Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis of CTB-001, a Recently Developed Generic of Bivalirudin
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CTB-001, a recently developed generic version of bivalirudin, an FDA-approved anticoagulant used for prophylaxis and treatment of cardiovascular diseases, has shown good efficacy and safety in clinical trials. We characterized the pharmacokinetics (PK) and pharmacodynamics (PD) of CTB-001 by modeling and simulation analysis.
PK/PD data were collected from a randomized, double-blind, placebo-controlled, single-dose, dose-escalation phase 1 study conducted in 24 healthy Korean male subjects. PK/PD analysis was conducted sequentially by nonlinear mixed-effects modeling implemented in NONMEM®. Monte-Carlo simulations were conducted for PK, activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT).
The CTB-101 PK was best described by a three-compartment linear model with a saturable binding peripheral compartment. All PD endpoints showed dose-response relationship, and their changes over time paralleled those of CTB-101 concentrations. A simple maximum effect model best described the aPTT, PT in INR, PT in seconds, and TT, whereas an inhibitory simple maximum effect model best described PT in percentages. The maximum duration of effect of CTB-001 on aPTT prolongation was 52.1 s.
The modeling and simulation analysis well-characterized the PK and PD of CTB-001 in healthy Koreans, which will be valuable for identifying optimal dosing regimens of CBT-001.
Key wordsanticoagulant CTB-101 pharmacodynamics pharmacokinetics NONMEM
Activated clotting time
Activated partial thromboplastin time
Maximum binding capacity
Conditional weighted residual
Half-maximal effective concentration
Half-maximal inhibitory concentration
International normalization ratio
Association rate constant
Dissociation rate constant
This research was supported by C-TRI Co., Ltd. (Gyeonggi-do, Republic of Korea), the manufacturer of CTB-001. W.J.K. was an employee of C-TRI Co., Ltd. at the time of the study. There are no other relationships or activities that could have influenced the results and interpretation of the submitted work.
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