Pharmaceutical Research

, Volume 33, Issue 5, pp 1115–1125 | Cite as

Simulation-Based Evaluation of PK/PD Indices for Meropenem Across Patient Groups and Experimental Designs

  • Anders N. Kristoffersson
  • Pascale David-Pierson
  • Neil J. Parrott
  • Olaf Kuhlmann
  • Thierry Lave
  • Lena E. Friberg
  • Elisabet I. Nielsen
Research Paper



Antibiotic dose predictions based on PK/PD indices rely on that the index type and magnitude is insensitive to the pharmacokinetics (PK), the dosing regimen, and bacterial susceptibility. In this work we perform simulations to challenge these assumptions for meropenem and Pseudomonas aeruginosa.


A published murine dose fractionation study was replicated in silico. The sensitivity of the PK/PD index towards experimental design, drug susceptibility, uncertainty in MIC and different PK profiles was evaluated.


The previous murine study data were well replicated with fT > MIC selected as the best predictor. However, for increased dosing frequencies fAUC/MIC was found to be more predictive and the magnitude of the index was sensitive to drug susceptibility. With human PK fT > MIC and fAUC/MIC had similar predictive capacities with preference for fT > MIC when short t1/2 and fAUC/MIC when long t1/2.


A longitudinal PKPD model based on in vitro data successfully predicted a previous in vivo study of meropenem. The type and magnitude of the PK/PD index were sensitive to the experimental design, the MIC and the PK. Therefore, it may be preferable to perform simulations for dose selection based on an integrated PK-PKPD model rather than using a fixed PK/PD index target.


antibiotic dose selection meropenem pharmacometric pseudomonas aeruginosa 



Area under the curve


Continuous infusion




Creatinine CL


Maximum concentration


Unbound AUC divided by the MIC


Unbound Cmax divided by the MIC

fT > MIC

Unbound time above the MIC


Fraction unbound




Intra venous


Rate constant


Absorption rate


Minimum inhibitory concentration






Dose interval


Inter compartmental CL


Coefficient of determination


Sub cutaneous


Serum creatinine




Half-life (elimination)


Half-life of the β-phase


Therapeutic drug monitoring




Central Volume (of distribution)


Peripheral volume (of distribution)







This work was in part supported by funding from F. Hoffmann-La Roche Ltd, Switzerland and by the Swedish Foundation for Strategic Research.

Compliance with ethical standards

Transparency declarations

The authors have no conflicts of interest related to the content of this study.


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Pharmaceutical BiosciencesUppsala UniversitetUppsalaSweden
  2. 2.F. Hoffmann-La Roche Ltd.Innovation Center Basel, Pharmaceuticals SciencesBaselSwitzerland

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