Kinetics of pharmacologic effects in man: The anticoagulant action of warfarin

The kinetics of many pharmacologic effects of drugs in man can be described by mathematical expressions that are based on apparent first‐order elimination of the drug and on an essentially linear relationship (over the clinically significant range) between the intensity of the elicited effect and the logarithm of the dose or concentration of the drug in the blood. The maximum prothrombinopenic response to the coumarin anticoagulant drug, warfarin, appears 2 to 4 days after the administration of a single dose of the drug and the occurrence of the peak plasma levels. However, it is shown in the present study that the pharmacologic effect of warfarin, when expressed in terms of the degree of inhibition of “prothrombin complex activity synthesis rate,” follows the classical relationship previously described. Thus, there is a linear relationship between the logarithm of drug concentration in plasma at a given time and the pharmacologic effect at that time, and the pharmacologic effect declines at a constant rate following cessation of therapy. The prothrombinopenic effect of warfarin as a function of time after drug administration can now be predicted effectively by use of a mathematical relationship based on the dose or the initial concentration of the drug, the rate constants for warfarin elimination and for prothrombin complex activity decline, and the slope of the log‐plasma concentration‐response plot for the drug. The pharmacokinetic approach used in this study may also be applicable in principle to the kinetic analysis of other types of apparently delayed pharmacologic effects.