RESUMO
PURPOSE: CTB-001, a recently developed generic version of bivalirudin, an FDA-approved anticoagulant used for prophylaxis and treatment of cardiovascular diseases, has shown good efficacy and safety in clinical trials. We characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of CTB-001 by modeling and simulation analysis. METHODS: PK/PD data were collected from a randomized, double-blind, placebo-controlled, single-dose, dose-escalation phase 1 study conducted in 24 healthy Korean male subjects. PK/PD analysis was conducted sequentially by nonlinear mixed-effects modeling implemented in NONMEM®. Monte-Carlo simulations were conducted for PK, activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT). RESULTS: The CTB-101 PK was best described by a three-compartment linear model with a saturable binding peripheral compartment. All PD endpoints showed dose-response relationship, and their changes over time paralleled those of CTB-101 concentrations. A simple maximum effect model best described the aPTT, PT in INR, PT in seconds, and TT, whereas an inhibitory simple maximum effect model best described PT in percentages. The maximum duration of effect of CTB-001 on aPTT prolongation was 52.1 s. CONCLUSIONS: The modeling and simulation analysis well-characterized the PK and PD of CTB-001 in healthy Koreans, which will be valuable for identifying optimal dosing regimens of CBT-001.
Assuntos
Anticoagulantes/farmacologia , Hirudinas/farmacologia , Modelos Biológicos , Fragmentos de Peptídeos/farmacologia , Adulto , Anticoagulantes/farmacocinética , Simulação por Computador , Relação Dose-Resposta a Droga , Método Duplo-Cego , Medicamentos Genéricos , Hirudinas/farmacocinética , Humanos , Masculino , Método de Monte Carlo , Fragmentos de Peptídeos/farmacocinética , Tempo de Protrombina , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , Resultado do Tratamento , Adulto JovemRESUMO
Bivalirudin is a valuable anticoagulant option in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention. Advantages over heparin as a parenteral anticoagulant include more predictable pharmacokinetics and pharmacodynamics, shorter half-life, no need for cofactors, some degree of antiplatelet effect, and the ability to inhibit clot-bound thrombin. Clinical evidence supporting the use of bivalirudin over heparin in current ACS guidelines, however, derives mostly from early randomised trials that may no longer reflect current management patterns, now including the use of oral antiplatelet agents more potent than clopidogrel (i.e. prasugrel or ticagrelor) and a broader implementation of strategies to reduce bleeding (i.e. radial access for percutaneous coronary intervention, and use of glycoprotein IIb/IIIa inhibitors only in bailout situations). Defining the fine balance between bivalirudin efficacy and safety over heparins in the context of other antithrombotic treatments remains a challenge in clinical practice, particularly in a fast-evolving scenario, such as ACS, where numerous new trials have been presented in very recent times. Here we provide an up-to-date overview of the evidence on the use of bivalirudin in ACS, with focus on new data, open issues, and future directions.
