Target-mediated drug disposition modeling of an anti-TFPI antibody (MG1113) in cynomolgus monkeys to predict human pharmacokinetics and pharmacodynamics
| Autor: | Myung Eun Jung, Jin Hyun Park, Ha Wook Jung, Min Ju Kim, Eun-Young Kwak |
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| Rok vydání: | 2020 |
| Předmět: |
Male
medicine.drug_class Lipoproteins 030204 cardiovascular system & hematology Pharmacology Monoclonal antibody Models Biological 03 medical and health sciences 0302 clinical medicine Tissue factor pathway inhibitor Pharmacokinetics medicine Animals Humans Dosing biology Drug disposition business.industry Hematology Macaca fascicularis Coagulation Pharmaceutical Preparations Pharmacodynamics biology.protein Antibody business |
| Zdroj: | Journal of thrombosis and haemostasis : JTHREFERENCES. 19(6) |
| ISSN: | 1538-7836 |
| Popis: | Background MG1113 is a human monoclonal antibody of tissue factor pathway inhibitor (TFPI) under development for prophylaxis for hemophilia patients with or without inhibitors against factor VIII products, which have been used for the treatment of hemophilia. Because TFPI is a negative regulator in the extrinsic coagulation pathway, neutralization of TFPI function by MG1113 can potentially increase coagulation activity by bypassing the intrinsic coagulation pathway, which factor VIII activates. Objectives This study aims to determine the correlation between pharmacokinetics (PK) and pharmacodynamics (PD) after administering MG1113 to monkeys and to predict the PK and PD of MG1113 in humans by the Target-Mediated Drug Disposition (TMDD) model using the results from monkeys. Methods The PK profile of MG1113 and the PD effect on the free TFPI level were evaluated after intravenous (IV) and subcutaneous (SC) administrations of MG1113 (2.5, 5, and 10 mg/kg) to male cynomolgus monkeys. After setting up the PK/PD model on monkeys, PK parameters on humans were calculated using allometric scaling, and then clinically effective doses were predicted applying the TMDD model. Results and conclusions MG1113 showed nonlinear PK after both IV and SC administrations at the dosing range from 2.5 to10 mg/kg. The concentrations of MG1113 versus TFPI could be characterized a dose-response relationship using a TMDD model. The TMDD modeling and simulation built in this study were used to simulate various dosage regimens of MG1113 to apply to the first-in-human study design, and moreover expected to be referred to establish the dose for further clinical trials. |
| Databáze: | OpenAIRE |
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