Clinical Pharmacokinetics of the Antimalarial Artemisinin Based on Saliva Sampling

Sammanfattning: Artemisinin is the parent compound of a novel family of antimalarials. Repetitive administrations of artemisinin to both healthy volunteers and malaria patients have been shown to result in decreased plasma concentrations of the compound, most probably due to an autoinduction of different CYP450 enzymes. The aim of this thesis was to investigate the clinical pharmacokinetics and efficacy of different dosage regimens of the drug, and study the kinetics of the enzyme induction. Moreover, the putative interaction of the compound with blood components was investigated in vitro. Artemisinin was found to distribute into red blood cells, competing with oxygen for binding to hemoglobin. The compound was stable in plasma and, in contrast to previous reports, did not bind to red blood cell membranes. To circumvent the logistical and ethical problems associated with plasma sampling, suitability of saliva as substitute was investigated. Moreover, due to the large number of collected samples, an HPLC method, enabling a direct injection of saliva and plasma samples, was developed. Saliva artemisinin concentrations were found to correlate with its unbound plasma levels, making saliva a suitable body fluid for pharmacokinetic studies of the compound. Based on saliva samples, artemisinin was shown to exhibit a dose-dependent kinetics and efficacy in malaria patients, with a possible sex-effect on the metabolism of the compound during the first treatment day. Moreover, the time-dependent kinetics of the compound was observed in both malaria patients and healthy subjects. A physiological approach was utilized to model the autoinduction in the latter group. A model with a feedback mechanism of enzymes was able to describe the data, with estimations of the half-lives of induction (3.15 hrs) and elimination of enzymes (32.9 hrs), as well as pharmacokinetic parameters of artemisinin. In conclusion, artemisinin was found to exhibit a fast induction of enzymes, with time- and dose-dependent drug kinetics and dose-dependent antimalarial efficacy.