Assuntos
Síndrome Coronariana Aguda/terapia , Anticoagulantes/uso terapêutico , Infarto do Miocárdio/terapia , Fragmentos de Peptídeos/uso terapêutico , Intervenção Coronária Percutânea , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/economia , Síndrome Coronariana Aguda/mortalidade , Anticoagulantes/efeitos adversos , Anticoagulantes/economia , Anticoagulantes/farmacocinética , Análise Custo-Benefício , Custos de Medicamentos , Hemorragia/induzido quimicamente , Hirudinas/efeitos adversos , Hirudinas/economia , Hirudinas/farmacocinética , Humanos , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/economia , Infarto do Miocárdio/mortalidade , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/economia , Fragmentos de Peptídeos/farmacocinética , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/economia , Intervenção Coronária Percutânea/mortalidade , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/economia , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Medição de Risco , Fatores de Risco , Resultado do TratamentoAssuntos
Antitrombinas/uso terapêutico , Artroplastia de Quadril/efeitos adversos , Fibrinolíticos/uso terapêutico , Trombose Venosa/prevenção & controle , Animais , Antitrombinas/administração & dosagem , Antitrombinas/efeitos adversos , Antitrombinas/economia , Antitrombinas/farmacocinética , Esquema de Medicação , Custos de Medicamentos , Fibrinolíticos/administração & dosagem , Fibrinolíticos/efeitos adversos , Fibrinolíticos/economia , Fibrinolíticos/farmacocinética , Hirudinas/administração & dosagem , Hirudinas/efeitos adversos , Hirudinas/economia , Hirudinas/farmacocinética , Humanos , Injeções Subcutâneas , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/economia , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Trombose Venosa/etiologiaRESUMO
Desirudin is a renally eliminated direct thrombin inhibitor approved to prevent venous thromboembolism. Empiric dosage adjustment and activated partial thromboplastin time (aPTT) monitoring in patients with moderate renal impairment are recommended, but supportive data are lacking. The objective of this study was to evaluate appropriate desirudin dosing in moderate renal impairment and the effect of desirudin on aPTT in moderate renal impairment. Desirudin plasma concentration and aPTT data were extracted from 6 studies. Participants with normal renal function or moderate renal impairment (creatinine clearance [ClCr] 31-60 mL/min) were included. Pharmacokinetic and Monte Carlo simulations were done. After administration of desirudin 15 mg every 12 hours subcutaneously (SC) to steady state, peak desirudin concentrations were 35 and 47 nmol/L in the normal and moderate renal function groups, respectively. Monte Carlo simulations found median 2-hour C(max) concentrations of 51.7 nmol/L in normal renal function and 52.4 nmol/L in moderate renal impairment. Desirudin exhibits a linear relationship when the square root of desirudin concentration is plotted versus the aPTT ratio (r(2) = 0.76). These analyses support the dosing of desirudin at 15 mg every 12 hours SC without aPTT monitoring in patients with moderate renal impairment.
Assuntos
Anticoagulantes/administração & dosagem , Anticoagulantes/farmacocinética , Monitoramento de Medicamentos/métodos , Hirudinas/administração & dosagem , Hirudinas/farmacocinética , Insuficiência Renal/sangue , Anticoagulantes/sangue , Esquema de Medicação , Hirudinas/sangue , Humanos , Injeções Subcutâneas , Método de Monte Carlo , Tempo de Tromboplastina Parcial , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/sangue , Proteínas Recombinantes/farmacocinéticaRESUMO
OBJECTIVE: Bivalirudin has a short elimination half-life of approximately 25 to 30 minutes, but no antidote is available. We assessed the effect of four different strategies of modified ultrafiltration after cardiopulmonary bypass on the bivalirudin elimination and postoperative blood loss. METHODS: Five groups of seven patients undergoing elective "on-pump" coronary artery bypass grafting were enrolled in this controlled randomized investigation. The filtration strategies varied with regard to the filtration flow, the filtrate volume, the addition of vacuum suction to the filter system, and the performance of hemodiafiltration. Filtration was started after weaning from cardiopulmonary bypass (CPB). The cumulative postoperative blood drainage at 12 hours was recorded. RESULTS: Bivalirudin half-life in the control group was 0.6 +/- 0.11 hours, and the blood loss was 958 +/- 472 mL. Hemofiltration with a constant flow of 300 mL/m(2) body surface area/min and a filtrate volume of 3000 mL reduced the elimination half-life significantly to 0.47 +/- 0.11 hours. Adding the process of dialysis to hemofiltration resulted in a half-life of 0.52 +/- 0.04 hours and reduced the 12-hour postoperative blood loss significantly, compared to the control group, to 444 +/- 220 mL. The other strategies failed to augment the bivalirudin elimination and postoperative drainage effectively. CONCLUSION: Zero-balanced modified hemodiafiltration without addition of vacuum suction is effective in improving the elimination of bivalirudin after CPB and reducing the postoperative blood loss. Zero-balanced hemodiafiltration should be considered for the augmented elimination of bivalirudin in complex surgical procedures with a high risk of bleeding complications. However, larger investigations are warranted to confirm these results.
