The Use of Time Step Simulations and Difference Equations (TSSADEQ) in Modeling Heparin Pharmacokinetics

A model in which the clearance of heparin requires the binding of heparin to a finite and regenerated pool of binding was constructed using time step simulations and difference equations (TSSADEQ). A simulation of a heparin IV bolus demonstrated a dose‐dependent, triphasic pharmacokinetic curve with (1) an initial log‐linear phase representing first‐order association of heparin with binding sites, (2) an intermediate plateau phase representing constant regeneration of heparin binding sites, and (3) a terminal log‐linear phase occurring when the quantity of regenerated sites exceeded the remaining heparin. Sensitivity analysis based on the literature produced estimates of the k at 1.39 to 2.77 h−1, the pool of binding sites of 50 units/kg, and the regeneration rate of 15 to 20 unit/kg/h—virtually identical to the empirically derived guidelines for the bolus size and infusion rate for un‐fractionated heparin. A pilot study of bolus dosing of un‐fractionated heparin in normal volunteers confirmed the model.