Pharmacokinetic-pharmacodynamic modelling of the antimalarial activity of mefloquine.
Treatment protocols for the chemotherapy of malaria are usually acquired through clinical trials. Once pharmacokinetic and pharmacodynamic information becomes available, it is possible to use mathematical modelling for testing these protocols and, possibly, for improving them. In this report the case of monotherapy by mefloquine is analysed. Published pharmacokinetic and clinical results are used to derive the essential model parameters such as kill rate, parasite growth rates, drug sensitivity and the pharmacokinetic parameters. Good agreement is obtained between clinical results and simulated parasite numbers using the derived parameters. It is demonstrated that the 2 exponential kinetics of mefloquine elimination can be reduced to an operational single exponent for pharmacodynamic modelling by educated choice of 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 for guiding the optimal choice of dosing intervals under different values of population pharmacokinetics, drug resistance and individual immunity parameters.
Hoshen
M B
MB
Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Israel.
Stein
W D
WD
Ginsburg
H D
HD
D000818:Animals; D000962:Antimalarials / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000378:metabolism; D008433:Mathematics; D015767:Mefloquine / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D008954:Models, Biological; D008956:Models, Chemical; D018512:Parasitemia / Q000188:drug therapy* / Q000378:metabolism; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development
D000962:Antimalarials; D015767:Mefloquine