Assuntos
Anticoagulantes/farmacocinética , Ponte de Artéria Coronária/efeitos adversos , Hemodiafiltração/métodos , Hirudinas/farmacocinética , Fragmentos de Peptídeos/farmacocinética , Hemorragia Pós-Operatória/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial , Estudos Prospectivos , Proteínas Recombinantes/farmacocinética , Medição de Risco , Fatores de Risco , Fatores de TempoRESUMO
Bivalirudin (Hirulog, Angiomax) is a specific, reversible and direct thrombin inhibitor with a predictable anticoagulant effect. It is cleared by both proteolytic cleavage and renal mechanisms, predominantly glomerular filtration. Bivalirudin inhibits both circulating thrombin and fibrin bound thrombin directly by binding to thrombin catalytic site and anion-binding exosite I in a concentration-dependent manner. Bivalirudin prolongs activated partial thromboplastin time, prothrombin time, thrombin time and activated clotting time (ACT). ACT levels with bivalirudin do not correlate with its clinical efficacy. Bivalirudin with a provisional GpIIb/IIIa inhibitor is indicated in elective contemporary percutaneous coronary intervention (PCI). In respect to combined ischemic and hemorrhagic endpoints of death, myocardial infarction, unplanned urgent revascularization and major bleeding during PCI (including subgroups of patients with renal impairment and diabetes) bivalirudin is not inferior to unfractioned heparin and planned GpIIb/IIIa inhibitors. In addition, bivalirudin has been consistently shown to have significantly less in-hospital major bleeding than heparin alone or heparin in combination with a GpIIb/IIIa inhibitor. Bivalirudin appears to be also safe and effective during PCI in patients with heparin-induced thrombocytopenia. Finally, data from PCI studies support the safety and efficacy of bivalirudin, although its direct randomized comparison with unfractionated heparin is lacking.
Assuntos
Anticoagulantes/farmacologia , Anticoagulantes/toxicidade , Anticoagulantes/uso terapêutico , Hirudinas/farmacologia , Hirudinas/toxicidade , Fragmentos de Peptídeos/farmacologia , Fragmentos de Peptídeos/toxicidade , Fragmentos de Peptídeos/uso terapêutico , Angioplastia Coronária com Balão , Animais , Anticoagulantes/química , Anticoagulantes/farmacocinética , Ponte Cardiopulmonar , Doença das Coronárias/tratamento farmacológico , Análise Custo-Benefício , Hirudinas/química , Hirudinas/farmacocinética , Humanos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacocinética , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/tratamento farmacológico , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Proteínas Recombinantes/toxicidade , Trombina/antagonistas & inibidoresRESUMO
Bivalent direct thrombin inhibitors reduce ischemic risk compared to heparin. Results from randomized, double-blind clinical trials have demonstrated that bivalirudin is superior to heparin alone and as effective as heparin plus routine glycoprotein (GP) IIb/IIIa therapy for the prevention of ischemic events with a statistically significant reduction in the rate of in-hospital major bleeding.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Antitrombinas/farmacologia , Antitrombinas/uso terapêutico , Doença das Coronárias/terapia , Angioplastia Coronária com Balão , Antitrombinas/farmacocinética , Ensaios Clínicos como Assunto , Doença das Coronárias/mortalidade , Custos e Análise de Custo , Angiopatias Diabéticas/terapia , Hirudinas/economia , Hirudinas/farmacocinética , Humanos , Fragmentos de Peptídeos/economia , Fragmentos de Peptídeos/farmacocinética , Fragmentos de Peptídeos/uso terapêutico , Proteínas Recombinantes/economia , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Medição de Risco , Resultado do TratamentoRESUMO
