Pharmacokinetic-pharmacodynamic modelling of the antimalarial activity of mefloquine

Treatment protocols for the chemotherapy of malaria are usually acquired th rough clinical trials. Once pharmacokinetic and pharmacodynamic information becomes available, it is possible to use mathematical modelling for testin g these protocols and, possibly, for improving them. In this report the cas e of monotherapy by mefloquine is analysed. Published pharmacokinetic and c linical results are used to derive the essential model parameters such as k ill rate, parasite growth rates, drug sensitivity and the pharmacokinetic p arameters. Good agreement is obtained between clinical results and simulate d parasite numbers using the derived parameters. It is demonstrated that th e 2 exponential kinetics of mefloquine elimination can be reduced to an ope rational single exponent for pharmacodynamic modelling by educated choice o f sampling times of plasma drug concentration. It is deduced that a second drug dose, at a properly chosen time-interval, results in radical cure even when resistant parasites are present and at maximal parasite growth rates such as those found in non-immune patients. Finally, a table is provided fo r guiding the optimal choice of dosing intervals under different values of population pharmacokinetics, drug resistance and individual immunity parame ters.