Doripenem population pharmacokinetics and dosing requirements for critically ill patients receiving continuous venovenous haemodiafiltration

• Published in: Journal of antimicrobial chemotherapy Vol. 69; no. 9; pp. 2508 - 2516
• Main Authors: Roberts, Jason A, Udy, Andrew A, Bulitta, Juergen B, Stuart, Janine, Jarrett, Paul, Starr, Therese, Lassig-Smith, Melissa, Roberts, Natasha A, Dunlop, Rachel, Hayashi, Yoshiro, Wallis, Steven C, Lipman, Jeffrey
• Format: Journal Article
• Language: English
• Published: England Oxford Publishing Limited (England) 01-09-2014
• Subjects: Acute Kidney Injury - therapy; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacokinetics; Antibiotics; Carbapenems - administration & dosage; Carbapenems - pharmacokinetics; Critical Illness; Drug dosages; Female; Hemodiafiltration; Hemodialysis; Humans; Infusions, Intravenous; Kinetics; Male; Metabolic Clearance Rate; Middle Aged; Pharmacology; Plasma - chemistry; Young Adult; β-lactams; intensive care; continuous renal replacement therapy; pharmacodynamics; carbapenems; CRRT; sepsis
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dku177

Doripenem is a newer carbapenem with little data available to guide effective dosing during renal replacement therapy in critically ill patients. The objective of this study was to determine the population pharmacokinetics of doripenem in critically ill patients undergoing continuous venovenous haemodiafiltration (CVVHDF) for acute kidney injury (AKI).
This was an observational pharmacokinetic study in 12 infected critically ill adult patients with AKI undergoing CVVHDF and receiving 500 mg of doripenem intravenously every 8 h as a 60 min infusion. Serial blood samples were taken on 2 days of treatment and used for population pharmacokinetic analysis with S-ADAPT.
The median (IQR) age was 62 (53-71) years, the median (IQR) weight was 77 (67-96) kg and the median (IQR) APACHE II score was 29 (19-32). The median blood, dialysate and replacement fluid rates were 200, 1000 and 1000 mL/h, respectively. A two-compartment linear model with doripenem clearance described by CVVHDF, renal or non-renal mechanisms was most appropriate. The mean value for total doripenem clearance was 4.46 L/h and volume of distribution was 38.0 L. Doripenem clearance by CVVHDF was significantly correlated with the replacement fluid flow rate and accounted for ∼30%-37% of total clearance. A dose of 500 mg intravenously every 8 h achieved favourable pharmacokinetic/pharmacodynamics for all patients up to an MIC of 4 mg/L.
This is the first paper describing the pharmacokinetics/pharmacodynamics of doripenem in critically ill patients with AKI receiving CVVHDF. A dose of 500 mg intravenously every 8 h was appropriate for our CVVHDF settings for infections caused by susceptible bacteria.