Dataset Information

Pharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials.

ABSTRACT:

Introduction

Docetaxel is widely used as intravenous (IV) chemotherapy. Oral docetaxel is co-administered with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir to increase oral bioavailability. This research explores the relationship between the pharmacokinetics (PK) and toxicity of this novel oral chemotherapy.

Methods

The patients in two phase I trials were treated with different oral docetaxel formulations in combination with ritonavir in different dose levels, ranging from 20 to 80 mg docetaxel with 100 to 200 mg ritonavir a day. The patients were categorized based on the absence or occurrence of severe treatment-related toxicity (grade ?3 or any grade leading to treatment alterations). The docetaxel area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C_max) were associated with toxicity.

Results

Thirty-four out of 138 patients experienced severe toxicity, most frequently observed as mucositis, fatigue, diarrhea, nausea and vomiting. The severe toxicity group had a significantly higher docetaxel AUC (2231 ± 1405 vs 1011 ± 830 ng/mL*h, p<0.0001) and C_max (218 ± 178 vs 119 ± 77 ng/mL, p<0.0001) as compared to the patients without severe toxicity. When extrapolated from IV PK data, the patients without severe toxicity had a similar cumulative docetaxel AUC as with standard 3-weekly IV docetaxel, while the C_max was up to 10-fold lower with oral docetaxel and ritonavir.

Conclusion

Severe toxicity was observed in 25% of the patients treated with oral docetaxel and ritonavir. This toxicity seems related to the PK, as the docetaxel AUC_0-inf and C_max were up to twofold higher in the severe toxicity group as compared to the non-severe toxicity group. Future randomized trials will provide a further evaluation of the toxicity and efficacy of the new weekly oral docetaxel and ritonavir regimen in comparison to standard IV docetaxel.

SUBMITTER: Vermunt M

PROVIDER: S-EPMC7850405 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Pharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials.

Vermunt Marit M Marchetti Serena S Beijnen Jos J

Clinical pharmacology : advances and applications 20210127

<h4>Introduction</h4>Docetaxel is widely used as intravenous (IV) chemotherapy. Oral docetaxel is co-administered with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir to increase oral bioavailability. This research explores the relationship between the pharmacokinetics (PK) and toxicity of this novel oral chemotherapy.<h4>Methods</h4>The patients in two phase I trials were treated with different oral docetaxel formulations in combination with ritonavir in different dose levels, ra ...[more]

PMID: 33536797

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Project description:BackgroundModraDoc006 is an oral formulation of docetaxel, which is co-administered with the cytochrome P450 3A4 and P-glycoprotein inhibitor ritonavir (r): ModraDoc006/r. Weekly treatment with ModraDoc006/r had been evaluated in phase I trials in patients with different types of advanced solid tumors, but up to this point in time not in patients with metastatic castration-resistant prostate cancer (mCRPC).AimWe assessed safety and pharmacokinetics (PK) of ModraDoc006/r to establish the recommended phase 2 dose (RP2D) in patients with mCRPC.MethodsmCRPC patients, treatment naïve or following abiraterone or enzalutamide treatment, were included. Dose-escalation of ModraDoc006/r was based on safety and docetaxel PK. Antitumor activity was assessed by serum prostate-specific antigen (PSA) and radiological evaluation.ResultsCohort 1 (n = 5) received once weekly ModraDoc006 30 mg with ritonavir 100 mg in the morning, and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30-20/100-100). The mean docetaxel area under the plasma concentration-time curve (mAUC0-inf) was 461 ng/mL × h with 1 dose limiting toxicity (DLT); grade 3 alanine transferase increase. In cohort 2 (n = 6, ModraDoc006/r 30-20/200-200), the mAUC0-inf was 1687 ng/mL × h with 2 DLTs; grade 3 diarrhea and mucositis. In cohort 3A (n = 6, ModraDoc006/r 30-20/200-100), the mAUC0-inf was 1517 ng/mL × h with 1 DLT; grade 3 diarrhea. In cohort 3B (n = 3, ModraDoc006/r 20-20/200-100), the mAUC0-inf was 558 ng/mL × h without DLTs. The mAUC0-inf exceeded estimated exposures of intravenous docetaxel in cohort 2 and 3A, was lower in cohort 1 and was in range in cohort 3B. PSA decreases of >50% occurred in 6/10 evaluable patients throughout the various cohorts. In five radiological evaluable patients, two confirmed partial responses were observed.ConclusionThe RP2D was established at weekly ModraDoc006/r 30-20/200-100. Observed PSA and radiological responses suggest promising clinical activity. These results have led to an ongoing randomized Phase 2b study, comparing weekly ModraDoc006/r with 3-weekly IV docetaxel in patients with mCRPC.

Dataset Information

Pharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials.

Introduction

Methods

Results

Conclusion

Publications

Pharmacokinetics and Toxicities of Oral Docetaxel Formulations Co-Administered with Ritonavir in Phase I Trials.

Similar Datasets

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