Target-mediated drug disposition modeling of an anti-TFPI antibody (MG1113) in cynomolgus monkeys to predict human pharmacokinetics and pharmacodynamics.

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.

Chemiluminescence lateral flow immunoassay based on Pt nanoparticle with peroxidase activity.

A lateral flow immunoassay (LF-immunoassay) with an enhanced sensitivity and thermostability was developed by using Pt nanoparticles with a peroxidase activity. The Pt nanoparticles were synthesized by citrate reduction method, and the peroxidase activity of Pt nanoparticles was optimized by adjusting reaction conditions. The peroxidase activity was estimated by using Michaelis-Menten kinetics model with TMB as a chromogenic substrate. The kinetics parameters of KM and Vmax were calculated and compared with horseradish peroxidase (HRP). The thermal stability of the Pt nanoparticles was compared with horseradish peroxidase (HRP) according to the storage temperature and long-term storage period. The feasibility of lateral flow immunoassay with a chemiluminescent signal band was demonstrated by the detection of human chorionic gonadotropin (hCG) as a model analyte, and the sensitivity was determined to be improved by as much as 1000-fold compared to the conventional rapid test based on colored gold-colloids.

A capacitive biosensor based on an interdigitated electrode with nanoislands.

A capacitive biosensor based on an interdigitated electrode (IDE) with nanoislands was developed for label-free detection of antigen-antibody interactions. To enable sensitive capacitive detection of protein adsorption, the nanoislands were fabricated between finger electrodes of the IDE. The effect of the nanoislands on the sensitive capacitive measurement was estimated using horseradish peroxidase (HRP) as a model protein. Additionally, a parylene-A film was coated on the IDE with nanoislands to improve the efficiency of protein immobilization. By using HRP and hepatitis B virus surface antigen (HBsAg) as model analytes, the effect of the parylene-A film on the capacitive detection of protein adsorption was demonstrated.