Skip to main content
SpringerLink
Log in

Caspofungin Population Pharmacokinetics in Critically Ill Patients Undergoing Continuous Veno-Venous Haemofiltration or Haemodiafiltration

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

Sepsis and continuous renal replacement therapy (CRRT) can both significantly affect antifungal pharmacokinetics. This study aimed to describe the pharmacokinetics of caspofungin in critically ill patients during different CRRT modes.

Methods

Patients receiving caspofungin and undergoing continuous veno-venous haemofiltration (CVVH) or haemodiafiltration (CVVHDF) were eligible to take part in the study. Blood samples were collected at seven sampling times during a dosing interval. Demographics and clinical data were recorded. Population pharmacokinetic analysis and Monte-Carlo simulation were undertaken using Pmetrics.

Results

Twelve pharmacokinetic profiles from nine patients were analysed. The caspofungin CRRT clearance (CL) was 0.048 ± 0.12 L/h for CVVH and 0.042 ± 0.042 L/h for CVVHDF. A two-compartment linear model best described the data. Patient weight was the only covariate affecting drug CL and central volume. The mean (standard deviation) parameter estimates were 0.64 ± 0.12 L/h for CL, 9.35 ± 3.56 L for central volume, 0.25 ± 0.19 per h for the rate constant for drug distribution from central to peripheral compartments and 0.19 ± 0.10 per h from peripheral to central compartments. Based on simulation results, a caspofungin 100 mg loading dose followed by a 50 mg maintenance dose for patients with a total body weight of ≤80 kg best achieved the pharmacokinetic/PD targets whilst a 70 mg maintenance dose was required for patients with a weight of >80 kg.

Conclusion

No caspofungin dosing adjustment is necessary for patients undergoing either form of CRRT. However, higher than recommended loading doses of caspofungin are required to achieve pharmacokinetic/pharmacodynamic targets in critically ill patients.

Registration: ClinicalTrials.gov Identifier NCT01403220

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
Fig. 4

Similar content being viewed by others

References

  1. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323–9.

    Article  CAS  PubMed  Google Scholar 

  2. Grim SA, Berger K, Teng C, Gupta S, Layden JE, Janda WM, et al. Timing of susceptibility-based antifungal drug administration in patients with Candida bloodstream infection: correlation with outcomes. J Antimicrob Chemother. 2012;67(3):707–14.

    Article  CAS  PubMed  Google Scholar 

  3. Kollef M, Micek S, Hampton N, Doherty JA, Kumar A. Septic shock attributed to Candida infection: importance of empiric therapy and source control. Clin Infect Dis. 2012;54(12):1739–46.

    Article  CAS  PubMed  Google Scholar 

  4. Bassetti M, Righi E, Ansaldi F, Merelli M, Trucchi C, De Pascale G, et al. A multicenter study of septic shock due to candidemia: outcomes and predictors of mortality. Intensive Care Med. 2014;40(6):839–45.

    Article  CAS  PubMed  Google Scholar 

  5. Roberts JA, Lipman J. Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med. 2009;37(3):840–51 (quiz 59).

    Article  CAS  PubMed  Google Scholar 

  6. Uchino S, Kellum JA, Bellomo R, Doig GS, Morimatsu H, Morgera S, et al. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005;294(7):813–8.

    Article  CAS  PubMed  Google Scholar 

  7. Friedrich JO, Wald R, Bagshaw SM, Burns KE, Adhikari NK. Hemofiltration compared to hemodialysis for acute kidney injury: systematic review and meta-analysis. Crit Care. 2012;16(4):R146.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Pea F, Viale P, Pavan F, Furlanut M. Pharmacokinetic considerations for antimicrobial therapy in patients receiving renal replacement therapy. Clin Pharmacokinet. 2007;46(12):997–1038.

    Article  CAS  PubMed  Google Scholar 

  9. Choi G, Gomersall CD, Tian Q, Joynt GM, Freebairn R, Lipman J. Principles of antibacterial dosing in continuous renal replacement therapy. Crit Care Med. 2009;37(7):2268–82.

    Article  CAS  PubMed  Google Scholar 

  10. Roger C, Wallis SC, Louart B, Lefrant JY, Lipman J, Muller L, et al. Comparison of equal doses of continuous venovenous haemofiltration and haemodiafiltration on ciprofloxacin population pharmacokinetics in critically ill patients. J Antimicrob Chemother. 2016;71(6):1643–50.

    Article  CAS  PubMed  Google Scholar 

  11. Leitner JM, Meyer B, Fuhrmann V, Saria K, Zuba C, Jager W, et al. Multiple-dose pharmacokinetics of anidulafungin during continuous venovenous haemofiltration. J Antimicrob Chemother. 2011;66(4):880–4.

    Article  CAS  PubMed  Google Scholar 

  12. Martial LC, Bruggemann RJ, Schouten JA, van Leeuwen HJ, van Zanten AR, de Lange DW, et al. Dose reduction of caspofungin in intensive care unit patients with Child Pugh B will result in suboptimal exposure. Clin Pharmacokinet. 2016;55(6):723–33. doi:10.1007/s40262-015-0347-2.

