Advertisement

Clinical Pharmacokinetics

, Volume 47, Issue 3, pp 173–180 | Cite as

Population Pharmacokinetics of Meropenem in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy

  • Arantxazu Isla
  • Alicia Rodríguez-Gascón
  • Iñaki F. Trocóniz
  • Lorea Bueno
  • María Ángeles Solinís
  • Javier Maynar
  • José Ángel Sánchez-Izquierdo
  • José Luis PedrazEmail author
Original Research Article

Abstract

Background and objective: Meropenem is a carbapenem antibacterial frequently prescribed for the treatment of severe infections in critically ill patients, including those receiving continuous renal replacement therapy (CRRT). The objective of this study was to develop a population pharmacokinetic model of meropenem in critically ill patients undergoing CRRT.

Patients and methods: A prospective, open-label study was conducted in 20 patients undergoing CRRT. Blood and dialysate-ultrafiltrate samples were obtained after administration of 500 mg, 1000 mg or 2000 mg of meropenem every 6 or 8 hours by intravenous infusion. The data were analysed under the population approach using NONMEM version V software. Age, bodyweight, dialysate plus ultrafiltrate flow, creatinine clearance (CLCR), the unbound drug fraction in plasma, the type of membrane, CRRT and the patient type (whether septic or severely polytraumatized) were the covariates studied.

Results: The pharmacokinetics of meropenem in plasma were best described by a two-compartment model. CLCR was found to have a significant correlation with the apparent total clearance (CL) of the drug during the development of the covariate model. However, the influence of CLCR on CL differed between septic and polytraumatized patients (CL = 6.63 + 0.064 × CLCR for septic patients and CL = 6.63 + 0.72 × CLCR for polytraumatized patients). The volume of distribution of the central compartment (V1) was also dependent on the patient type, with values of 15.7 L for septic patients and 69.5 L for polytraumatized patients. The population clearance was 15 L/h, and the population apparent volume of distribution of the peripheral compartment was 19.8 L. From the base to the final model, the interindividual variabilities in CL and the V1 were significantly reduced. When computer simulations were carried out and efficacy indexes were calculated, it was shown that polytraumatized patients and septic patients with conserved renal function may not achieve adequate efficacy indexes to deal with specific infections. Continuous infusion of meropenem is recommended for critically septic patients and polytraumatized patients when pathogens with a minimum inhibitory concentration (MIC) of ≥4 mg/L are isolated. Infections caused by pathogens with an MIC of ≥8 mg/L should not be treated with meropenem in polytraumatized patients without or with moderate renal failure because excessive doses of meropenem would be necessary.

Conclusion: A population pharmacokinetic model of meropenem in intensive care patients undergoing CRRT was developed and validated. CLCR and the patient type (whether septic or polytraumatized) were identified as significant covariates. The population pharmacokinetic model developed in the present study has been employed to recommend continuous infusion protocols in patients treated with CRRT.

Keywords

Minimum Inhibitory Concentration Septic Patient Meropenem Continuous Renal Replacement Therapy Patient Type 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

The authors would like to thank the Basque Government for the pre-doctoral research grant to Arantxazu Isla. No sources of funding were used to assist in the preparation of this study. The authors have no conflicts of interest that are directly relevant to the content of this study.

