’‐hydroxy midazolam did not differ between the two groups for both oral administration (p = 0.67) and IV administration (p = 0.26). CYP3A4 and CYP3A5 genotypes did not influence midazolam pharmacokinetics. The observed difference in docetaxel pharmacokinetics between both patient groups therefore appears to be neither explained by a difference in midazolam Cl nor by a difference in metabolic conversion rate of midazolam.This article is protected by copyright. All rights reserved

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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

Cited by 13 publications

References 38 publications

Enhancement of the Oral Availability of Cabazitaxel Using the Cytochrome P450 3A (CYP3A) Inhibitor Ritonavir in Mice

Enhancement of the Oral Availability of Cabazitaxel Using the Cytochrome P450 3A (CYP3A) Inhibitor Ritonavir in Mice

Precision Medicine in Head and Neck Cancers: Genomic and Preclinical Approaches

Is Higher Docetaxel Clearance in Prostate Cancer Patients Explained by Higher CYP3A? An In Vivo Phenotyping Study with Midazolam

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