Pharmacodynamics of intravenous and subcutaneous tinzaparin and heparin inhealthy volunteers

The pharmacodynamics of i.v. and subcutaneous (s.c.) tinzaparin sodium comp ared with heparin in healthy volunteers were studied. A randomized, open-label, five-treatment, five-period-crossover study with a Latin square design was performed in 30 healthy men to estimate tinzapari n pharmacodynamics (anti-Xa and anti-IIa activities) after single-dose im. and s.c. administration to evaluate absolute bioavailability to determine t he effect of a preservative (benzyl alcohol), to evaluate the dose-activity relationship, and to compare tinzaparin with unfractionated heparin. Treat ments were (1) heparin 5,000 units s.c., (2) tinzaparin 4,500 anti-Xa IU wi thout preservative s.c., (3) tinzaparin 4,500 anti-Xa IU without preservati ve i.v., (4) tinzaparin 12,250 anti-Xa IU with preservative s.c., and (5) t inzaparin 4,500 anti-Xa IU with preservative s.c. Blood samples for the mea surement of anti-Xa and anti-IIa activities were drawn over 24 hours. Anti- Xa and anti-IIa activities were determined by chromogenic methods; data wer e analyzed by using a noncompartmental approach. The clearance of tinzaparin based on anti-Xa activity ranged from 1.14 to 2 .04 L/hr hr. The volume of distribution was 3.1-5.0 L, suggesting that the molecular entities responsible for anti-Xa and anti-IIa, activities are con fined to the intravascular space. Mean peak anti-Xa activity occurred three to four hours after s.c. injection, independent of the dose. The mean half -life of anti-Xa activity after s.c. injection ranged from 3.41 to 4.13 hou rs and was independent of the dose. The mean absolute bioavailability of s. c. tinzaparin was 86.7%. Intersubject pharmacodynamic variability was low f or tinzaparin compared with heparin. Benzyl alcohol did not affect tinzapar in pharmacodynamics. A clear dose-activity relationship was seen for the tw o fixed doses of tinzaparin (12,250 and 4,500 IU). Single doses of tinzapar in were safe and well tolerated after administration by either route, The a nti-Xa profile of tinzaparin supports the pharmacodynamic superiority of lo w-molecular-weight heparins over standard i.v.. heparin administration. This pharmacodynamic study in healthy volunteers indicates that s.c. tinzap arin sodium was well absorbed; the presence of a preservative, benzyl alcoh ol, did not affect the activity of tinzaparin; and tinzaparin activity is d ose-related.