References

  1. 1.
    Drusano GL, Hutchison M. The pharmacokinetics of meropenem. Scand J Infect Dis 1995; 96 Suppl.: 11–6Google Scholar
  2. 2.
    Dandekar PK, Maglio D, Sutherland CA, et al. Pharmacokinetics of meropenem 0.5 and 2g every 8 hours as a 3-hour infusion. Pharmacotherapy 2003 Aug; 23(8): 988–91PubMedCrossRefGoogle Scholar
  3. 3.
    Hurst M, Lamb HM. Meropenem: a review of its use in patients in intensive care. Drugs 2000 Mar; 59(3): 653–80PubMedCrossRefGoogle Scholar
  4. 4.
    Mouton JW, van den Anker JN. Meropenem clinical pharmacokinetics. Clin Pharmacokinet 1995 Apr; 28(4): 275–86PubMedCrossRefGoogle Scholar
  5. 5.
    Pea F, Viale P, Furlanut M. Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin Pharmacokinet 2005; 44(10): 1009–34PubMedCrossRefGoogle Scholar
  6. 6.
    Thalhammer F, Hörl WH. Pharmacokinetics of meropenem in patients with renal failure and patients receiving renal replacement therapy. Clin Pharmacokinet 2000 Oct; 39(4): 271–9PubMedCrossRefGoogle Scholar
  7. 7.
    Thalhammer F, Schenk P, Burgmann H, et al. Single-dose pharmacokinetics of meropenem during continuous venovenous hemofiltration. Antimicrob Agents Chemother 1998 Sep; 42(9): 2417–20PubMedGoogle Scholar
  8. 8.
    Krueger WA, Schroeder TH, Hutchison M, et al. Pharmacokinetics of meropenem in critically ill patients with acute renal failure treated by continuous hemodiafiltration. Antimicrob Agents Chemother 1998 Sep; 42(9): 2421–4PubMedGoogle Scholar
  9. 9.
    Meyer MM, Munar MY, Kohlhepp SJ, et al. Meropenem pharmacokinetics in a patient with multiorgan failure from meningococcemia undergoing continuous venovenous hemodiafiltration. Am J Kidney Dis 1999 Apr; 33(4): 790–5PubMedCrossRefGoogle Scholar
  10. 10.
    Tegeder I, Neumann F, Bremer F, et al. Pharmacokinetics of meropenem in critically ill patients with acute renal failure undergoing continuous venovenous hemofiltration. Clin Pharmacol Ther 1999 Jan; 65(1): 50–7PubMedCrossRefGoogle Scholar
  11. 11.
    Giles LJ, Jennings AC, Thomson AH, et al. Pharmacokinetics of meropenem in intensive care unit patients receiving continuous veno-venous hemofiltration or hemodiafiltration. Crit Care Med 2000 Mar; 28(3): 632–7PubMedCrossRefGoogle Scholar
  12. 12.
    Ververs TF, van Dijk A, Vinks SA, et al. Pharmacokinetics and dosing regimen of meropenem in critically ill patients receiving continuous venovenous hemofiltration. Crit Care Med 2000 Oct; 28(10): 3412–6PubMedCrossRefGoogle Scholar
  13. 13.
    Valtonen M, Tiula E, Backman JT, et al. Elimination of meropenem during continuous veno-venous haemofiltration and haemodiafiltration in patients with acute renal failure. J Antimicrob Chemother 2000 May; 45(5): 701–4PubMedCrossRefGoogle Scholar
  14. 14.
    Krueger WA, Neeser G, Schuster H, et al. Correlation of meropenem plasma levels with pharmacodynamic requirements in critically ill patients receiving continuous veno-venous hemofiltration. Chemotherapy 2003 Dec; 49(6): 280–6PubMedCrossRefGoogle Scholar
  15. 15.
    Robatel C, Decosterd LA, Biollaz J, et al. Pharmacokinetics and dosage adaptation of meropenem during continuous venovenous hemodiafiltration in critically ill patients. J Clin Pharmacol 2003 Dec; 43(12): 1329–40PubMedCrossRefGoogle Scholar
  16. 16.
    Isla A, Maynar J, Sánchez-Izquierdo JA, et al. Meropenem and continuous renal replacement therapy: in vitro permeability of 2 continuous renal replacement therapy membranes and influence of patient renal function on the pharmacokinetics in critically ill patients. J Clin Pharmacol 2005 Nov; 45(11): 1294–304PubMedCrossRefGoogle Scholar
  17. 17.
    Sun H, Fadiran EO, Jones CD, et al. Population pharmacokinetics: a regulatory perspective. Clin Pharmacokinet 1999 Jul; 37(1): 41–58PubMedCrossRefGoogle Scholar
  18. 18.
