Establishing the dose-dependent daily variations of a low molecular weightheparin (Fraxiparine (R)) 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(R)) 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 pa rtial thromboplastin time (APTT) were measured. A population approach analy sis to assess daily variations was used. With standard methods, interindivi dual variability may mask potential time-related effects, while the populat ion approach analysis overcomes this difficulty. Bleeding time was at its peak at 04:00 and at its trough at 22:00, suggesti ng that platelet activity was time of day dependent. For the pharmacologica l activity of the drug, we compared several pharmacokinetic models derived from a monocompartmental model. The model that describes the anti-Xa pharma cological activity best is expressed through parameters that depend on anim al weight and drug level. The model for APTT is of a sinusoidal type for wh ich the clearance depends on the dosing time. The most interesting result i s that the amplitude of this daily variation is linearly dependent on drug level.