Patrick Mismetti, Silvy Laporte, Pascal Girard, Hervé Decousus
Clininal Pharmacology Unit, University Hospital, Saint-Etienne and Lyon, France.
The pharmacodynamic marker generally used for adaptative control of oral anticoagulant was the Prothrombin Time (PT). But a more direct and reliable PD marker, the decarboxy prothrombin (PIVKA II) could be strongler correlated with clinical efficacy. The objectif of this study was to determine the PK-PD parameters of an oral anticoagulant (Acenocoumarol) using an indirect response model with two different PD markers: PT and PIVKA II. A single orally dose of 12 mg of acenocoumarol were given to 8 young healthy volunteers. A rich sampling had been performed resulting in 20 plasma observations per subject over a 96 hours period after acenocoumarol administration. Simultaneous analysis of PK and indirect PD was performed, using the subroutine NONMEM software version IV. We use a one-compartmental PK model to estimate apparent volume of distribution (V1) and elimination rate (K) of Acenocoumarol. We use also an indirect response model i) based on an inhibition of the synthesis for the PT marker and ii) based on an inhibition of the degradation for the PIVKA II marker. The elimination rate K and volume of distribution V1 were estimated to 0.0736 L/h and 43.4 L, yielding a half-time about 9.4 hours. The constant rate of production (Kin) of drug response for PT was about 1.2 ng/ml/h, the drug concentration yielding 50% of maximum inhibition of the drug (IC50) about 23 ng/ml, and the sigmoidicity factor (n) about 2.3. The simultaneous PK-PD model with PIVKA II is as simple as PT and the goodness of fit is comparable. We currently carry out a second study including 100 patients followed during 3 months, with a sparse sampling design and for which concentration, PT, PIVKA II and compliance data are available (electronic pill count).
Reference: PAGE 7 (1998) Abstr 283 [www.page-meeting.org/?abstract=283]
Poster: poster