Analysis of antiplatelet effect of ticlopidine in humans: Modeling based on irreversible inhibition of platelet precursors in bone marrow

The relationship between plasma concentration of ticlopidine and its inhibi tory effect on platelet aggregation in human was analyzed using a pharmacok inetic/pharmacodynamic (PK/PD) model. The data of plasma concentration and inhibitory effect on platelet aggregation were taken from the literature. A two-compartment open model was fitted to plasma ticlopidine concentrations . Assuming that ticlopidine acts on platelet precursors in the bone marrow, the apparent reaction rate constant of ticlopidine and platelet precursors (K), apparent transformation rate constant of platelet precursors (k(r)) a nd apparent elimination rate constant of platelets (k(e)) were estimated. T he estimated values+/-S.D. were 1.01 +/- 1.08 ml mu g(-1) hr(-1) for K, 0.2 65 +/- 0.259 hr(-1) for k(r) and 0.0747 +/- 0.0112 hr(-1) for k(e). The ant iaggregation effects of ticlopidine on platelets after administration of 10 0, 200, and 300 mg (bid for 8 days) were simulated using the PD parameters of K, k(r), and k(e). While the antiaggregation effect reached steady state within 3-4 days without dose dependency of the interval, the maximum effec t increased with dose. Furthermore, changing the elimination rate constant of ticlopidine from the central compartment in the model significantly chan ged the duration of inhibitory effect of ticlopidine on platelet aggregatio n. Therefore, the reported long duration of antiplatelet effect after disco ntinuation of ticlopidine, which is believed to be irreversible binding to the platelet, might have been partially caused by the delayed plasma elimin ation after a long therapy of ticlopidine. On the other hand, the mean life -span of platelets in the blood estimated by 1/k(e) after administration of ticlopidine was 14 hr, far below the lifespan of platelets in the blood. F or a more detailed analysis of the antiplatelet effect of ticlopidine, the possible contribution of reversible binding of the drug to glycoprotein IIb /IIIa should be considered in future PK/PD models.