An improved pharmacodynamic model for formation of methemoglobin by antimalarial drugs

The widely used 8-aminoquinoline antimalarial group of compounds and the derivatives such as WR242511 that are being developed for possible prophylactic anticyanide applications have complex interactions with erythrocytes. Methemoglobin (MetHb) levels following the use of this drug predicted by earlier authors grossly deviated from the observed steady state levels under multiple-dose conditions. We propose a pharmacokinetic-pharmacodynamic model to characterize literature data for blood levels of MetHb generated after administration of WR242511. The model is based on an indirect mechanism involving WR242511 putative metabolite concentration, Cm on the formation of MetHb (rate constant, kr) and on depletion of reducing equivalents leading to accumulation of MetHb. Eventual depletion of MetHb is modeled as related to the disposition of both the drug metabolite and MetHb. The rate of change of MetHb concentration in the blood under the influence of a dose of WR242511 in dogs was governed by this relationship: d[MetHb]/d(t) = kr.Cm.[Hb]-kh.[MetHb], where kr is 2.9 x 10(-5) ml.ng-1.hr-1 and kh is 0.0418 hr-1. This model was validated with multiple-dose data. The model is simple and compatible with the physiological behavior of MetHb in vivo under single-dose and multiple-dose conditions of WR242511 administration.