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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
  • 58 Downloads

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.

Key words

anticoagulant CTB-101 pharmacodynamics pharmacokinetics NONMEM 

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

Notes

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.

References

  1. 1.
    Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl J Med. 2013;368(21):2004–13.CrossRefGoogle Scholar
  2. 2.
    Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KAA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006;114(8):774–82.CrossRefGoogle Scholar
  3. 3.
    Verheugt FWA, Steinhubl SR, Hamon M, Darius H, Steg PG, Valgimigli M, et al. Incidence, prognostic impact, and influence of antithrombotic therapy on access and nonaccess site bleeding in percutaneous coronary intervention. JACC Cardiovasc Interv. 2011;4(2):191–7.CrossRefGoogle Scholar
  4. 4.
    Di Nisio M, Middeldorp S, Büller HR. Direct thrombin inhibitors. N Engl J Med. 2005;353(10):1028–40.CrossRefGoogle Scholar
  5. 5.
    Warkentin TE, Greinacher A, Koster A. Bivalirudin. Thromb Haemost. 2008;99(5):830–9.PubMedGoogle Scholar
  6. 6.
    Hirsh J, Warkentin TE, Raschke R, Granger C, Ohman EM, Dalen JE. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest. 1998;114(5 Suppl):489S–510S.CrossRefGoogle Scholar
  7. 7.
    Allie DE, Lirtzman MD, Wyatt CH, Keller VA, Khan MH, Khan MA, et al. Bivalirudin as a foundation anticoagulant in peripheral vascular disease: a safe and feasible alternative for renal and iliac interventions. J Invasive Cardiol. 2003;15(6):334–42.PubMedGoogle Scholar
  8. 8.
    Buck ML. Bivalirudin as an Alternative to Heparin for Anticoagulation in Infants and Children. J Pediatr Pharmacol Ther. 2015;20(6):408–17.  https://doi.org/10.5863/1551-6776-20.6.408.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Edrich T, Frendl G, Rawn JD, Paschalidis Y. Modeling the effects of bivalirudin in cardiac surgical patients. Conf Proc IEEE Eng Med Biol Soc. 2011;2011:120–3.PubMedGoogle Scholar
  10. 10.
    Chai D, Wang R, Bai N, Cai Y, Liang B. Development and validation of a LC-MS/MS method for determination of bivalirudin in human plasma: application to a clinical pharmacokinetic study. Biomed Chromatogr. 2013;27(12):1788–93.CrossRefGoogle Scholar
  11. 11.
    Capodanno D, Gargiulo G, Capranzano P, Mehran R, Tamburino C, Stone GW. Bivalirudin versus heparin with or without glycoprotein IIb/IIIa inhibitors in patients with STEMI undergoing primary PCI: an updated meta-analysis of 10,350 patients from five randomized clinical trials. Eur Heart J Acute Cardiovasc Care. 2016;5(3):253–62.CrossRefGoogle Scholar
  12. 12.
    Fox I, Dawson A, Loynds P, Eisner J, Findlen K, Levin E, et al. Anticoagulant activity of Hirulog, a direct thrombin inhibitor, in humans. Thromb Haemost. 1993;69(2):157–63.CrossRefGoogle Scholar
  13. 13.
    Robson R. The use of bivalirudin in patients with renal impairment. J Invasive Cardiol. 2000;12(Suppl F):33F–6.PubMedGoogle Scholar
  14. 14.
    Shammas NW. Bivalirudin: pharmacology and clinical applications. Cardiovasc Drug Rev. 2005;23(4):345–60.CrossRefGoogle Scholar
  15. 15.
    Robson R, White H, Aylward P, Frampton C. Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose, and gender. Clin Pharmacol Ther. 2002;71(6):433–9.CrossRefGoogle Scholar

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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