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

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 04:00 and at its trough at 22:00, 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.