Abstract
Most anticancer chemotherapeutic drugs are given intravenously. However, there is a growing interest in developing anticancer drugs for oral application. Different classes of anticancer drugs are already orally available and widely applied such as the tyrosine kinase inhibitors (imatinib, erlotinib, gefitinib, sorafenib and sunitinib), alkylating agents (temozolamide and cyclophosphamide) and
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the 5FU prodrug, capecitabine, a drug for which the intravenous-to-oral switch has already been successfully implemented in clinical practice. One of the aims of this thesis was to investigate the oral application of docetaxel. Docetaxel has a low bioavailability due to affinity for drug transporters, especially ABCB1 (P-glycoprotein, P-gp), extensive first pass metabolism by cytochrome P450 3A4 (CYP3A4) and poor drug solubility. In previous studies it has been demonstrated that the low systemic exposure to docetaxel is primarily determined by CYP3A4 in gut and liver. Inhibition of CYP3A4 in mice using low-dose ritonavir was found to increase the systemic exposure in mice by 50-fold. In patients the apparent bioavailability of docetaxel increased to more than 100% after co-administration of ritonavir. The studies described in this thesis investigated the pharmacology of orally administered docetaxel more thoroughly in order to determine the optimal boosted oral docetaxel regimen. We demonstrated that the concept of boosting docetaxel is possible with any strong CYP3A4 inhibitor. We selected low-dose ritonavir for the further development of boosted orally administered docetaxel, since ritonavir resulted in high systemic exposure to docetaxel, had a good safety profile and since ritonavir is used as booster as standard practice in multiple anti-HIV regimens. Most studies described in this thesis were conducted with a novel solid docetaxel formulation, ModraDoc001 capsules. To improve the poor aqueous solubility, a solid dispersion formulation of docetaxel has been designed by the pharmacy of the Slotervaart Hospital. This formulation was investigated in 55 patients and resulted in high systemic exposure to docetaxel. The variability was modest and of the same order as after intravenous administration of docetaxel. This is an important finding since high variability may lead to unexpected severe toxicity or under-dosing. The safety of weekly oral docetaxel in combination with ritonavir was determined in a dose escalation study. The most observed adverse event was diarrhea with an overall incidence of 66%. Major treatment limiting adverse effects observed after intravenous therapy with docetaxel, e.g. fluid retention, hematological toxicity and infusion reactions were not observed. Consequently, high doses of dexamethason to prevent fluid retention and allergic reactions were not required. Furthermore, the anti-tumor activity observed at the two highest dose-levels strengthens the concept that oral administration of docetaxel is feasible and potentially active. Concluding, the oral application of the taxanes docetaxel and paclitaxel was found to be feasible. The presented pharmacokinetic data demonstrated that the systemic exposure to the taxanes was high and signs of antitumor activity were observed after treatment with ritonavir boosted ModraDoc001 capsules. Plans for phase II clinical testing of ritonavir boosted ModraDoc001 are made for maintenance or second line treatment of patients with non-small-cell-lung-cancer
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