    Article  CAS  PubMed  Google Scholar 

  13. Muilwijk EW, Schouten JA, van Leeuwen HJ, van Zanten AR, de Lange DW, Colbers A, et al. Pharmacokinetics of caspofungin in ICU patients. J Antimicrob Chemother. 2014;69(12):3294–9.

    Article  CAS  PubMed  Google Scholar 

  14. Yang Q, Wang T, Xie J, Wang Y, Zheng X, Chen L, et al. Pharmacokinetic/pharmacodynamic adequacy of echinocandins against Candida spp. in intensive care unit patients and general patient populations. Int J Antimicrob Agents. 2016;47(5):397–402.

    Article  CAS  PubMed  Google Scholar 

  15. Sinnollareddy MG, Roberts JA, Lipman J, Akova M, Bassetti M, De Waele JJ, et al. Pharmacokinetic variability and exposures of fluconazole, anidulafungin, and caspofungin in intensive care unit patients: data from multinational Defining Antibiotic Levels in Intensive care unit (DALI) patients study. Crit Care. 2015;19:33.

    Article  PubMed  PubMed Central  Google Scholar 

  16. European Medicines Agency. Cancidas: EPAR. Last updated 1 Jun 2015. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000379/WC500021033.pdf. Accessed 8 July 2016.

  17. Pound MW, Townsend ML, Drew RH. Echinocandin pharmacodynamics: review and clinical implications. J Antimicrob Chemother. 2010;65(6):1108–18.

    Article  CAS  PubMed  Google Scholar 

  18. Weiler S, Seger C, Pfisterer H, Stienecke E, Stippler F, Welte R, et al. Pharmacokinetics of caspofungin in critically ill patients on continuous renal replacement therapy. Antimicrob Agents Chemother. 2013;57(8):4053–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Joannidis M, Oudemans-van Straaten HM. Clinical review: patency of the circuit in continuous renal replacement therapy. Crit Care. 2007;11(4):218.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA. 1993;270(24):2957–63.

    Article  Google Scholar 

  21. Vincent JL, de Mendonca A, Cantraine F, Moreno R, Takala J, Suter PM, et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit Care Med. 1998;26(11):1793–800.

    Article  CAS  PubMed  Google Scholar 

  22. Neely MN, van Guilder MG, Yamada WM, Schumitzky A, Jelliffe RW. Accurate detection of outliers and subpopulations with Pmetrics, a nonparametric and parametric pharmacometric modeling and simulation package for R. Ther Drug Monit. 2012;34(4):467–76.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tatarinova T, Neely M, Bartroff J, van Guilder M, Yamada W, Bayard D, et al. Two general methods for population pharmacokinetic modeling: non-parametric adaptive grid and non-parametric Bayesian. J Pharmacokinet Pharmacodyn. 2013;40(2):189–99.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Mentre F, Escolano S. Prediction discrepancies for the evaluation of nonlinear mixed-effects models. J Pharmacokinet Pharmacodyn. 2006;33(3):345–67.

    Article  PubMed  Google Scholar 

  25. Andes D, Diekema DJ, Pfaller MA, Bohrmuller J, Marchillo K, Lepak A. In vivo comparison of the pharmacodynamic targets for echinocandin drugs against Candida species. Antimicrob Agents Chemother. 2010;54(6):2497–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Pfaller MA, Messer SA, Woosley LN, Jones RN, Castanheira M. Echinocandin and triazole antifungal susceptibility profiles for clinical opportunistic yeast and mold isolates collected from 2010 to 2011: application of new CLSI clinical breakpoints and epidemiological cutoff values for characterization of geographic and temporal trends of antifungal resistance. J Clin Microbiol. 2013;51(8):2571–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Gonzalez de Molina F, Martinez-Alberici Mde L, Ferrer R. Treatment with echinocandins during continuous renal replacement therapy. Crit Care. 2014;18(2):218.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Stone JA, Xu X, Winchell GA, Deutsch PJ, Pearson PG, Migoya EM, et al. Disposition of caspofungin: role of distribution in determining pharmacokinetics in plasma. Antimicrob Agents Chemother. 2004;48(3):815–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wurthwein G, Cornely OA, Trame MN, Vehreschild JJ, Vehreschild MJ, Farowski F, et al. Population pharmacokinetics of escalating doses of caspofungin in a phase II study of patients with invasive aspergillosis. Antimicrob Agents Chemother. 2013;57(4):1664–71.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Betts RF, Nucci M, Talwar D, Gareca M, Queiroz-Telles F, Bedimo RJ, et al. A Multicenter, double-blind trial of a high-dose caspofungin treatment regimen versus a standard caspofungin treatment regimen for adult patients with invasive candidiasis. Clin Infect Dis. 2009;48(12):1676–84.

