LAPORTE Silvy (1), GIRARD Pascal (2) and MISMETTI Patrick (1), for the OSAP Study Group.
(1) Thrombosis Research Group (Pr H. Decousus), Clininal Pharmacology Unit, University Hospital Bellevue, Saint-Etienne France, and (2) Pharsight, CA Mountain View USA
Background For all oral anticoagulants, the pharmacodynamic (PD) marker generally used for individual monitoring is the Prothrombin Time ratio (PTr). But other markers like the Factor II could be strongler correlated with clinical efficacy with a lower interindividual variability. In addition, some authors think that the interindividual PD variabilities with a short half-life elimination oral anticoagulant (like Acenocoumarol, Sintrom®) are higher than those observed with a long half-life drug (like Warfarin, Coumadine®). This study was designed to investigate the pharmacokinetics and pharmacodynamics, evaluated by PTr and Factor II, of multiple doses of Acenocoumarol or Warfarin in patients.
Methods In a parallel group design, 86 patients who needed an oral anticoagulant treatment for at least 3 months were randomly assigned to Acenocoumarol group or Warfarin group. During the 7-day hospitalisation, 5 blood samples were taken after the first dose, and 1 after the five following doses. The sampling times were randomly choosen within a priori sampling time windows of 4 hours. Concentrations of Acenocoumarol and Warfarin, PTr and factor II were measured. Some covariates were also considered: age, body weight and sex. A two-compartment PK model was used for both treatments, and an indirect-response pharmacodynamic model was used for each effect. Analysis were performed with NONMEM® software version V.
Results PK and PD data were avalaible for 44/44 patients in the Acenocoumarol group and 41/42 patients in the Warfarin group.
· For Acenocoumarol, the central volume of distribution (V1) seems to be influenced by body weight and age. The interindividual variablity of the constant rate elimination (K) and V1 were estimated to 47% and 32% respectively. An effect of sex on the concentration yielding 50% of maximum inhibition of the synthesis of clotting factors (C50) was found for PTr, and an effect of body weight on C50 was found for the Factor II. The inter-individual variability estimates of these parameters seem to be similar for both anticoagulant effects (see table).
· For Warfarin, V1 seems to be influenced by weight. The interindividual variablity of K and V1 were estimated to 55% and 26% respectively. An effect of age (lower or greater than 85 years) on C50 was found for PTr, and an effect of sex on Kin was found for the Factor II.
Interindividual variability estimates of PD parameters
| Acenocoumarol, PTr | Acenocoumarol, Factor II | Warfarin, PTr | Warfarin, Factor II | |
| Kin | 13 % | – | – | 59 % |
| C50 | 81 % | 63 % | 49 % | 65 % |
| Sigmoid coef. | 28 % | 4 % | 31 % | 10 % |
Discussion The first application of the indirect-response model to multiple Acenocoumarol doses, compared to multiple Warfarin doses in patients, showed that the substantial interindividual variability is similar with a short or long half-life elimination oral anticoagulant. Even if some covariates are detected, other sources of variability remain unknown.
Reference: PAGE 10 (2001) Abstr 209 [www.page-meeting.org/?abstract=209]
Poster: poster