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

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ABSTRACT

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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Abbreviations

AUC:

Area under the curve

c.i.:

Continuous infusion

CL:

Clearance

CLCR :

Creatinine CL

Cmax :

Maximum concentration

fAUC/MIC:

Unbound AUC divided by the MIC

fCmax/MIC:

Unbound Cmax divided by the MIC

fT > MIC:

Unbound time above the MIC

fu:

Fraction unbound

h:

Hour

i.v.:

Intra venous

k:

Rate constant

ka :

Absorption rate

MIC:

Minimum inhibitory concentration

PD:

Pharmacodynamic

PK:

Pharmacokinetic

q:

Dose interval

Q:

Inter compartmental CL

R2 :

Coefficient of determination

s.c.:

Sub cutaneous

SCr:

Serum creatinine

T:

Time

t1/2 :

Half-life (elimination)

t1/2β :

Half-life of the β-phase

TDM:

Therapeutic drug monitoring

V:

Volume

Vc:

Central Volume (of distribution)

Vp:

Peripheral volume (of distribution)

w:

Week

WT:

Weight

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ACKNOWLEDGMENTS AND DISCLOSURES

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

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Correspondence to Anders N. Kristoffersson.

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Kristoffersson, A.N., David-Pierson, P., Parrott, N.J. et al. Simulation-Based Evaluation of PK/PD Indices for Meropenem Across Patient Groups and Experimental Designs. Pharm Res 33, 1115–1125 (2016). https://doi.org/10.1007/s11095-016-1856-x

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  • DOI: https://doi.org/10.1007/s11095-016-1856-x

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