    Article  CAS  PubMed  Google Scholar 

  31. Migoya EM, Mistry GC, Stone JA, Comisar W, Sun P, Norcross A, et al. Safety and pharmacokinetics of higher doses of caspofungin in healthy adult participants. J Clin Pharmacol. 2011;51(2):202–11.

    Article  CAS  PubMed  Google Scholar 

  32. Louie A, Deziel M, Liu W, Drusano MF, Gumbo T, Drusano GL. Pharmacodynamics of caspofungin in a murine model of systemic candidiasis: importance of persistence of caspofungin in tissues to understanding drug activity. Antimicrob Agents Chemother. 2005;49(12):5058–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Espinel-Ingroff A, Arendrup MC, Pfaller MA, Bonfietti LX, Bustamante B, Canton E, et al. Interlaboratory variability of Caspofungin MICs for Candida spp. Using CLSI and EUCAST methods: should the clinical laboratory be testing this agent? Antimicrob Agents Chemother. 2013;57(12):5836–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Nguyen TH, Hoppe-Tichy T, Geiss HK, Rastall AC, Swoboda S, Schmidt J, et al. Factors influencing caspofungin plasma concentrations in patients of a surgical intensive care unit. J Antimicrob Chemother. 2007;60(1):100–6.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Loubna Elotmani, Audrey Ayral, Sophie Lloret, Jenny Ordonez and all ICU nurses for their help in sampling, collecting data and assay.

Authors’ contributions

CR made substantial contributions to conception, study design, acquisition and interpretation of data, drafting of the manuscript and approved the final version to be published. SCW made substantial contributions to acquisition, analysis and interpretation of data, revision of the manuscript for important intellectual content and approved the final version to be published. LM made substantial contributions to conception, study design, interpretation of data, drafting of the manuscript and approved the final version to be published. GS made substantial contributions to acquisition, analysis and interpretation of data, revision of the manuscript for important intellectual content and approved the final version to be published. JL made substantial contributions to conception, study design, interpretation of data, revision of the manuscript for important intellectual content and approved the final version to be published. RB made substantial contributions to interpretation of data, drafting of the manuscript and approved the final version to be published. JY made substantial contributions to conception, study design, interpretation of data, drafting of the manuscript and approved the final version to be published. JAR made substantial contributions to conception, study design, analysis and interpretation of data, drafting of the manuscript, revision of the manuscript for important intellectual content and approved the final version to be published.

Author information

Authors and Affiliations

  1. Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, Nîmes, France

    Claire Roger, Laurent Muller, Gilbert Saissi & Jean-Yves Lefrant

  2. Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Brisbane, QLD, Australia

    Claire Roger, Steven C. Wallis, Jeffrey Lipman & Jason A. Roberts

  3. School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia

    Jeffrey Lipman & Jason A. Roberts

  4. Department of Intensive Care Medicine, Royal Brisbane and Womens’ Hospital, Brisbane, QLD, Australia

    Jeffrey Lipman & Jason A. Roberts

  5. Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands

    Roger J. Brüggemann

  6. Center of Expertise in Mycology Radboudumc/CWZ, Nijmegen, The Netherlands

    Roger J. Brüggemann

  7. Radboud Institute of Health Science, Nijmegen, The Netherlands

    Roger J. Brüggemann

  8. Pharmacy Department, Royal Brisbane and Womens’ Hospital, Brisbane, QLD, Australia

    Jason A. Roberts

Authors
  1. Claire Roger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steven C. Wallis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laurent Muller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gilbert Saissi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeffrey Lipman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Roger J. Brüggemann
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jean-Yves Lefrant
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jason A. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claire Roger.

Ethics declarations

Ethics approval and consent to participate

Ethics approval was obtained from the local ethics committee in Nîmes, France (Comité de Protection des Personnes Sud Mediterranée III 2012.02.05). Written informed consent was obtained from either the patient or their nominated substitute decision maker.

Conflict of interest

JAR is funded by a Career Development Fellowship from the National Health and Medical Research Council of Australia (APP1048652). The authors would like to acknowledge other funding to the Burns Trauma Critical Care Research Centre from the National Health and Medical Research Council of Australia for a Project Grant (APP1044941) and Centre for Research Excellence (APP1099452). RJB declares that he has served as a consultant to and has received unrestricted and research grants from Astellas Pharma Inc., Gilead Sciences, Merck Sharpe and Dohme Corp., and Pfizer Inc. All payments were invoiced by the Radboud University Medical Center. CR, SW, LM, GS, JYL, JL have no conflict of interest to declare.

Funding

This work was supported by academic Grant from the Nîmes University Hospital.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 45 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Roger, C., Wallis, S.C., Muller, L. et al. Caspofungin Population Pharmacokinetics in Critically Ill Patients Undergoing Continuous Veno-Venous Haemofiltration or Haemodiafiltration. Clin Pharmacokinet 56, 1057–1068 (2017). https://doi.org/10.1007/s40262-016-0495-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-016-0495-z

Keywords

Search

Navigation