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Antidote strategies to reverse anticoagulation with TB‐402, a long‐acting partial inhibitor of factor VIII
Author(s) -
TANGELDER M.,
LONG C.,
EMMERECHTS J.,
JACQUEMIN M.,
PEERLINCK K.,
VANASSCHE T.,
GLAZER S.,
GIESEN P.,
HOYLAERTS M.,
VERHAMME P.
Publication year - 2012
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2012.04762.x
Subject(s) - antidote , pharmacology , medicine , toxicity
Summary. Background: TB‐402 is a partially inhibiting antibody of factor VIII that is under development as a long‐acting anticoagulant. Patients and Methods: The reversibility of FVIII inhibition by TB‐402 was evaluated in vitro after spiking with recombinant human FVIII (rhFVIII), human plasma‐derived FVIII (hpdFVIII), recombinant activated human FVII (rhFVIIa), FVIII inhibitor bypassing activity (FEIBA), and prothrombin complex concentrate (PCC). Twelve subjects were randomized to placebo or 35 or 70 IU kg −1 rhFVIII 48 h after a single dose of 620 μg kg −1 TB‐402. TB‐402 concentrations, FVIII activity (FVIII:C), activated partial thromboplastin time (APTT) and thrombin generation were measured over a period of 8 weeks. Results: In spiked samples, TB‐402 inhibited FVIII:C by 30%, prolonged APTT by 4.5 s, and reduced the peak height in the thrombin generation assay to 56% ± 13% of the control value. In the presence of 10 μg mL −1 TB‐402, rhFVIII restored FVIII:C and APTT to the values obtained in the absence of TB‐402. The inhibitory effect of TB‐402 on thrombin generation was entirely reversed by rhFVIII, hpdFVIII, rhFVIIa, FEIBA, and PCC. In men, the mean half‐life ( t 1/2 ) of TB‐402 was 14.2 days. TB‐402 lowered the endogenous thrombin potential by 23% for ∼ 35 days. Infusion of 35 IU kg −1 rhFVIII had a marginal effect, whereas 70 IU kg −1 rhFVIII restored FVIII:C, reduced APTT back to baseline for 9 h, and restored thrombin generation for ∼ 3 h. Conclusions: TB‐402 resulted in a stable long‐term anticoagulant effect. rhFVIII and other procoagulants counteracted the effect of TB‐402 temporarily, and may be effective antidotes for future clinical practice.