Phase I, randomized, double-blind, placebo-controlled, single-dose escalation study of the recombinant factor VIIa variant BAY 86-6150 in hemophilia
| Autor: | J. Schroeder, Johnny Mahlangu, Jerzy Windyga, M. J. Coetzee, Michael Laffan, J. Haaning, Thynn Thynn Yee, G. Lemm, J. E. Siegel |
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| Rok vydání: | 2012 |
| Předmět: |
Adult
Male medicine.medical_specialty Adolescent Factor VIIa Pharmacology Placebo Hemophilia A Gastroenterology Hemophilia B Placebos South Africa Young Adult Pharmacokinetics Double-Blind Method Internal medicine medicine Humans Aged Prothrombin time medicine.diagnostic_test biology Dose-Response Relationship Drug business.industry Coagulants Thrombin Hematology Middle Aged Antibodies Neutralizing Recombinant Proteins Europe Treatment Outcome Tolerability Recombinant factor VIIa Pharmacodynamics biology.protein Prothrombin Time Partial Thromboplastin Time Drug Monitoring business Blood sampling Partial thromboplastin time Half-Life |
| Zdroj: | Journal of thrombosis and haemostasis : JTH. 10(5) |
| ISSN: | 1538-7836 |
| Popis: | Summary. Background: BAY 86-6150 is a new human recombinant factor VIIa variant developed for high procoagulant activity and longer action in people with hemophilia with inhibitors. Objectives: To investigate the safety, tolerability, pharmacodynamics, pharmacokinetics and immunogenicity of BAY 86-6150 in non-bleeding hemophilia subjects. Methods: The study included non-bleeding men (18–65 years of age) with moderate or severe hemophilia A or B with or without inhibitors. Sixteen subjects were randomized 3 : 1 to four cohorts of escalating doses of BAY 86-6150 (6.5, 20, 50 or 90 μg kg−1 [n = 3 per cohort]) or placebo (n = 1 per cohort); an independent data-monitoring committee reviewed previous cohort data before the next dose escalation. Blood sampling was performed predose and postdose; subjects were monitored for 50 days postdose. Results: At the tested doses, BAY 86-6150 was not associated with clinically significant adverse events or dose-limiting toxicities. BAY 86-6150 pharmacokinetics exhibited a linear dose response, with a half-life of 5–7 h. Subjects demonstrated consistent, dose-dependent thrombin generation ex vivo in platelet-poor plasma (PPP) (mean peak effect, 26–237 nm thrombin from 6.5 to 90 μg kg−1). Peak thrombin levels over time paralleled BAY 86-6150, with thrombin kinetics appearing to be slightly shorter; thus, circulating BAY 86-6150 retained activity. There were corresponding decreases in activated partial thromboplastin and prothrombin times. No subject developed de novo anti-BAY 86-6150 neutralizing antibodies during the 50-day follow-up. Conclusions: In this first-in-human, multicenter, randomized, double-blind, placebo-controlled, single-dose escalation study, BAY 86-6150 was tolerated at the highest dose (90 μg kg−1), with no safety concerns. Safety and efficacy will be further evaluated in phase II/III studies. |
| Databáze: | OpenAIRE |
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