Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

Abdul‐Aziz, Mohd H.; Rahman, Arifur; Mat-Nor, Mohd-Basri; Sulaiman, Helmi; Wallis, Steven C.; Lipman, Jeffrey; Roberts, Jason A.; Staatz, C. E.

doi:10.1128/aac.01543-15

Cited by 13 publications

(15 citation statements)

References 52 publications

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“…Abdul-Aziz et al performed population pharmacokinetics analysis of DRPM using a nonlinear mixed-effects modeling in 12 critically ill patients with sepsis in a Malaysian ICU. 28) They showed the typical total clearance and distribution volume of DRPM were 0.14 L/kg/h and 0.47 L/kg, respectively, which are almost the same parameters (Total clearance: 0.14 L/kg/h, distribution volume: 0.40 L/kg) as the patients of our report. However, previous Monte Carlo simulation revealed that the PK/PD breakpoints for standard or higher DRPM regimen in every group with Ccr of 70, 50 and 30 mL/min were 2 or 4 µg/mL, respectively, 28) which is slightly higher than that in present study.…”

Section: Discussionsupporting

confidence: 60%

Pharmacokinetic/Pharmacodynamic Analysis for Doripenem Regimens in Intensive Care Unit Patient

Tanaka

Sato

Goto

et al. 2017

Biological & Pharmaceutical Bulletin

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Doripenem (DRPM) is a broad-spectrum antibacterial agent often used as empirical therapy for critically ill patients, although there is a lack of studies validating the recommended dosage regimen for patients admitted to intensive care unit (ICU), based on pharmacokinetic (PK)/pharmacodynamic (PD) index. In this study, we estimated the free time above minimum inhibitory concentration (fT>MIC (%)) of DRPM using population PK analysis of 12 patients in ICU, and evaluated the validity of the dosage regimen stratified by creatinine clearance. Using a 2-compartment population PK model reported previously, the mean total clearance or distribution volume of DRPM estimated by Bayesian estimation was significantly lower or higher than that of based on population PK model. The estimated fT>MIC (%) of the recommended standard (normal renal function: 0.5 g every 8 h, moderate: 0.25 g every 8 h, severe renal impairment: 0.25 g every 12 h) and higher doses (normal: 1.0 g every 8 h, moderate: 0.5 g every 8 h, severe: 0.25 g every 8 h) against MICs of 0.5, 1 and 2 µg/mL exceeded 40% in all patients. When stratified by creatinine clearance, the PK/PD breakpoints estimated by Monte Carlo simulation in three grades of renal function tended to be higher than the previously reported PK/PD breakpoints for patients with urinary tract infection, an infection of lesser severity than ICU patients. These results suggest that the dosage regimen stratified by renal function derived from Japanese package insert may be sufficient to achieve effective treatment in ICU patients.Key words doripenem; pharmacokinetic/pharmacodynamic analysis; intensive care unit; breakpoint Doripenem (DRPM) is a newer carbapenem antimicrobial agent with potent and broad spectrum activities against Grampositive, Gram-negative and anaerobic bacteria, and is more potent against Pseudomonas aeruginosa than other carbapenems.1-3) Doses of 0.5-3.0 g daily in two or three divided doses administered by 0.5 or 1 h infusion are used commonly to treat infectious diseases such as pneumonia, complicated urinary tract infection and intra-abdominal infections. In order to provide optimal antimicrobial therapy, selecting an effective and well-tolerated dosage regimen based on pharmacokinetic (PK)/ pharmacodynamic (PD) index is important. For DRPM and other β-lactams with time-dependent antimicrobial activity, an effective dosage regimen requires that the blood concentrations exceed the minimum inhibitory concentration (MIC) of the infecting bacteria for at least 40% of the dosing interval.4) Therefore, the appropriate dosage regimen based on time above MIC (%T>MIC) is of great importance when using DRPM.Critically ill patients in the intensive care unit (ICU) are often affected by infections, and are given antimicrobial agents with a broad spectrum. 5) In particular, since severe sepsis and septic shock are major causes of morbidity and mortality in the ICU, early use of carbapenems including DRPM as an empirical therapy is recommended by international guidelines for the manageme...

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Section: Discussionsupporting

confidence: 60%

Pharmacokinetic/Pharmacodynamic Analysis for Doripenem Regimens in Intensive Care Unit Patient

Tanaka

Sato

Goto

et al. 2017

Biological & Pharmaceutical Bulletin

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“…The lower doripenem CL in Korean patients with either normal or lower levels of renal function, possibly due to differences in BW and body mass between Korean and other populations (42,43), may result in a greater chance of attaining a PK or PD target, even with lower doripenem doses. Nevertheless, a cautious interpretation of our results is necessary until a firmer understanding of the interethnic differences in the pharmacokinetics of doripenem is obtained, because several recent studies did not show significant differences in doripenem PK among different popu-lations (15,16). Data regarding ethnic differences in PK/PD would be precious for the optimization and individualization of doripenem dosing regimens.…”

