Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit.
Doripenem has been recently introduced in Malaysia and is used for severe infections in the intensive care unit. However, limited data currently exist to guide optimal dosing in this scenario. We aimed to describe the population pharmacokinetics of doripenem in Malaysian critically ill patients with sepsis and use Monte Carlo dosing simulations to develop clinically relevant dosing guidelines for these patients. In this pharmacokinetic study, 12 critically ill adult patients with sepsis receiving 500 mg of doripenem every 8 h as a 1-hour infusion were enrolled. Serial blood samples were collected on 2 different days, and population pharmacokinetic analysis was performed using a nonlinear mixed-effects modeling approach. A two-compartment linear model with between-subject and between-occasion variability on clearance was adequate in describing the data. The typical volume of distribution and clearance of doripenem in this cohort were 0.47 liters/kg and 0.14 liters/kg/h, respectively. Doripenem clearance was significantly influenced by patients' creatinine clearance (CL(CR)), such that a 30-ml/min increase in the estimated CL(CR) would increase doripenem CL by 52%. Monte Carlo dosing simulations suggested that, for pathogens with a MIC of 8 mg/liter, a dose of 1,000 mg every 8 h as a 4-h infusion is optimal for patients with a CL(CR) of 30 to 100 ml/min, while a dose of 2,000 mg every 8 h as a 4-h infusion is best for patients manifesting a CL(CR) of >100 ml/min. Findings from this study suggest that, for doripenem usage in Malaysian critically ill patients, an alternative dosing approach may be meritorious, particularly when multidrug resistance pathogens are involved.
Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Brisbane, Australia School of Pharmacy, International Islamic University of Malaysia, Kuantan, Pahang, Malaysia mohd.abdulaziz1@uqconnect.edu.au.
Mohd H
http://orcid.org/0000-0002-8889-5579
MH
Abdul-Aziz
School of Pharmacy, International Islamic University of Malaysia, Kuantan, Pahang, Malaysia School of Pharmacy, The University of Queensland, Brisbane, Australia.
Azrin N
AN
Abd Rahman
Department of Anesthesiology and Intensive Care, School of Medicine, International Islamic University of Malaysia, Kuantan, Pahang, Malaysia.
Mohd-Basri
MB
Mat-Nor
Infectious Diseases Unit, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
Helmi
H
Sulaiman
Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Brisbane, Australia.
Steven C
SC
Wallis
Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Brisbane, Australia Royal Brisbane and Women's Hospital, Brisbane, Australia.
Jeffrey
J
Lipman
Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Brisbane, Australia Royal Brisbane and Women's Hospital, Brisbane, Australia.
Jason A
JA
Roberts
School of Pharmacy, The University of Queensland, Brisbane, Australia Australian Centre of Pharmacometrics, Brisbane, Australia.
Christine E
CE
Staatz
D040981:Acinetobacter baumannii / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D015780:Carbapenems / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D003404:Creatinine / Q000097:blood; D016638:Critical Illness; D000077726:Doripenem; D005260:Female; D016905:Gram-Negative Bacterial Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D006801:Humans; D007362:Intensive Care Units; D008296:Malaysia; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D015233:Models, Statistical; D009010:Monte Carlo Method; D011446:Prospective Studies; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity; D018805:Sepsis / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality; D016019:Survival Analysis
D000900:Anti-Bacterial Agents; D015780:Carbapenems; D003404:Creatinine; D000077726:Doripenem