Skip to main content
SpringerLink
Log in

Population pharmacokinetics of meropenem in elderly patients: dosing simulations based on renal function

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

Abstract

Objectives

The aim of this study was to evaluate different dosage regimens of meropenem in elderly patients in relation with renal function using a population pharmacokinetic (popPK) model.

Methods

The data of 178 elderly patients treated with meropenem was collected from different sources. A popPK model was developed by using NONMEM® and the influence of different covariates on meropenem CL and V1 was observed. Monte Carlo dosing simulations were performed at steady state to observe the % T > MIC for targets of 40, 60 and 80% of dosage intervals at different levels of creatinine clearance (CLCR).

Results

The data was described by a two-compartment model and the values of parameter estimates for CL, V1, Q and V2 were 5.27 L/h, 17.2 L, 9.92 L/h and 10.6 L, respectively. The CLCR, body weight and centre had a significant influence on meropenem CL while no direct influence of age was observed. Extended infusions had pharmacokinetic and pharmacodynamic (PK/PD) breakpoint one dilution greater than corresponding short infusion regimens for each target of % T > MIC.

Conclusion

Meropenem CL was significantly lower in the elderly compared to CL reported in younger patients due to the reduced renal function. An extended infusion of 1000 mg q8h can be considered for empirical treatment of infections in elderly patients when CLCR is ≤ 50 mL/min. A continuous infusion of 3000 mg daily dose is preferred if CLCR > 50 mL/min. However, a higher daily dose of meropenem would be required for resistant strains (MIC >8 mg/L) of bacteria if CLCR is >100 mL/min.

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. Wiseman LR et al (1995) Meropenem. A review of its antibacterial activity, pharmacokinetic properties and clinical efficacy. Drugs 50(1):73–101

    Article  CAS  PubMed  Google Scholar 

  2. Spellberg B et al (2011) Combating antimicrobial resistance: policy recommendations to save lives. Clin Infect Dis 52(Suppl 5):S397–S428

    PubMed  Google Scholar 

  3. Boucher HW et al (2009) Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis 48(1):1–12

    Article  PubMed  Google Scholar 

  4. Wittau, M., et al. 2015. Population pharmacokinetics and target attainment of meropenem in plasma and tissue of morbidly obese patients after laparoscopic intraperitoneal surgery. Antimicrob Agents Chemother

  5. Craig WA (1998) Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26(1):1–10 quiz 11-2

    Article  CAS  PubMed  Google Scholar 

  6. Nicolau DP (2008) Pharmacokinetic and pharmacodynamic properties of meropenem. Clin Infect Dis 47(Suppl 1):S32–S40

    Article  CAS  PubMed  Google Scholar 

  7. Shekar K et al (2014) The combined effects of extracorporeal membrane oxygenation and renal replacement therapy on meropenem pharmacokinetics: a matched cohort study. Crit Care 18(6):565

    Article  PubMed  PubMed Central  Google Scholar 

  8. Li C et al (2007) Clinical pharmacodynamics of meropenem in patients with lower respiratory tract infections. Antimicrob Agents Chemother 51(5):1725–1730

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. De Waele JJ et al (2014) Therapeutic drug monitoring-based dose optimisation of piperacillin and meropenem: a randomised controlled trial. Intensive Care Med 40(3):380–387

    Article  CAS  PubMed  Google Scholar 

  10. Ulldemolins, M., et al. 2015 Meropenem population pharmacokinetics in critically ill patients with septic shock and continuous renal replacement therapy: influence of residual diuresis on dose requirements. Antimicrob Agents Chemother

  11. Mouton JW, van den Anker JN (1995) Meropenem clinical pharmacokinetics. Clin Pharmacokinet 28(4):275–286

    Article  CAS  PubMed  Google Scholar 

  12. Udy AA et al (2012) Subtherapeutic initial beta-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations. Chest 142(1):30–39

    Article  CAS  PubMed  Google Scholar 

  13. Taccone FS et al (2010) Insufficient beta-lactam concentrations in the early phase of severe sepsis and septic shock. Crit Care 14(4):R126

