Pharmaceutical Research

, 36:146 | Cite as

Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis of CTB-001, a Recently Developed Generic of Bivalirudin

  • Sungpil Han
  • Yo-Han Kim
  • Hee Youn Choi
  • Mi-Jo Kim
  • Wan Joo Kim
  • Hyunjung Park
  • Kyun-Seop Bae
  • Hyeong-Seok LimEmail author
Research Paper



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 words

anticoagulant CTB-101 pharmacodynamics pharmacokinetics NONMEM 



Activated clotting time


Activated partial thromboplastin time


Maximum binding capacity


Conditional weighted residual


Half-maximal effective concentration


Maximum effect


Half-maximal inhibitory concentration


International normalization ratio


Association rate constant


Dissociation rate constant






Prothrombin time


Thrombin time



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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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Sungpil Han
    • 1
  • Yo-Han Kim
    • 1
  • Hee Youn Choi
    • 1
  • Mi-Jo Kim
    • 1
  • Wan Joo Kim
    • 1
  • Hyunjung Park
    • 2
  • Kyun-Seop Bae
    • 1
  • Hyeong-Seok Lim
    • 1
    Email author
  1. 1.Department of Clinical Pharmacology and Therapeutics, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulSouth Korea
  2. 2.Clinical Pharmacology Laboratory, Asan Institute for Life Sciences Building, ASAN Medical CenterSeoulRepublic of Korea

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