2016 - Lisboa - Portugal

PAGE 2016: Drug/Disease modeling - Infection
Lisa Ehmann

Pharmacokinetics of meropenem in critically ill patients with varying renal function

Ehmann L. (1,2)*, Zoller M. (3)*, Minichmayr I.K. (1,2), Scharf C. (3), Frey L. (3), Vogeser M. (4), Huisinga W. (5), Zander J. (4)**, Kloft C. (1)**

(1) Dept. of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Germany, (2) and Graduate Research Training program PharMetrX, Germany, (3) Dept. of Anaesthesiology, Hospital of the Ludwig-Maximilians-University of Munich, Germany, (4) Institute of Laboratory Medicine, Hospital of the Ludwig-Maximilians-University of Munich, Germany, (5) Institute of Mathematics, Universitaet Potsdam, Germany, * These authors contributed equally to this work, ** Shared senior authorship

Objectives: Meropenem (MER) is a carbapenem antibiotic frequently used to treat severe infections in critically ill patients, e.g. caused by Pseudomonas aeruginosa [1]. In those patients an early initiation of appropriate antibiotic therapy is crucial [2]. MER is primarily excreted renally and its activity is considered to correlate with the time that concentrations are above the MIC (T>MIC) [3]. The objective of the present work was to analyse standard dosing of MER in critically ill patients with varying renal function regarding pharmacokinetic/pharmacodynamic (PK/PD) target attainment.

Methods: MER serum concentrations (ntotal=1424) and creatinine clearance (CLCR, estimated according to Cockcroft-Gault [4]) were obtained over 4 days in 41 critically ill patients treated with standard doses of MER as intravenous 30-min infusions every 8 h. A population PK model was developed in NONMEM 7.3 and used to simulate 1000 PK profiles for varying CLCR values (15-130 mL/min) for the first day of treatment. The probability to attain 40%T>MIC (=bactericidal target) was calculated for the MIC distribution of Pseudomonas aeruginosa (0.008-256 mg/L) [3,5]. A probability of target attainment of ≥90% was considered successful treatment.

Results: A two-compartment model adequately described MER PK in the critically ill population (CL: 8.66 L/h, Q: 30.0 L/h, Vc: 8.48 L, Vp: 17.6 L). Interindividual variability (IIV) was implemented on CL, Vc and Vp, and CLCR was found to be a significant and clinically relevant covariate on CL, explaining ~1/4 of IIV on CL. If infected with susceptible isolates (MIC ≤2 mg/L), the PK/PD target was attained for all patients - irrespective of their renal function. For the I/R breakpoint (MIC 8 mg/L) only patients with severe renal insufficiency reliably reached the target; for resistant isolates (MIC >8 mg/L), none of the investigated patients attained the target.

Conclusions: A population PK model was successfully developed to describe concentration-time profiles of MER in a critically ill population. Highest IIV was found on CL, one fourth could be explained by renal function. Standard dosing of MER resulted in adequate MER concentrations given susceptible Pseudomonas aeruginosa isolates. For intermediate isolates, dose adjustment seems to be required dependent on the renal function of the patient. Next, additional covariate types will be analysed to further explain the high PK variability in this vulnerable patient population.



References:
[1] GG Zhanel, R Wiebe: Comparative review of the carbapenems. Drugs 67: 1027-1052 (2007)
[2] C McKenzie: Antibiotic dosing in critical illness. J Antimicrob Chemother 66: ii25-ii31 (2011)
[3] DP Nicolau: Pharmacokinetic and Pharmacodynamic Properties of Meropenem. Clin Infect Dis 47: 32-40 (2008)
[4] DW Cockcroft, MH Gault: Prediction of creatinine clearance from serum creatinine. Nephron 16: 31-41 (1976)
[5] www.eucast.org (date of access: 18 February 2016)


Reference: PAGE 25 (2016) Abstr 5771 [www.page-meeting.org/?abstract=5771]
Poster: Drug/Disease modeling - Infection
Click to open PDF poster/presentation (click to open)
Top