    Article  PubMed  PubMed Central  Google Scholar 

  14. Varghese JM, Roberts JA, Lipman J (2011) Antimicrobial pharmacokinetic and pharmacodynamic issues in the critically ill with severe sepsis and septic shock. Crit Care Clin 27(1):19–34

    Article  CAS  PubMed  Google Scholar 

  15. Taccone FS et al (2011) Appropriate antibiotic dosage levels in the treatment of severe sepsis and septic shock. Curr Infect Dis Rep 13(5):406–415

    Article  PubMed  Google Scholar 

  16. Blanchet B et al (2008) Influence of burns on pharmacokinetics and pharmacodynamics of drugs used in the care of burn patients. Clin Pharmacokinet 47(10):635–654

    Article  CAS  PubMed  Google Scholar 

  17. Beumier M et al (2015) Elevated beta-lactam concentrations associated with neurological deterioration in ICU septic patients. Minerva Anestesiol 81(5):497–506

    CAS  PubMed  Google Scholar 

  18. Verhave JC et al (2005) Estimation of renal function in subjects with normal serum creatinine levels: influence of age and body mass index. Am J Kidney Dis 46(2):233–241

    Article  CAS  PubMed  Google Scholar 

  19. Jaruratanasirikul S et al (2015) Population pharmacokinetics and Monte Carlo dosing simulations of meropenem during the early phase of severe sepsis and septic shock in critically ill patients in intensive care units. Antimicrob Agents Chemother 59(6):2995–3001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Goncalves-Pereira J et al (2014) Assessment of pharmacokinetic changes of meropenem during therapy in septic critically ill patients. BMC Pharmacol Toxicol 15:21

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ramon-Lopez A et al (2015) Dosing regimen of meropenem for adults with severe burns: a population pharmacokinetic study with Monte Carlo simulations. J Antimicrob Chemother 70(3):882–890

    Article  CAS  PubMed  Google Scholar 

  22. Doh K et al (2010) Population pharmacokinetics of meropenem in burn patients. J Antimicrob Chemother 65(11):2428–2435

    Article  CAS  PubMed  Google Scholar 

  23. Isla A et al (2008) Population pharmacokinetics of meropenem in critically ill patients undergoing continuous renal replacement therapy. Clin Pharmacokinet 47(3):173–180

    Article  CAS  PubMed  Google Scholar 

  24. Jamal JA et al (2015) Pharmacokinetics of meropenem in critically ill patients receiving continuous venovenous haemofiltration: a randomised controlled trial of continuous infusion versus intermittent bolus administration. Int J Antimicrob Agents 45(1):41–45

    Article  CAS  PubMed  Google Scholar 

  25. Kees, M.G., et al. 2015 Population pharmacokinetics of meropenem during continuous infusion in surgical ICU patients. J Clin Pharmacol

  26. Alobaid, A.S., et al. 2015 What is the effect of obesity on piperacillin and meropenem trough concentrations in critically ill patients? J Antimicrob Chemother

  27. Bias M, Frey O, Köberer A (2010) HPLC-Methode zur quantitativen Bestimmung von Meropenem im Serum. Krankenhauspharmazie 31(11):482–485

    Google Scholar 

  28. Lindbom L, Pihlgren P, Jonsson EN (2005) PsN-toolkit—a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Prog Biomed 79(3):241–257

    Article  Google Scholar 

  29. Keizer RJ et al (2011) Pirana and PCluster: a modeling environment and cluster infrastructure for NONMEM. Comput Methods Prog Biomed 101(1):72–79

    Article  Google Scholar 

  30. European Committee of Antimicrobial Susceptibility testing (EUCAST) 2016 Clinical breakpoints. [cited 2016 28 Feb 2016]; Available from: http://www.eucast.org/clinical_breakpoints

  31. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16(1):31–41

    Article  CAS  PubMed  Google Scholar 

  32. Devine BJ (1974) Gentamicin therapy. Drug Intell Clin Pharm 8:650–655

    Google Scholar 

  33. Zhou QT et al (2011) Pharmacokinetics and pharmacodynamics of meropenem in elderly chinese with lower respiratory tract infections: population pharmacokinetics analysis using nonlinear mixed-effects modelling and clinical pharmacodynamics study. Drugs Aging 28(11):903–912

