Clinical pharmacology of novel anticancer drug formulations

Abstract

Studies outlined in this thesis describe the impact of drug formulations on pharmacology of anticancer drugs. It consists of four parts and starts with a review describing the mechanisms of low oral bioavailability of anti-cancer drugs and strategies for improvement of the bioavailability. The majority of new anti-cancer drugs are oral pharmaceutical formulations, consisting of new chemical entities, like molecular targeted agents and novel variants of existing drugs. The development of oral formulations is, however, often hampered by low and variable bioavailability. Since most anti-cancer drugs have a narrow therapeutic window and are dosed at or close to the maximum tolerated dose, a wide variability in bioavailability can have a negative impact on treatment outcome. The extent of oral bioavailability depends on many factors, including release of the drug from the pharmaceutical dosage form, a drug’s stability in the gastro-intestinal tract, factors affecting dissolution, the rate of passage through the gut wall and the pre-systemic metabolism in gut wall and liver. There are several strategies to reduce or to overcome these limitations. First, pharmaceutical adjustment of the formulation or the physicochemical characteristics of the drug can improve the dissolution rate and absorption. Second, pharmacological interventions by combining the drug with inhibitors of transporter proteins and/or pre-systemic metabolizing enzymes can overcome the physiological endogenous limitations. Third, chemical modification of a drug by synthesis of a derivative, salt form or prodrug could enhance the bioavailability by improving the absorption and bypassing physiological endogenous limitations.

In the three other parts of this thesis, these strategies are applied to docetaxel, paclitaxel and gemcitabine. These existing drugs are anticancer drugs with documented significant anti-tumor activity and are already in use as first or second line treatment for several malignancies. Despite their proven anti-tumor activity, the registered drug formulations or mode of administration could be responsible for severe side effects, or lead to suboptimal dosing schedules. The results of this thesis show that drug formulations can have an impact on pharmacology of anticancer drugs. These results are used for further development of novel dosage forms of docetaxel, paclitaxel and gemcitabine, but are also relevant for the development of new drugs.