Studies on the pharmacokinetics and pharmacodynamics of recombinant hirudin (rHV2-Lys 47) after intravenous and subcutaneous administration in dogs

lyer, Lalitha; Koza, Michael J.; Iqbal, Omar; Calabria, Robert; Fareed, Jawed

doi:10.1016/0049-3848(93)90023-h

Cited by 8 publications

(4 citation statements)

References 11 publications

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“…The observed distribution half-life of 10 and 15 mins in horses resembles the distribution phase in man (Schenk et al 1996), dogs (Marbet et al 1993;Iyer and Fareed 1996) and rats (Markwardt et al 1988). The terminal half-life of 60-80 mins was also similar to other species (man, rats, rabbits and dogs), with reported half-lives of 0.8-1.2 h (Markwardt et al 1988(Markwardt et al , 1991Bichler et al 1991;Iyer et al 1993;Schenk et al 1996). Clearance (Cl tot = 1.9-2.7 ml/min/kg bwt) of r-hirudin was similar to that in man, with a reported clearance of 2.4-2.7 ml/min/kg bwt (Markwardt et al 1988(Markwardt et al , 1991Bichler et al 1991;Schenk et al 1996).…”

Section: Discussionsupporting

confidence: 67%

“…The pharmacokinetics of r-hirudin appear to be similar in a number of animal species (rats, rabbits, dogs) and in man (Markwardt et al 1988(Markwardt et al , 1991Iyer et al 1993;Anon 1996;Wallis 1996). Toxicity studies have been limited to laboratory animals, such as monkeys and dogs, but side effects were few, even at high dosages (Markwardt et al 1988;Anon 1996).…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics of recombinant hirudin in healthy horses

Feige

Dennler

Kästner

et al. 2004

Equine Veterinary Journal

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Summary Reasons for performing study: Recombinant (r)‐hirudin is a specific inhibitor of thrombin that is independent of the activity of antithrombin. Objectives: To evaluate pharmacokinetic properties and coagulatory changes of r‐hirudin in healthy horses. Methods: Two clinically healthy horses received a single i.v. bolus of 0.4 mg/kg bwt r‐hirudin and 6 clinically healthy horses received the same dose subcutaneously (subcut.) q. 12 h for 3 days. Coagulation times and r‐hirudin plasma concentration were determined over 720 mins and 3 days after i.v. and subcut. administration, respectively. Results: In all horses, treatment with r‐hirudin was not associated with systemic or local side effects. After i.v. injection, the 2 horses showed an elimination half‐life of 58 and 80 mins, respectively. After subcut. administration, maximum plasma concentration of r‐hirudin occurred at 128 ± 55 mins and declined with a terminal half‐life of 561 ± 364 mins. Maximum response of activated partial thromboplastin time (aPTT) occurred 1.5 h after administration of r‐hirudin. A prolongation of 1.9 ± 0.2 times the pretreatment value was noted. Conclusions: Pharmacokinetics of r‐hirudin in healthy horses were similar to those in man and other animal species. Potential relevance: The results of this study indicate that r‐hirudin can be used in horses, but further studies should be performed in order to prove its effectiveness in diseased horses.;

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of recombinant hirudin in healthy horses

Feige

Dennler

Kästner

et al. 2004

Equine Veterinary Journal

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“…The sandwich and competitive ELISA methods de scribed have been used to determine plasma concentra tions of rHV2 in pharmacokinetic studies in dogs 24,25 and rabbits. 26 These methods have also been used to quantitate rH in urine samples (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of Two Enzyme-Linked Immunosorbent Assay (ELISA) Methods for Recombinant Hirudin

Iyer¹,

Adam²,

Amiral³

et al. 1995

Semin Thromb Hemost

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Recombinant hirudin is currently being developed as a potential prophylactic and therapeutic antithrombotic drug in various clinical indications such as angina and deep venous thrombosis. In this report, we have discussed the production of specific polyclonal antibodies to recombinant hirudin (rH) and the development of two ELISA methods to measure rH concentrations in biological fluids: a sandwich and a competitive ELISA method. Intra- and inter-assay variations in the two methods are extremely low (3-7%). The competitive ELISA method is rapid, simple and highly reproducible. Saturation binding curves, selection of appropriate incubation times, recovery of different hirudin variants and reactivity in the presence of thrombin are discussed. The methods can be easily adapted to monitor hirudin concentrations in the clinical laboratory for diagnostic purposes as well as for performing pharmacokinetic studies.

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“…To estimate the maximum plasma concentration or plasma radioactive count rate, an exponential association function was fitted to the data points obtained during the infusion period and extrapolated to maximum (i.e., an estimate of steady-state levels). 12 For the bolus injection, CLtotal was calculated by dividing the total dose, or the total counts injected, by the area under the curve (AUC0-∞) of the plasma lepirudin concentration (µg/mL)-time or plasma radioactivity (radioactive count rate/ml)-time profiles. The area under the plasma concentration-time and plasma radioactive counts rate-time curves up to 90 min (AUC0-90) were calculated using the trapezoid rule.…”

Section: Methodsmentioning

confidence: 99%

Sites of elimination and pharmacokinetics of recombinant [131I]lepirudin in baboons

Meiring

Badenhorst

et al. 1999

Journal of Pharmaceutical Sciences

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Lepirudin has a short half-life, and only 50-60% of the intravenously administered dose is excreted by the kidneys. The fate of the remainder is unknown. We designed a study to determine the fate of this lepirudin. In each of six baboons, [131I]lepirudin was given intravenously as a bolus or infused over 30 min, 24 h apart. The in vivo redistribution of [131I]lepirudin was determined and quantified by scintillation camera imaging. In all studies, the half-life of [131I]lepirudin, as determined from the disappearance of radioactivity, was 21 +/- 3 min. The half-life determined from the disappearance of lepirudin, measured by the Ecarin Clotting Time (ECT) method, was similar at 23 +/- 8 min. Results obtained with the labeled lepirudin are therefore comparable with those obtained using the plasma concentration of lepirudin. When lepirudin was administered as a bolus, the half-life was 18 +/- 4 min, and lepirudin was cleared from the plasma at a rate of 42 +/- 12 mL/min and by the kidneys at 23 +/- 2 mL/min. Following infusion over 30 min, the half-life and total and renal clearances were not significantly different. In both studies, between 50 and 60% of the administered lepirudin was excreted by the kidney. Studies on sacrificed baboons showed that appreciable amounts of lepirudin were present in the bile, indicating the liver as a contributor to the elimination of lepirudin.

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Studies on the pharmacokinetics and pharmacodynamics of recombinant hirudin (rHV2-Lys 47) after intravenous and subcutaneous administration in dogs

Cited by 8 publications

References 11 publications

Pharmacokinetics of recombinant hirudin in healthy horses

Pharmacokinetics of recombinant hirudin in healthy horses

Development and Validation of Two Enzyme-Linked Immunosorbent Assay (ELISA) Methods for Recombinant Hirudin

Sites of elimination and pharmacokinetics of recombinant [131I]lepirudin in baboons

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