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

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Abstract

Purpose

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.

Methods

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).

Results

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.

Conclusions

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.

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Abbreviations

ACT:

Activated clotting time

aPTT:

Activated partial thromboplastin time

BCmax :

Maximum binding capacity

CWRES:

Conditional weighted residual

EC50 :

Half-maximal effective concentration

Emax :

Maximum effect

IC50 :

Half-maximal inhibitory concentration

INR:

International normalization ratio

Kassoc :

Association rate constant

Kdissoc :

Dissociation rate constant

PD:

Pharmacodynamic

PK:

Pharmacokinetic

PT:

Prothrombin time

TT:

Thrombin time

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Acknowledgments

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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Authors and Affiliations

  1. Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea

    Sungpil Han, Yo-Han Kim, Hee Youn Choi, Mi-Jo Kim, Wan Joo Kim, Kyun-Seop Bae & Hyeong-Seok Lim

  2. Clinical Pharmacology Laboratory, Asan Institute for Life Sciences Building, ASAN Medical Center, Seoul, Republic of Korea

    Hyunjung Park

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  1. Sungpil Han
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  2. Yo-Han Kim
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  4. Mi-Jo Kim
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  5. Wan Joo Kim
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Correspondence to Hyeong-Seok Lim.

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Han, S., Kim, YH., Choi, H.Y. et al. Pharmacokinetic and Pharmacodynamic Modeling and Simulation Analysis of CTB-001, a Recently Developed Generic of Bivalirudin. Pharm Res 36, 146 (2019). https://doi.org/10.1007/s11095-019-2676-6

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  • DOI: https://doi.org/10.1007/s11095-019-2676-6

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