Skip to main content
SpringerLink
Log in

Challenges in collecting pharmacokinetic and pharmacodynamic information in an intensive care setting: PK/PD modelling of clazosentan in patients with aneurysmal subarachnoid haemorrhage

  • Clinical Trial
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

This paper describes the pharmacokinetic/pharmacodynamic modelling of clazosentan in patients with aneurysmal subarachnoid haemorrhage (aSAH), and the impact of collecting data in an intensive care unit (ICU) setting. Factors influencing data quality, analysis, and interpretation are provided with recommendations for future clinical studies in ICU settings.

Methods

CONSCIOUS-2 was a phase III study involving 1,157 patients with aSAH. Secured by surgical clipping, patients were infused with clazosentan or placebo for up to 14 days post-aSAH. Clazosentan exposure relationships with vital signs, QT intervals, and AST/ALT values as well as efficacy and safety endpoints were characterised using population PK/PD and logistic regression models.

Results

Clazosentan clearance was influenced by age, sex, Asian origin, and disease status at baseline, and increased with time. Volume of distribution showed a sex difference. Exposure had no relationship with any efficacy endpoint or ALT/AST values, but was related to the increasing probability of lung complications. Blood pressure decreased proportionally to clazosentan concentrations, and the presence of clazosentan was associated with QT interval increases. Implausible values in the concentration data reflect the specific ICU challenges, possibly arising from PK sampling from the infusion arm or haemodilution.

Conclusions

Population PK/PD modelling of CONCIOUS-2 data provided clinically relevant knowledge about various effects of clazosentan in the aSAH patient population in a real clinical setting. The quality of data and analyses could be improved by the collection of additional data and stricter training of study personnel. Differences in clinical practice between sites and geographical regions are more challenging to overcome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Hackett ML, Anderson CS (2000) Health outcomes 1 year after subarachnoid hemorrhage. An international population-based study. Neurology 55:658–662

    Article  CAS  PubMed  Google Scholar 

  2. Mayer SA, Kreiter KT, Copeland D et al (2002) Global and domain-specific cognitive impairment and outcome after subarachnoid hemorrhage. Neurology 59:1750–1758

    Article  CAS  PubMed  Google Scholar 

  3. Dorhout Mees SM, Rinkel GJ, Feigin (2007) Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 3:CD000277

    PubMed  Google Scholar 

  4. Egge A, Waterloo K, Sjoholm H, Solberg T, Ingebrigtsen T, Romner B (2001) Prophylactic hyperdynamic postoperative fluid therapy after aneurysmal subarachnoid hemorrhage: a clinical, prospective, randomized, controlled study. Neurosurgery 49:593–606

    CAS  PubMed  Google Scholar 

  5. Rabinstein AA, Lanzino G, Wijdicks EF et al (2010) Multidisciplinary management and emerging therapeutic strategies in aneurysmal subarachnoid haemorrhage. Lancet Neurol 9:504–519

    Article  CAS  PubMed  Google Scholar 

  6. Gaab MR, Haubitz I, Brawanski A, Korn A, Czech T (1985) Acute effects of nimodipine on the cerebral blood flow and intracranial pressure. Neurochirurgia 28(Suppl 1):93–99

    PubMed  Google Scholar 

  7. Pickard JD, Murray GD, Illingworth R et al (1990) Oral nimodipine and cerebral ischaemia following subarachnoid haemorrhage. Br J Clin Pract 44:66–67

    CAS  PubMed  Google Scholar 

  8. Tettenborn D, Dycka J (1990) Prevention and treatment of delayed ischemic dysfunction in patients with aneurysmal subarachnoid hemorrhage. Stroke 21(12 Suppl):IV85–IV89

    CAS  PubMed  Google Scholar 

  9. Macdonald RL, Pluta RM, Zhang JH (2007) Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution. Nat Clin Pract Neurol 3:256–263

    Article  CAS  PubMed  Google Scholar 

  10. Roux S, Löffler BM, Gray GA, Sprecher U, Clozel M, Clozel JP (1995) The role of endothelin in experimental cerebral vasospasm. Neurosurgery 37:78–85

    Article  CAS  PubMed  Google Scholar 

  11. van Giersbergen PL, Dingemanse J (2007) Tolerability, pharmacokinetics, and pharmacodynamics of clazosentan, a parenteral endothelin receptor antagonist. Eur J Clin Pharmacol 63:151–158

    Article  CAS  PubMed  Google Scholar 

  12. Bruderer S, Sasu B, Tsvitbaum N, Dingemanse J (2011) Influence of severe renal impairment on the pharmacokinetics of clazosentan. J Clin Pharmacol 51:413–421

    Article  CAS  PubMed  Google Scholar 

  13. Vajkoczy P, Meyer B, Weidauer S et al (2005) Clazosentan (AXV-034343), a selective endothelin a receptor antagonist, in the prevention of cerebral vasospasm following severe aneurysmal subarachnoid hemorrhage: results of a randomized, double-blind, placebo-controlled, multicenter phase IIa study. J Neurosurg 103:9–17

