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

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.