A pharmacokinetic model of the adjustment of phenprocoumon (Falithrom) dosage

The model presented here is based on a phenprocoumon (PPC) standard dose calculated per kg body weight by adapting it to experimentally obtained mean values of biological half-life (t1/2) and relative volume of distribution (Vrel) of PPC taken from the literature. Moreover, this dose is apt to produce a desired plasma PPC concentration leading to an optimum pharmacodynamic effect. This dose which amounts to 35.2 micrograms PPC per kg body weight will nearly be equal to the clinically used 3-mg dose related to a normal subject of 70 kg, if an absorption loss of 15 per cent is taken into consideration. By means of mathematical equations derived for this purpose, the course of plasma PPC concentration versus time curves is simulated over a time period from the administration of a standard loading dose of 376.8 micrograms PPC per kg body weight until steady state is reached. The simulation of curves is based on the presupposition that the values of t1/2 and Vrel of PPC in an individual subject do not correspond to the values of these parameters underlying the calculation of the standard dose. More than 50 per cent of the combinations of t1/2 and Vrel tested leads to the desired plasma PPC concentration at steady state. The model is suited to estimate the extent of extreme deviations of plasma PPC concentration, i.e., further accumulation of PPC or decrease in plasma PPC level, and to obtain information about the respective combinations of t1/2 and Vrel causing these deviations. Application of the basic principles of the present model to clinical practice would allow to further optimize and individualize the adjustment of multiple dosing regimen of the oral anticoagulant PPC.