Relationship between pharmacokinetics and pharmacodynamics of tinzaparin (logiparin), a low molecular weight heparin, in dogs

Abstract

1. Pharmacodynamic models relating the plasma concentrations (C) of radioactive heparin material to anticoagulant effect (E) have been investigated after single i.v. and s.c. doses of ³H-tinzaparin (1 and 4 mg/kg), a radiolabelled low molecular weight heparin, to six dogs.

2. A counterclockwise hysteresis, characterizing the C versus E relationship, was observed in all animals after s.c., but not i.v., doses indicating a possible delay (lag-time) in the systemic availability of pharmacologically-active heparin material following extra-vascular administration. A constant (K_e) was introduced into the model to account for this hysteresis.

3. At high plasma concentrations of radioactivity (> 10 μg/ml), E was related to C by a sum of two sigmoid E_max models, whereas, at lower concentrations, this reduced to the well-known sigmoid E_max model. It was proposed that tinzaparin activates two ‘receptors’ having different affinities for the drug. The values of EC₅₀ associated with the activation of a single ‘receptor’ and of a proposed additional ‘receptor’ were 3 and 13 μg/ml of heparin material, respectively.

4. Heparin material was predominantly eliminated by renal excretion and underwent widespread tissue distribution. After s.c. administration, input of heparin material into systemic plasma was complete within 12 h post-dose, and the absorption process was characterized by a bi-exponential function.

5. We conclude that sigmoid E_max models adequately describe the C versus E relationship after s.c. and i.v. doses of ³H-tinzaparin in dogs and that the interindividual variation of the pharmacodynamic parameters derived from this model was relatively small.