The chemistry and pharmacology, pharmacokinetics, pharmacodynamics, adverse effects, drug interactions, dosing and administration, and pharmacoeconomics of bivalirudin are reviewed; clinical trials of bivalirudin's application in percutaneous coronary intervention (PCI) are also discussed. Bivalirudin is a direct thrombin inhibitor approved for use in PCI. It reversibly binds to thrombin's catalytic site and substrate recognition site and blocks both circulating and fibrin-bound thrombin. Peak concentrations occur in less than 5 minutes after bolus-dose administration, and its half-life is approximately 25 minutes. It is primarily eliminated renally, and dosage reduction may be required in patients with severe renal dysfunction. Two clinical trials have demonstrated that bivalirudin is at least as effective as unfractionated heparin (UFH) in preventing ischemic complications in PCI. Other trials have shown that bivalirudin has beneficial ischemic and hemorrhagic outcomes in a more modern PCI setting (i.e., intracoronary stent placement, clopidogrel, and glycoprotein IIb/IIIa-receptor inhibitors). Bivalirudin combined with provisional glycoprotein IIb/IIIa inhibitors was noninferior to UFH with planned glycoprotein IIb/IIIa inhibitors and superior to UFH alone with respect to ischemic and hemorrhagic endopoints in PCI. Major bleeding with bivalirudin has occurred in approximately 3% of patients in clinical trials, and it is not known to have any interactions with the cytochrome P-450 isoenzyme system. The acquisition cost of bivalirudin in one study was less than the combination of UFH and glycoprotein IIb/IIIa inhibitors. Bivalirudin combined with provisional glycoprotein IIb/IIIa inhibitors appears to be an acceptable alternative to the standard of care and is superior to UFH alone in PCI.
Assuntos
Angioplastia Coronária com Balão , Fibrinolíticos/uso terapêutico , Hirudinas/análogos & derivados , Fragmentos de Peptídeos/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Trombina/antagonistas & inibidores , Doença Aguda , Angioplastia Coronária com Balão/efeitos adversos , Ensaios Clínicos como Assunto , Doença das Coronárias/terapia , Interações Medicamentosas , Fibrinolíticos/economia , Fibrinolíticos/farmacocinética , Hirudinas/economia , Hirudinas/farmacocinética , Humanos , Fragmentos de Peptídeos/economia , Fragmentos de Peptídeos/farmacocinética , Proteínas Recombinantes/economia , Proteínas Recombinantes/farmacocinética , Trombose/etiologia , Trombose/prevenção & controleRESUMO
The economics of bleeding complications and the role of antithrombotic therapies in percutaneous coronary intervention (PCI) are discussed. More than 1 million PCI procedures are performed annually in the United States, at a mean cost of hospitalization of approximately $9,000 and billions of dollars in total health care costs. Ischemic complications have been reduced to the point that bleeding has become the most common complication. Bleeding complications and transfusions are also among the most costly complications in PCI, accounting for an incremental cost of hospitalization after PCI that may exceed $10,000, due to increased length of stay and the use of additional resources such as ultrasound evaluation and surgical repair of the vascular site. Anemia and transfusions are also associated with increased morbidity and mortality, contributing to additional treatment costs beyond those directly attributable to correcting the bleeding complication. In the past decade, significant reductions in heparin dose and warfarin use were associated with reduced bleeding complications, but glycoprotein IIb/IIIa inhibitors have been shown to increase the clinical and economic costs of bleeding complications. The replacement of heparin with bivalirudin is associated with significant reductions in the costs of antithrombotic therapy and in complications. Reductions in bleeding complications have become a primary target for further improvements in both clinical and economic outcomes.