    Article  CAS  PubMed  Google Scholar 

  14. Macdonald RL, Kassell NF, Mayer S et al (2008) Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke 39:3015–3021

    Article  CAS  PubMed  Google Scholar 

  15. Macdonald RL, Higashida RT, Keller E et al (2010) Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials. Neurocrit Care 13:416–424

    Article  PubMed  Google Scholar 

  16. Macdonald RL, Higashida RT, Keller E et al (2011) Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomized, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol 10:618–625

    Article  CAS  PubMed  Google Scholar 

  17. Teasdale G, Jennet B (1974) Assessment of coma and impaired consciousness. A practical scale. Lancet 2:81–84

    Article  CAS  PubMed  Google Scholar 

  18. Bruderer S, Detishin V, Tsvitbaum N, Dingemanse J (2011) Influence of different degrees of liver impairment on the pharmacokinetics of clazosentan. Br J Clin Pharmacol 71:52–60

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Beal S, Sheiner LB, Boeckmann A, Bauer RJ (2009) NONMEM user’s guides (1989–2009). Icon Development Solutions, Ellicott City

    Google Scholar 

  20. Visual-NM Software, version 5.1 (1998) Montpellier, France: RDPP

  21. SAS Software Package, version 8.2 (2001) Cary, NC: SAS Institute Inc

  22. Sigma Plot, version 8.02 (2002) San Jose, CA: Systat Software Inc

  23. Dingemanse J, Giersbergen PL (2004) Clinical pharmacology of bosentan, a dual endothelin receptor antagonist. Clin Pharmacokinet 43:1089–1115

    Article  CAS  PubMed  Google Scholar 

  24. Venitz J, Zack J, Gillies H, Allard M, Regnault J, Dufton C (2012) Clinical pharmacokinetics and drug-drug interactions of endothelin receptor antagonists in pulmonary arterial hypertension. J Clin Pharmacol 52:1784–1805

    Article  CAS  PubMed  Google Scholar 

  25. van Giersbergen PL, Treiber A, Dingemanse J (2009) In vitro and in vivo pharmacokinetic characteristics of clazosentan, an intravenous endothelin receptor antagonist, in humans. Int J Clin Pharmacol Ther 47:169–177

    Article  PubMed  Google Scholar 

  26. Benet LZ, Hoener BA (2002) Changes in plasma protein binding have little clinical relevance. Clin Pharm Ther 71:115–121

    Article  CAS  Google Scholar 

  27. van Giersbergen PL, Gunawardena KA, Dingemanse J (2007) Influence of ethnic origin and sex on the pharmacokinetics of clazosentan. J Clin Pharmacol 47:1374–1380

    Article  PubMed  Google Scholar 

  28. van Giersbergen PL, Dingemanse J (2007) Effect of gender on the tolerability, safety and pharmacokinetics of clazosentan following long-term infusion. Clin Drug Investig 27:797–802

    Article  PubMed  Google Scholar 

  29. van Giersbergen PL, Dingemanse J (2008) Pharmacokinetic and pharmacodynamic aspects of the interaction between clazosentan and nimodipine in healthy subjects. Acta Neurochir Suppl 104:127–130

    Article  Google Scholar 

  30. Sen J, Belli A, Albon H, Morgan L, Petzold A, Kitchen N (2003) Triple-H therapy in the management of aneurysmal subarachnoid haemorrhage. Lancet Neurol 2:614–621

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Sébastien Roux (Actelion Pharmaceuticals Ltd) is acknowledged for the helpful discussions on clinical topics. Jürgen Karg at Inovalab, Reinach, Switzerland was responsible for the bioanalytical measurements.

Conflict of interest

Actelion Pharmaceuticals Ltd provided funding for this clinical trial and for the work conducted by Eliane Fuseau (EMF Consulting). Jochen Zisowsky, Shirin Bruderer, Andreas Krause, and Jasper Dingemanse are current employees and shareholders of Actelion Pharmaceuticals Ltd.

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland

    Jochen Zisowsky, Shirin Bruderer, Andreas Krause & Jasper Dingemanse

  2. EMF Consulting, 52 Rue Marcel Roche, 13290, Les Milles, France

    Eliane Fuseau

Authors
  1. Jochen Zisowsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eliane Fuseau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shirin Bruderer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Andreas Krause
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jasper Dingemanse
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jochen Zisowsky.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Online Resource 1

(PDF 30 kb)

Online Resource 2

(PDF 30 kb)

Online Resource 3

(PDF 33 kb)

Online Resource 4

(PDF 38 kb)

Online Resource 5

(PDF 575 kb)

Online Resource 6

(PDF 206 kb)

Online Resource 7

(PDF 98 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zisowsky, J., Fuseau, E., Bruderer, S. et al. Challenges in collecting pharmacokinetic and pharmacodynamic information in an intensive care setting: PK/PD modelling of clazosentan in patients with aneurysmal subarachnoid haemorrhage. Eur J Clin Pharmacol 70, 409–419 (2014). https://doi.org/10.1007/s00228-014-1647-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-014-1647-4

Keywords

Search

Navigation