Establishing the dose-dependent daily variations of a low molecular weight heparin (Fraxiparine) through a population approach analysis in the rat.

ABSTRACT

The effects of dose and dosing time on the anticoagulant activity of a low molecular weight heparin (Fraxiparine) were studied in rats. Three doses were administered at four evenly spaced dosing times. Rats were kept under a light-dark cycle of 24h, and all the main external factors were constant. The bleeding time, the anti-Xa activity of the drug, and the activated partial thromboplastin time (APTT) were measured. A population approach analysis to assess daily variations was used. With standard methods, interindividual variability may mask potential time-related effects, while the population approach analysis overcomes this difficulty. Bleeding time was at its peak at 0400 and at its trough at 2200, suggesting that platelet activity was time of day dependent. For the pharmacological activity of the drug, we compared several pharmacokinetic models derived from a monocompartmental model. The model that describes the anti-Xa pharmacological activity best is expressed through parameters that depend on animal weight and drug level. The model for APTT is of a sinusoidal type for which the clearance depends on the dosing time. The most inter esting result is that the amplitude of this daily variation is linearly dependent on drug level.