<scp>ModraDoc006</scp>, an oral docetaxel formulation in combination with ritonavir (<scp>ModraDoc006</scp>/r), in metastatic castration‐resistant prostate cancer patients: A phase Ib study

Vermunt, Marit A C; Robbrecht, Debbie G.J.; Devriese, Lot A.; Janssen, Julie M; Thijssen, Bram; Keessen, Marianne; Eijk, Maarten van; Kessels, Rob; Eskens, Ferry A.L.M.; Beijnen, Jos H.; Mehra, Niven; Bergman, Andries M.

doi:10.1002/cnr2.1367

Cited by 10 publications

(9 citation statements)

References 20 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%

“…10 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. 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.…”

Section: ■ Discussionmentioning

confidence: 99%

“…5,6 However, it will still be challenging to design a suitable oral formulation of cabazitaxel, but possibly a similar formulation as for oral paclitaxel and docetaxel could be considered. 9,37,39,40 ■ CONCLUSIONS…”

Section: ■ Discussionmentioning

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: 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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“…Future analyses demonstrating ABCB1 amplification as a biomarker of primary resistance to either taxane for mCRPC would allow for the consideration of alternative treatment strategies, including the selection of patients for co-administration of an inhibitor of ABCB1/P-glycoprotein. These inhibitors have shown promising activity in reversing taxane resistance in vitro [37][38][39], and ritonavir is being used as a P-glycoprotein inhibitor in combination with oral docetaxel to increase the bioavailability of the taxane [40]. Because prior clinical trials of ABCB1/P-glycoprotein inhibitors have demonstrated notable toxicities, while novel inhibitors are in development [41], the ability to select for patients most likely to benefit from these agents is potentially clinically relevant.…”

Section: Discussionmentioning

confidence: 99%

Circulating Cell-Free DNA as Biomarker of Taxane Resistance in Metastatic Castration-Resistant Prostate Cancer

Francini

Rhoades

et al. 2021

Cancers

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There are no biomarkers predictive of resistance to docetaxel or cabazitaxel validated for patients with metastatic castration-resistant prostate cancer (mCRPC). We assessed the association between ABCB1 amplification and primary resistance to docetaxel or cabazitaxel for patients with mCRPC, using circulating cell-free DNA (cfDNA). Patients with ≥1 plasma sample drawn within 12 months before starting docetaxel (cohort A) or cabazitaxel (cohort B) for mCRPC were identified from the Dana–Farber Cancer Institute IRB approved database. Sparse whole genome sequencing was performed on the selected cfDNA samples and tumor fractions were estimated using the computational tool ichorCNA. We evaluated the association between ABCB1 amplification or other copy number alterations and primary resistance to docetaxel or cabazitaxel. Of the selected 176 patients, 45 samples in cohort A and 21 samples in cohort B had sufficient tumor content. No significant association was found between ABCB1 amplification and primary resistance to docetaxel (p = 0.58; odds ratio (OR) = 1.49) or cabazitaxel (p = 0.97; OR = 1.06). No significant association was found between exploratory biomarkers and primary resistance to docetaxel or cabazitaxel. In this study, ABCB1 amplification did not predict primary resistance to docetaxel or cabazitaxel for mCRPC. Future studies including ABCB1 amplification in a suite of putative biomarkers and a larger cohort may aid in drawing definitive conclusions.

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“…Therefore, how to improve poor oral bioavailability is the key to the development of oral chemotherapeutic agents. Docetaxel as the rst line antitumor agent was currently used for prostate cancer, non-small cell lung cancer (NSCLC) [2][3]. The recommended dose schedule was intravenously administered decetaxel every 3 weeks, which was restricted by myelosuppression in clinic.…”

Section: Introductionmentioning

confidence: 99%

A self-microemulsion enhances oral absorption of docetaxel by inhibiting P-glycoprotein and CYP metabolism

Tong

Zhou²,

Wang³

et al. 2022

Drug Deliv. and Transl. Res.

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Oral absorption of docetaxel was limited by drug e ux pump p-glycoprotein (P-gp) and cytochrome P450 enzyme (CYP 450). Therefore, co-loading agent that inhibits P-gp and CYP 450 in self-nanoemulsifying drug delivery system (SMEs) is considered as a promising strategy for oral delivery of docetaxel. In this study, curcumin was selected as an inhibitor of P-gp and CYP 450, and it was coencapsuled in SMEs to improve the oral bioavailability of docetaxel. SMEs quickly dispersed in water within 20 seconds, and the droplet size was 32.23 ± 2.21 nm. The release rate of curcumin from DC-SMEs was higher than that of docetaxel in vitro. Compared with free docetaxel, SMEs signi cantly increased the permeability of docetaxel by 4.6 times. And competitive experiments showed that the increased permeability was the result of inhibition of p-gp. The half-life and oral bioavailabilty of DC-SMEs increased about 1.7 times and 1.6 times than docetaxel SMEs, which indicated that its good pharmacokinetic behavior was releated to the restriction of hepatic rst-pass metabolism. In conclusion, DC-SMEs was an ideal platform to facilitate oral delivery of docetaxel through inhibited P-gp and CYP 450.

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ModraDoc006, an oral docetaxel formulation in combination with ritonavir (ModraDoc006/r), in metastatic castration‐resistant prostate cancer patients: A phase Ib study

Cited by 10 publications

References 20 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

Circulating Cell-Free DNA as Biomarker of Taxane Resistance in Metastatic Castration-Resistant Prostate Cancer

A self-microemulsion enhances oral absorption of docetaxel by inhibiting P-glycoprotein and CYP metabolism

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