Mathematical modelling of the chemotherapy of Plasmodium falciparum malaria with artesunate: postulation of 'dormancy', a partial cytostatic effect of the drug, and its implication for treatment regimens

Although artesunate, one of the potent derivatives of the qinghaosu family of drugs for treating falciparum malaria, is already in use in the field, i ts therapeutic protocol has only been developed empirically by hit-or-miss. A pharmacokinetic-pharmacodynamic (PK-PD) model, required for creating suc h a protocol, is nor straightforward. Artesunate presents extremely fast ph armacokinetics. As a result the stage specificity of its action must be tre ated explicitly. Also, use of standard PK-PD modelling fails to explain the clinical results. Our PK-PD modelling of its activity leads us to the post ulation of the existence of a novel effect: a small fraction of the parasit es, as a result of chemotherapeutic pressure, become cytostatic, or 'dorman t'. At this stage, the parasite cycle is halted, making them unsusceptible to further dosing until wakening. This slows down the antimalarial activity of the drug, entailing either many frequent doses or an extended period of treatment and surveillance. Based on our modelling, we suggest a method fo r deciding on rational models of chemotherapy against falciparum malaria.