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Population Pharmacokinetic–Pharmacodynamic Target Attainment Analysis of Imipenem Plasma and Urine Data in Neonates and Children

Yoshizawa, Kenichi MS*; Ikawa, Kazuro PhD*; Ikeda, Kayo PhD*; Ohge, Hiroki MD, PhD; Morikawa, Norifumi PhD*

The Pediatric Infectious Disease Journal: November 2013 - Volume 32 - Issue 11 - p 1208–1216
doi: 10.1097/INF.0b013e31829b5880
Antimicrobial Reviews

Background: Population pharmacokinetic (PK)–pharmacodynamic target attainment analysis of imipenem was performed to elucidate the PK properties in neonates and children and to rationalize and optimize dosing regimens.

Methods: Population PK models were separately developed in neonates and children by simultaneously fitting plasma and urine data from 60 neonates and 39 children. The newly developed models were then used to estimate the probability of attaining the pharmacodynamic target (40% of the time above the minimum inhibitory concentration) against clinical isolates of common bacteria in pediatric patients.

Results: The data were best described by a 1-compartment model in neonates and a 2-compartment model in children, respectively. Renal clearance in children (0.187 L/h/kg) was double that of neonates (0.0783 L/h/kg), whereas the volume of distribution at steady-state was approximately 1.8-fold larger in neonates (0.466 L/kg) than in children (0.260 L/kg). Age was not a statistically significant covariate in the PK of both groups. Infusions (0.5 h) of 15 mg/kg every 8 h (45 mg/kg/day) and 25 mg/kg every 12 h (50 mg/kg/day) were shown to be sufficient against common bacterial isolates in both patient populations. However, 1.5-h infusions of 25 mg/kg every 8 h (75 mg/kg/day) in neonates and 25 mg/kg every 6 h (100 mg/kg/day) in children were required to be effective against Pseudomonas aeruginosa (minimum inhibitory concentration for 90% of the isolates = 16 μg/mL).

Conclusions: These results explain the changes in imipenem PK properties during the human growth process and provide guidance for tailoring dosing regimens in each pediatric age group.

From the *Department of Clinical Pharmacotherapy, Hiroshima University; and Department of Infectious Diseases, Hiroshima University Hospital, Minami-ku, Hiroshima, Japan.

Accepted for publication May 4, 2013.

This study was not supported by any grants, pharmaceutical companies or industry partners. The authors have no other funding or conflicts of interest to disclose.

Address for correspondence: Kazuro Ikawa, PhD, Department of Clinical Pharmacotherapy, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734–8551, Japan. E-mail:

© 2013 by Lippincott Williams & Wilkins, Inc.