Assuntos
Angioplastia Coronária com Balão/economia , Anticoagulantes/efeitos adversos , Doença das Coronárias/terapia , Hirudinas/análogos & derivados , Hospitalização/economia , Hemorragia Pós-Operatória/economia , Anticoagulantes/economia , Doença das Coronárias/economia , Heparina/efeitos adversos , Heparina/economia , Hirudinas/economia , Hirudinas/farmacocinética , Humanos , Tempo de Internação , Fragmentos de Peptídeos/economia , Fragmentos de Peptídeos/farmacocinética , Fragmentos de Peptídeos/uso terapêutico , Hemorragia Pós-Operatória/induzido quimicamente , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes/economia , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Stents/economiaRESUMO
BACKGROUND: Studies of the anticoagulant effects of hirudin, which is derived from the saliva of the leech Hirudo medicinalis, led to the development of compounds that can directly inhibit thrombin activity without the need for additional cofactors. One of these is the direct thrombin inhibitor bivalirudin, which has recently been approved by the US Food and Drug Administration for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty. OBJECTIVE: This is a review of the pharmacologic properties, efficacy, tolerability, and potential cost-effectiveness of bivalirudin in the treatment of ischemic coronary syndromes. METHODS: Articles were identified by searches of MEDLINE (1966-September 2001), International Pharmaceutical Abstracts (1970-September 2001), and the Iowa Drug Information Service (1966-September 2001) using the terms bivalirudin and Hirulog. The reference lists of retrieved articles were also reviewed for relevant articles. RESULTS: Bivalirudin is a synthetic polypeptide that directly inhibits thrombin by binding simultaneously to its active catalytic site and its substrate recognition site. After intravenous administration, peak plasma concentrations occur in 2 minutes. In patients given a 1.0-mg/kg bolus followed by a 2.5-mg/kg per hour infusion, a median activated clotting time of 346 seconds is achieved with little interpatient or intrapatient variability. Clearance of bivalirudin occurs through a combination of renal elimination and proteolytic cleavage, and doses may need to be decreased in the presence of renal dysfunction. In patients undergoing percutaneous coronary interventions, bivalirudin has been associated with equivalent efficacy but lower bleeding rates (P < 0.001) than unfractionated heparin (UFH). Data from the Hirulog Early Reperfusion/Occlusion-2 study suggest no reduction in mortality with bivalirudin compared with heparin when either is added to aspirin and streptokinase in patients with acute myocardial infarction, despite a lower reinfarction rate (P < 0.001). Experience with bivalirudin in patients with unstable angina and heparin-induced thrombocytopenia (HIT), as well as in patients receiving glycoprotein IIb/IIIla inhibitors, is limited. The differences in bleeding rates between bivalirudin and heparin in published clinical trials probably reflect differences in levels of anticoagulation achieved in comparator groups. CONCLUSIONS: Given its high cost, bivalirudin should be reserved for use as an alternative to UFH, primarily in patients with HIT, until clinical trials have more clearly demonstrated its benefits in terms of efficacy or safety.
Assuntos
Anticoagulantes/uso terapêutico , Antitrombinas/uso terapêutico , Terapia com Hirudina , Hirudinas/análogos & derivados , Fragmentos de Peptídeos/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Trombose/prevenção & controle , Angina Instável/tratamento farmacológico , Angioplastia Coronária com Balão , Anticoagulantes/efeitos adversos , Anticoagulantes/economia , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Antitrombinas/efeitos adversos , Antitrombinas/farmacocinética , Antitrombinas/farmacologia , Ensaios Clínicos como Assunto , Hirudinas/efeitos adversos , Hirudinas/economia , Hirudinas/farmacocinética , Hirudinas/farmacologia , Humanos , Infarto do Miocárdio/tratamento farmacológico , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/economia , Fragmentos de Peptídeos/farmacocinética , Fragmentos de Peptídeos/farmacologia , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/economia , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , Trombocitopenia/tratamento farmacológico , Trombose/sangue , Trombose/economiaRESUMO
Pharmacokinetic (PK) models describe the relationship between the administered dose and the concentration of drug (and/or metabolite) in the blood as a function of time. Pharmacodynamic (PD) models describe the relationship between the concentration in the blood (or the dose) and the biologic response. Population PK/PD studies aim to determine the sources of variability in the observed concentrations/responses across groups of individuals. In this article, we consider the joint modeling of PK/PD data. The natural approach is to specify a joint model in which the concentration and response data are simultaneously modeled. Unfortunately, this approach may not be optimal if, due to sparsity of concentration data, an overly simple PK model is specified. As an alternative, we propose an errors-in-variables approach in which the observed-concentration data are assumed to be measured with error without reference to a specific PK model. We give an example of an analysis of PK/PD data obtained following administration of an anticoagulant drug. The study was originally carried out in order to make dosage recommendations. The prior for the distribution of the true concentrations, which may incorporate an individual's covariate information, is derived as a predictive distribution from an earlier study. The errors-in-variables approach is compared with the joint modeling approach and more naive methods in which the observed concentrations, or the separately modeled concentrations, are substituted into the response model. Throughout, a Bayesian approach is taken with implementation via Markov chain Monte Carlo methods.
