Anticoagulant pharmacodynamics of tinzaparin following 175 IU/kg subcutaneous administration to healthy volunteers

Tinzaparin, a sodium salt of a low-molecular-weight heparin (LMWH) produced via heparinase digestion, is used for the treatment of deep vein thrombosi s (DVT) and pulmonary embolism in conjunction with warfarin for the prevent ion of DVT in patients undergoing hip or knee replacement surgery, and as a n anticoagulant in hemodialysis circuits. Its average molecular weight rang es between 5500 and 7500 daltons (Da); the percentage of chains with molecu lar weight lower than 2000 Da is not more than 10% in the marketed tinzapar in formulation. While this fraction is generally considered pharmacological ly inactive, this has never been evaluated in vivo. The importance of the < 2000 Da fraction on the anticoagulant pharmacodynamics of tinzaparin assess ed by anti-Xa and anti-IIa activity was studied in a two-way crossover tria l. In this trial, 30 healthy volunteers received a single 175 IU/kg subcuta neous administration of tinzaparin containing approximately 3.5% of the <20 00 Da fraction and a tinzaparin-like LMWH containing 18.3% of the <2000 Da fraction. The anti-Xa/anti-IIa ratios of the drug substances were comparabl e at 1.5 and 1.7 for tinzaparin and the tinzaparin-like LMWH, respectively. Both formulations were safe and well tolerated. Mean maximum plasma anti-X a activity (A(max)) was approximately 0.818 IU/ml at 4 h following tinzapar in injection. Mean maximum plasma anti-IIa activity was 0.308 IU/ml at 5 h postdose. Intersubject variation was lower (<18% for both anti-Xa and anti- IIa metrics) than in previous fixed-dose administration studies. There was no correlation between anti-Xa or anti-IIa AUC or A(max) and bodyweight in the present study supporting the weight-adjusted dosing regimen. Individual anti-Xa and anti-IIa profiles following the single 175 IU/kg subcutaneous administration of the tinzaparin-like LMWH were similar to that obtained wi th tinzaparin. Based on average equivalence criteria, the two LMWH preparat ions were determined to be bioequivalent using either anti-Xa or anti-IIa a ctivity as biomarkers. The calculated intrasubject variabilities were low ( <14% for anti-Xa activity and <18% for anti-IIa activity) yielding little e vidence for a significant Subject x Formulation interaction. In summary, an ti-Xa and anti-IIa activity following a single subcutaneous administration of tinzaparin 175 IU/kg to healthy volunteers yielded activity consistent w ith targeted therapeutic levels derived from previous trials in adult DVT p atients. Weight-based dosing for the treatment of DVT appears rational base d on the reduction in anti-Xa and anti-IIa variability consistent with the recommendation derived from earlier fixed-dose pharmacokinetic studies. Fur thermore, differences in the percentage of molecules in the < 2000 Da molec ular weight fraction of tinzaparin do not translate into differences in ant i-Xa and anti-IIa activity in vivo. (C) 2001 Elsevier Science Ltd. All righ ts reserved.