Header

UZH-Logo

Maintenance Infos

Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial


Chowdary, P; Lethagen, S; Friedrich, U; Brand, B; Hay, C; Abdul Karim, F; Klamroth, R; Knoebl, P; Laffan, M; Mahlangu, J; Miesbach, W; Daalsgaard Nielsen, J; Martin-Salces, M; Angchaisuksiri, P (2015). Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial. Journal of Thrombosis and Haemostasis, 13(5):743-754.

Abstract

BACKGROUND: Prophylaxis with either intravenous (i.v.) factor VIII (FVIII) or FIX is the gold standard of care for patients with severe hemophilia. A monoclonal antibody (concizumab) targeting tissue factor pathway inhibitor (TFPI) that can be administered subcutaneously (s.c.) has the potential to alter current concepts of prophylaxis in hemophilia.
OBJECTIVES: To evaluate the safety and describe the pharmacokinetics and pharmacodynamics of single-dose concizumab in healthy volunteers and patients with hemophilia A or B.
METHODS: In this first human dose, phase 1, multicenter, randomized, double-blind, placebo-controlled trial escalating single i.v. (0.5-9000 μg kg(-1) ) or s.c. (50-3000 μg kg(-1) ) doses of concizumab were administered to healthy volunteers (n = 28) and hemophilia patients (n = 24).
RESULTS: Concizumab had a favorable safety profile after single i.v. or s.c. administration. There were no serious adverse events and no anti-concizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed due to target-mediated clearance. A maximum mean AUC0-∞ of 33 960 h μg mL(-1) and a maximum mean concentration of 247 μg mL(-1) was measured at the highest dose.
CONCLUSIONS: Concizumab showed a favorable safety profile after i.v. or s.c. administration and nonlinear pharmacokinetics was observed due to target-mediated clearance. A concentration-dependent procoagulant effect of concizumab was observed, supporting further study into the potential use of s.c. concizumab for hemophilia treatment.

Abstract

BACKGROUND: Prophylaxis with either intravenous (i.v.) factor VIII (FVIII) or FIX is the gold standard of care for patients with severe hemophilia. A monoclonal antibody (concizumab) targeting tissue factor pathway inhibitor (TFPI) that can be administered subcutaneously (s.c.) has the potential to alter current concepts of prophylaxis in hemophilia.
OBJECTIVES: To evaluate the safety and describe the pharmacokinetics and pharmacodynamics of single-dose concizumab in healthy volunteers and patients with hemophilia A or B.
METHODS: In this first human dose, phase 1, multicenter, randomized, double-blind, placebo-controlled trial escalating single i.v. (0.5-9000 μg kg(-1) ) or s.c. (50-3000 μg kg(-1) ) doses of concizumab were administered to healthy volunteers (n = 28) and hemophilia patients (n = 24).
RESULTS: Concizumab had a favorable safety profile after single i.v. or s.c. administration. There were no serious adverse events and no anti-concizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed due to target-mediated clearance. A maximum mean AUC0-∞ of 33 960 h μg mL(-1) and a maximum mean concentration of 247 μg mL(-1) was measured at the highest dose.
CONCLUSIONS: Concizumab showed a favorable safety profile after i.v. or s.c. administration and nonlinear pharmacokinetics was observed due to target-mediated clearance. A concentration-dependent procoagulant effect of concizumab was observed, supporting further study into the potential use of s.c. concizumab for hemophilia treatment.

Statistics

Citations

35 citations in Web of Science®
36 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

30 downloads since deposited on 09 Feb 2016
12 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Hematology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:May 2015
Deposited On:09 Feb 2016 12:03
Last Modified:21 Nov 2017 18:21
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1538-7933
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1111/jth.12864
PubMed ID:25641556

Download

Download PDF  'Safety and pharmacokinetics of anti-TFPI antibody (concizumab) in healthy volunteers and patients with hemophilia: a randomized first human dose trial'.
Preview
Content: Published Version
Filetype: PDF
Size: 886kB
View at publisher
Licence: Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)