    Article  CAS  PubMed  Google Scholar 

  34. Krueger WA et al (2005) Evaluation by Monte Carlo simulation of the pharmacokinetics of two doses of meropenem administered intermittently or as a continuous infusion in healthy volunteers. Antimicrob Agents Chemother 49(5):1881–1889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Roberts JA et al (2009) Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother 64(1):142–150

    Article  CAS  PubMed  Google Scholar 

  36. Lodise TP et al (2007) Pharmacodynamics of ceftazidime and meropenem in cerebrospinal fluid: results of population pharmacokinetic modelling and Monte Carlo simulation. J Antimicrob Chemother 60(5):1038–1044

    Article  CAS  PubMed  Google Scholar 

  37. Li C et al (2006) Population pharmacokinetic analysis and dosing regimen optimization of meropenem in adult patients. J Clin Pharmacol 46(10):1171–1178

    Article  CAS  PubMed  Google Scholar 

  38. Ariano RE et al (2005) Pharmacokinetics and pharmacodynamics of meropenem in febrile neutropenic patients with bacteremia. Ann Pharmacother 39(1):32–38

    Article  CAS  PubMed  Google Scholar 

  39. Christensson BA et al (1992) Pharmacokinetics of meropenem in subjects with various degrees of renal impairment. Antimicrob Agents Chemother 36(7):1532–1537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ikawa K et al (2010) Population pharmacokinetics and pharmacodynamics of meropenem in Japanese pediatric patients. J Infect Chemother 16(2):139–143

    Article  CAS  PubMed  Google Scholar 

  41. Shino N et al (2015) Development and assessment of a nomogram to propose the initial dosage regimen of a meropenem infusion based on serum creatinine and age using a Monte Carlo simulation. Chem Pharm Bull (Tokyo) 63(12):986–991

    Article  CAS  Google Scholar 

  42. Frippiat F et al (2015) Modelled target attainment after meropenem infusion in patients with severe nosocomial pneumonia: the PROMESSE study. J Antimicrob Chemother 70(1):207–216

    Article  CAS  PubMed  Google Scholar 

  43. Lorente L et al (2006) Meropenem by continuous versus intermittent infusion in ventilator-associated pneumonia due to gram-negative bacilli. Ann Pharmacother 40(2):219–223

    Article  CAS  PubMed  Google Scholar 

  44. Berthoin K et al (2010) Stability of meropenem and doripenem solutions for administration by continuous infusion. J Antimicrob Chemother 65(5):1073–1075

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

We are highly thankful to Dr. Arantxazu Isla and Dr. Dong-Seok Yim for providing us the meropenem data of elderly patients.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical and Medicinal Chemistry - Clinical Pharmacy, University of Muenster, Corrensstr. 48, 48149, Muenster, Germany

    Muhammad Usman & Georg Hempel

  2. Institute of Pharmaceutical Sciences, University of Veterinary and Animal Sciences, Lahore, Pakistan

    Muhammad Usman

  3. Department of Pharmacy, Hospital of Heidenheim, Heidenheim, Germany

    Otto R. Frey

Authors
  1. Muhammad Usman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Otto R. Frey
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Georg Hempel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Georg Hempel.

Ethics declarations

The medical ethics committees of the respective centres approved collection of samples. Moreover, sample collection was in accordance with good clinical practices as described in Helsinki Declaration of Good Clinical Practice guidelines.

Conflict of interest

The Higher Education Commission (HEC) of Pakistan supported MU financially via the German Academic Exchange Service (DAAD) Germany. Funding program number 50015451.

OF and GH have no conflict of interest for conducting this study.

Electronic supplementary material

Supplementary file S1

(DOCX 12 kb).

Supplementary file S2

(DOCX 17 kb).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Usman, M., Frey, O.R. & Hempel, G. Population pharmacokinetics of meropenem in elderly patients: dosing simulations based on renal function. Eur J Clin Pharmacol 73, 333–342 (2017). https://doi.org/10.1007/s00228-016-2172-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-016-2172-4

Keywords

Search

Navigation