Assuntos
Biometria , Hirudinas/análogos & derivados , Modelos Biológicos , Farmacocinética , Farmacologia/estatística & dados numéricos , Anticoagulantes/farmacocinética , Anticoagulantes/farmacologia , Teorema de Bayes , Hirudinas/farmacocinética , Hirudinas/farmacologia , Humanos , Cadeias de Markov , Método de Monte Carlo , Tempo de Tromboplastina Parcial , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologiaAssuntos
Angioplastia , Anticoagulantes/uso terapêutico , Terapia com Hirudina , Hirudinas/análogos & derivados , Fragmentos de Peptídeos/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Anticoagulantes/efeitos adversos , Anticoagulantes/farmacocinética , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Honorários Farmacêuticos , Hemorragia/induzido quimicamente , Hirudinas/efeitos adversos , Hirudinas/farmacocinética , Humanos , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/farmacocinética , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/farmacocinética , Trombina/antagonistas & inibidoresRESUMO
Population pharmacokinetic data consists of dose histories, individual covariates and measured drug concentrations with associated sampling times. Population pharmacodynamic data consist of dose histories, covariates and some response measure. Population analyses, whether they be pharmacokinetic or pharmacodynamic attempt to explain the variability observed in the recorded measurements and are increasingly being seen as an important aid in drug development. In this paper a general Bayesian population pharmacokinetic/pharmacodynamic model is described and an analysis of data for the drug recombinant hirudin is presented. The model we use allows for both outliers and censoring in the concentration data and outlying individual pharmacokinetic parameters. We attempt to address directly important questions such as recommended dose size using predictive distributions for response.
Assuntos
Teorema de Bayes , Relação Dose-Resposta a Droga , Modelos Estatísticos , Coagulação Sanguínea/efeitos dos fármacos , Ensaios Clínicos Fase II como Assunto/estatística & dados numéricos , Ensaios Clínicos Fase III como Assunto/estatística & dados numéricos , Interpretação Estatística de Dados , Interações Medicamentosas , Quimioterapia Combinada , Heparina/farmacologia , Hirudinas/farmacocinética , Hirudinas/farmacologia , Humanos , Injeções Intravenosas , Cadeias de MarkovRESUMO
The pharmacokinetics and the anticoagulant effects of hirudin were investigated in 12 healthy volunteers after single subcutaneous or intravenous bolus administrations. Hirudin concentrations in citrated plasma and urine were determined with a radioimmunobioassay, which detects the inhibitor by its thrombin-binding capacity. Plasma profiles could be adequately described by the equation for an open two-compartment model (intravenous route) and by the Bateman equation (subcutaneous route), respectively. Within 24 h half of the administered hirudin dose was recovered in the urine in biologically active form. The prolongation of clotting times (activated partial thromboplastin and thrombin time) was dependent on the hirudin plasma concentration. All test subjects tolerated the hirudin injection without visible or measurable side effects. No hirudin-specific antibodies were found after single parenteral administrations.