Absorption and Excretion of Oral Docetaxel

Solid Tumor, Adult Clinical Trial

Official title: Absorption and Excretion of Docetaxel (as ModraDoc 006 Tablets) After Oral Administration in Combination With Ritonavir

Status Withdrawn

Clinical Trial Summary

This is an open-label, phase I study to investigate the influence of the bi-daily weekly dosing of ModraDoc006/ritonavir on the absorption and excretion of docetaxel in patients with advanced solid tumours. The pharmacokinetics, absorption and excretion of docetaxel will be investigated during the study. Patients will receive 30 mg in the morning / 20 mg in the afternoon ModraDoc006 with BID 100 mg ritonavir in a fasted condition (i.e. at least 1 hour before or 2 hours after any food assumption), followed by collection of plasma, faeces and urine samples.

Clinical Trial Description

Oral administration of (anticancer) drugs has many advantages over the intravenous route. However, oral bioavailability of the docetaxel IV-formulation is low and variable. The bioavailability of docetaxel is limited due to metabolizing cytochrome P450 (CYP) enzymes, especially CYP3A, which are abundantly present in the gastrointestinal tract. Inhibition of CYP3A4 enzymes with ritonavir has proven to enhance the bioavailability of oral docetaxel in several pre-clinical and early clinical studies. The Pharmacy of The Netherlands Cancer Institute has developed a new oral formulation of docetaxel (ModraDoc006), which contains a spray dried docetaxel powder resulting in an increased apparent solubility and therefore improved uptake from the gastrointestinal tract. The oral docetaxel ModraDoc006 tablet formulation, has been investigated in two phase I trials in combination with ritonavir. The combination of ModraDoc006/ritonavir resulted in a significantly increased bioavailability, reaching an exposure in terms of the area under plasma concentration-time curve (AUC) comparable to exposure observed after intravenous administration of weekly docetaxel at 35 mg/m2. Commonly observed toxicities in the phase I trials were nausea, diarrhea, fatigue, vomiting and alopecia, most being of grade 1-2. The metabolism of docetaxel (as ModraDoc006) after oral administration in combination with ritonavir has not been investigated yet, nor have the routes of elimination been explored. Phase I clinical trials have focused on safety and pharmacokinetics of oral docetaxel after weekly once daily and bi-daily administration. An absorption and excretion study after oral administration of a bi-daily dose of ModraDoc006/ritonavir can provide essential knowledge on the absorption, metabolism and excretion of this formulation of docetaxel. This knowledge can be used for further development. Using validated LC-MS/MS assays, docetaxel can be quantified in plasma, urine and faeces. Further analysis using a combination of chromatography, UV spectrometry and mass spectrometry may result in detection and quantification of its known metabolites M1, M2, M3 and M4 and as yet unidentified metabolites. ;

Related Conditions & MeSH terms

• Solid Tumor, Adult

• NCT number: NCT05242926
• Study type: Interventional
• Source: Modra Pharmaceuticals
• Status: Withdrawn
• Phase: Phase 1
• Start date: October 2017
• Completion date: June 2018