Pharmacokinetics, drug metabolism and clinical effects of the antimalarial artemisinin : Time-dependencies and modeling aspects

Abstract: The mechanism behind artemisinin time-dependent bioavailability was investigated using a rat in-situ single-pass jejunal perfusion technique. The consequence for drug combination therapy was studied in healthy volunteers and in patients with Plasmodium falciparum. In the latter, parasite versus time data was modelled using NONMEM and a pharmacodynamic model based on the parasite life cycle was developed. In addition, the hepatic in vitro metabolism of artemisinin in human and rat was assessed using microsomal preparations.The work in this thesis demonstrates that artemisinin pharmacokinetics in healthy subjects exhibit marked time-dependency with a five-fold increase in attemisinin oral clearance after seven days of administration. The absence of a corresponding change in artemisinin's half-life is compatible with that alterations in hepatic intrinsic clearance will primarily affect the bioavailability. It is unlikely that the reduced bioavailability of artemisinin can be explained by induction of P-glycoprotein or a general decrease in jejunal transport, since there was no difference in the effective permeability of rat jejunum to artemisinin after pretreatment withartemisinin. The inductive capacity by artemisinin was demonstrated by its ability to increase the CYP2C19 mediated elimination of omeprazole. The results do not indicate that CYP2C19 induction is the cause of the time-dependent pharmacokinetics of artemisinin, since the decrease in artemisinin AUC was independent of CYP2C19 phenotype. The in vitro metabolism studies supported this finding in that CYP2C19 was shown not be an enzyme of importance in artemisinin metabolism. Instead, CYP2B6 was found to be the primary enzyme with secondary contribution by CYP3A4 and CYP2A6. Artemisinin was shown not to be an inducer of CYP3A4 in humans at clinical concentrations, which is why it is unlikely that induction of gut metabolismis the cause of the time-dependent pharmacokinetics in man.In conclusion, artemisinin time-dependent bioavailability is most likely an (auto)-induction of drug metabolism phenomenon and as such can influence the pharmacokinetics of drugs given simultaneously.