Clinical pharmacology of novel anticancer agents: Focus on oral formulations

Abstract

The taxanes paclitaxel and docetaxel have a low oral bioavailability, as a result of poor water solubility and high first-pass effect. The water-solubility could be improved by the development of solid dispersion formulations for oral use. In this thesis it is shown that the combination of the solid dispersion and inhibitors of CYP3A4 and/or P-gp (e.g. ritonavir) the oral bioavailability of both paclitaxel and docetaxel can be increased. The combination of oral docetaxel (as ModraDoc001 capsule or ModraDoc006 tablet) with ritonavir resulted in clinically relevant exposure at the maximum tolerable dose, which was comparable to a weekly iv docetaxel dose of 35 mg/m2. Partial response was the best response to treatment. Toxicity was manageable with dose-interruptions and dose-reductions. Most common (dose-limiting) toxicities were diarrhea, nausea, vomiting and fatigue. The results are considered promising, further development of oral docetaxel in combination ritonavir is therefore persued in phase II studies. The preliminary design of one of those phase II studies is also described in the thesis. Oral paclitaxel (as ModraPac001 capsule or ModraPac005 tablet) administration in a metronomic schedule in combination with ritonavir was found feasible and safe in a phase I dose-escalation trial. Antitumor activity was thus far limited with stable disease as best response to treatment. Further development will therefore likely focus on combination treatment with other anticancer agents. The novel HDM-p53 interaction inhibitor SAR405838 was investigated in monotherapy and in combination with the MEK inhibitor pimasertib. Anti-tumor efficacy in monotherapy was limited to prolonged stable disease. It was however safe with thrombocytopenia, as the only dose-limiting toxicity. In the combination with pimasertib the antitumor activity was promising with a partial response and prolonged stable disease (>6 months) in seven patients. The toxicity associated with the combination, however led to premature discontinuation of the study. Dose-limiting toxicities were thrombocytopenia, lipase increase and inability to continue treatment as a result of grade 1-2 toxicity. Further studies are needed to ultimately assess the usefulness of this class of anticancer agents in clinical practice.