    Bellomo R, Ronco C. Nomenclature for continuous renal replacement therapies. In: Ronco C, Bellomo R, editors. Critical care nephrology. Dordrecht: Kluwer Academic Publishers; 1998: 1169–76CrossRefGoogle Scholar
  19. 19.
    Shah VP, Midha KK, Findlay JW, et al. Bioanalytical method validation: a revisit with a decade of progress. Pharm Res 2000 Dec; 17(12): 1551–7PubMedCrossRefGoogle Scholar
  20. 20.
    US FDA. Guidance for industry: bioanalytical methods validation for human studies. Rockville (MD): Center for Drug Evaluation and Research, 1998Google Scholar
  21. 21.
    Beal SL, Sheiner LB. NONMEM user’s guide. San Francisco (CA): University of California NONMEM Project Group, 1992Google Scholar
  22. 22.
    Akaike H. A new look at the statistical model identification. IEEE Transactions on Automated Control 1974; 19: 716–23CrossRefGoogle Scholar
  23. 23.
    Wuyts B, Bernard D, Van den Noortgate N, et al. Reevaluation of formulas for predicting creatinine clearance in adults and children, using compensated creatinine methods. Clin Chem 2003 Jun; 49 (6 Pt 1): 1011–4PubMedCrossRefGoogle Scholar
  24. 24.
    Holford N. The visual predictive check: superiority to standard diagnostic (Rorschach) plots [abstract/poster no. 738; online]. Annual Meeting of the Population Approach Group in Europe, 2005 Jun 16–17; Pamplona. Available from URL: http://www.page-meeting.org/?abstract=738 [Accessed 2007 Dec 6]Google Scholar
  25. 25.
    Hanes SD, Wood GC, Herring V, et al. Intermittent and continuous ceftazidime infusion for critically ill trauma patients. Am J Surg 2000 Jun; 179(6): 436–40PubMedCrossRefGoogle Scholar
  26. 26.
    Reed RL, Ericsson CD, Wu A, et al. The pharmacokinetics of prophylactic antibiotics in trauma. J Trauma 1992 Jan; 32(1): 21–7PubMedCrossRefGoogle Scholar
  27. 27.
    Townsend PL, Fink MP, Stein KL, et al. Aminoglycoside pharmacokinetics: dosage requirements and nephrotoxicity in trauma patients. Crit Care Med 1989 Feb; 17(2): 154–7PubMedCrossRefGoogle Scholar
  28. 28.
    Botha FJ, van der Bijl P, Seifart HI, et al. Fluctuation of the volume of distribution of amikacin and its effect on once-daily dosage and clearance in a seriously ill patient. Intensive Care Med 1996 May; 22(5): 443–6PubMedCrossRefGoogle Scholar
  29. 29.
    Fernández de Gatta MM, Méndez ME, Romano S, et al. Pharmacokinetics of amikacin in intensive care unit patients. J Clin Pharm Ther 1996 Dec; 21(6): 417–21PubMedCrossRefGoogle Scholar
  30. 30.
    Arzuaga A, Maynar J, Gascón AR, et al. Influence of renal function on the pharmacokinetics of piperacillin/tazobactam in intensive care unit patients during continuous venovenous hemofiltration. J Clin Pharmacol 2005 Feb; 45(2): 168–76PubMedCrossRefGoogle Scholar
  31. 31.
    Performance standards for antimicrobial susceptibility testing: fourteenth informational supplement [NCCLS document no. M100-S14, 2004]. Wayne (PA): US National Committee for Clinical Laboratory Standards (NCCLS), 2007Google Scholar
  32. 32.
    Mariat C, Venet C, Jehl F, et al. Continuous infusion of ceftazidime in critically ill patients undergoing continuous venovenous haemodiafiltration: pharmacokinetic evaluation and dose recommendation. Crit Care 2006 Feb; 10(1): R26PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Arantxazu Isla
    • 1
  • Alicia Rodríguez-Gascón
    • 1
  • Iñaki F. Trocóniz
    • 2
  • Lorea Bueno
    • 2
  • María Ángeles Solinís
    • 1
  • Javier Maynar
    • 3
  • José Ángel Sánchez-Izquierdo
    • 4
  • José Luis Pedraz
    • 1
    Email author
  1. 1.Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of PharmacyUniversity of the Basque CountryVitoria-GasteizSpain
  2. 2.Department of Pharmacy and Pharmaceutical Technology, Faculty of PharmacyUniversity of NavarraPamplonaSpain
  3. 3.Intensive Care UnitSantiago Apóstol HospitalVitoria-GasteizSpain
  4. 4.Intensive Care UnitDoce de Octubre HospitalMadridSpain

Personalised recommendations