Pharmacokinetic of inhaled low molecular weight heparin

Abstract

7209 Background: Treatment with Heparin and low molecular weight (LMW) Heparin is frequently used in oncology settings. Usually, these drugs are delivered by subcutaneous (s.c.) administration. Since 1963, the clinical relevance of inhalation of unfractionated as well as LMW-Heparin has been investigated in various studies with over 500 subjects. In this study, a single inhalation of the LMW-Heparin Certoparin (Mono-Embolex, Novartis) was investigated in 10 healthy subjects. The goal was to assess the pharmacokinetic behavior. Inhalations were performed using a novel inhalation system, which allows an accurate dosing in the lungs by controlling patient’s breathing pattern (AKITA). Lung deposition is about 85% of the emitted dose. Methods: 10 non-smoking healthy subjects participated in this study. Inhalation of 9000 IU of LMW-Heparin was compared to 3000 IU s.c. administration to achieve factor-Xa-activity in the plasma of 0.2 to 0.3 U/ml. Intravenous blood samples were taken 0.25, 0.5, 1, 2, 4, 6, 24, 48 hrs after administration. Factor-Xa-activity in plasma was assessed using the Berichrom assay (Dade Behring, Marburg, Germany). Results: Inhalation of LMW-Heparin was well tolerated and did not result in any side effects or changes in lung function. The maximum anti-Xa-activity in the plasma was 0.3 U/ml for the s.c. administration of Certoparin and 0.32 U/ml after inhalation of 9000 IU. However, pharmacokinetics was considerably different. Inhaled LMW-Heparin resulted in a prolonged anti-Xa-activity. After 6 (24) hours, the anti-Xa-activity after s.c. administration was down at 0.16 U/ml (0.10) and after inhalation at 0.30 (0.18) U/ml. Even after 48 hrs, the anti-Xa-activity after inhalation was significantly higher than the baseline value. Comparing area under the curve (AUC), bioavailability for the inhalation was 9.4 U · h/ml ± 14% compared to 5.7 U · h/ml ± 27% after s.c. administration. Conclusions: These results suggest that with controlled inhalation, this administration route is an attractive alternative to s.c. administration, with the result of longer bioavailability and less variability. A once daily administration is possible. Inhalation therapy with these kind of systems might also be useful with different anticancer agents, which cannot be administered orally. [Table: see text]