PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
PAGE 24 (2015) Abstr 3445 [www.page-meeting.org/?abstract=3445]
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Poster: Drug/Disease modeling - Infection
Sebastian G. Wicha (1), Alexander Solms (2), Wilhelm Huisinga (2) and Charlotte Kloft (1)
(1) Dept. of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany, (2) Institute of Mathematics, University of Potsdam, Germany
Objectives: To assess therapeutic success or failure of antibiotic treatments pharmacokinetic (PK)/pharmacodynamic (PD) breakpoints are frequently used in probability of target attainment (PTA) analyses. For this purpose, commonly time-consuming Monte-Carlo simulations (MCS) considering the interindividual variability in PK are performed. PTA is then calculated as the fraction of scenarios for which the PK/PD breakpoint is attained.
Methods: A published population PK model of the beta-lactam antibiotic meropenem (MER)  was used for evaluation of MCS- and DM-based PTAs. PK covariates were set to their typical values , serum creatinine to 0.7 mg/dL, minimal inhibitory concentration to 4 mg/L and the PK/PD breakpoint for MER to fT>MIC of 40% . Short (1 h TID), prolonged (4 h TID) and continuous infusion (24 h) dosing regimens were assessed. Interindividual variability of the PK parameters was varied from 20% to 70% CV.
Results: For MCS, the variability of PTA was 0.014 (SD) at n=1000 replicates. Differences between MCS-based and DM-based PTAs ranged from -0.05 and 0.03 (mean: -0.004) and were independent of the set interindividual PK variability. Both methods correlated well (R²=0.995, DM=MCS×1.04-0.031). CPU time was ca. 1.3 sec. for DM and ca. 48 sec. for MCS for computation of a single dosing scenario.
Conclusion: DM-based computation of PTAs was in well agreement with the conventionally used MCS-based approach thereby reducing the required CPU time by > factor 35. The DM-based algorithm for PTA calculation was hence integrated in TDMx facilitating rapid empiric dosing decisions prior to initialising antibiotic treatment.