Section: Discussionmentioning

confidence: 99%

“…Although there are conflicting results regarding the association between low or undetectable blood ␤-lactam levels and poor clinical outcomes in infected patients (27,28), the increased glomerular filtration and drug elimination caused by augmented renal function is known to predict subtherapeutic ␤-lactam concentrations (20,29). Limited data evaluating doripenem PK in patients with augmented renal function indicate a decreased PTA in such patients, which favors the use of extended infusions (16,21). Furthermore, one recent study comparing the clinical outcomes of patients with ventilator-associated pneumonia due to Gram-negative bacteria treated with doripenem versus imipenem-cilastatin suggested that doripenem-treated patients with a supranormal renal function (CL CR Ն 150 ml/min) had poor clinical cure rates (44%, 8/18 patients) (30).…”

Section: Discussionmentioning

confidence: 99%

“…Several recent studies analyzing the PK of doripenem in Asian populations (15,16) reported equations for calculating antibiotic CL according to renal function, reflected by creatinine clearance (CL CR ); however, most studies have been conducted in Western populations (12,17,18). To our knowledge, there are no studies that have specifically addressed the population PK of doripenem in Korean patients with infections.…”

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confidence: 84%

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Population Pharmacokinetic Analysis of Doripenem after Intravenous Infusion in Korean Patients with Acute Infections

Lee

Kim

Jin

et al. 2017

Antimicrob Agents Chemother

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We investigated the population pharmacokinetics (PK) of doripenem in Korean patients with acute infections and determined an appropriate dosing regimen using a Monte Carlo simulation for predicting pharmacodynamics (PD). Patients (n ϭ 37) with a creatinine clearance (CL CR ) of 20 to 50 ml/min or Ͼ50 ml/min who received a 250-mg or 500-mg dose of doripenem over the course of 1 h every 8 h, respectively, were included in this study. Blood samples were taken predosing and 0 h, 0.5 h, and 4 to 6 h after the fourth infusion. A nonlinear mixed-effect modeling tool was used for the PK analysis and pharmacodynamic simulation; doripenem PK were well described by a one-compartment model. The population mean values of the body weight (WT)-normalized clearance (CL/WT) and the body weight-normalized volume of distribution (V/WT) were 0.109 liter/h/kg of body weight (relative standard error, 9.197%) and 0.280 liter/kg (relative standard error, 9.56%), respectively. Doripenem CL was significantly influenced by CL CR . The proposed equation to estimate doripenem CL in Korean patients was CL/WT ϭ 0.109 ϫ WT ϫ (CL CR /57) 0.688 , where CL/WT is in liters per hour per kilogram. CL in Korean patients was expected to be lower than that in Caucasian patients, regardless of renal function. The Monte Carlo simulation showed that 90% attainment of target PK/PD magnitudes could be achieved with the usual dosing regimens when the MIC was Յ1 mg/liter. However, prolonged infusions (4 h) should be considered, especially when patients have augmented renal function and for patients infected with pathogens with a high MIC. Our results provide an individualized doripenem dosing regimen for patients with various renal functions and for patients infected with bacteria with decreased susceptibility.

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“…Changes in antibiotic Vd have been noted in critically ill patients [6,[53][54][55][56][57], and the contributing factors are discussed below.…”

Section: Changes Of Volume Of Distributionmentioning

confidence: 99%

Optimizing beta-lactam antibiotic dosing in critically ill patients: Prolonged infusion versus intermittent bolus administration

Abdul‐Aziz¹,

Mohd²

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Severe sepsis is a major burden in the intensive care unit (ICU) with persistently high mortality rates. Optimization of antibiotic dosing has been suggested as an intervention to improve clinical outcomes for critically ill patients with severe sepsis. However, current antibiotic dosing guidelines may not be appropriate for these patients, as they rarely consider the altered physiology and illness severity associated with this population. Optimizing antibiotic dosing using pharmacokinetic (PK) and pharmacodynamic (PD) principles can address these critical illness-related changes and promote therapeutic success. Due to their wide spectrum of antibiotic activity and excellent safety profile, beta-lactam antibiotics are commonly used for severe infections in the ICU. Two alternative dosing approaches to traditional intermittent bolus (IB) dosing, namely continuous infusion (CI) and extended infusion (EI), have been suggested to maximize the therapeutic potential of these antibiotics in critically ill patients. Collectively, the two dosing approaches can also be referred as prolonged infusion (PI).This Thesis aims to better characterize the pharmacokinetics/pharmacodynamics (PK/PD) of betalactam antibiotics to determine whether there is any therapeutic advantage associated with PI dosing (CI and/or EI) as compared to IB dosing. This Thesis comprises of eight chapters. Chapter 1 is an introductory chapter which provides an overview of the published literature on the area of research. The discussion in Chapter 1 presents a theoretical framework behind the Thesis objectives. Chapter 1 concludes with the specific aims of this Thesis.Chapter 2 reports the findings of a prospective PK study which aimed to describe the population PK of doripenem in critically ill patients with sepsis and perform dosing simulations to develop clinically relevant dosing guidelines for these patients. Twelve critically ill participants receiving 500 mg of doripenem 8-hourly as a 1-hr infusion were enrolled. The volume of distribution (Vd) and clearance (CL) of doripenem in this patient cohort were substantially different than those usually described in non-critically patients. As current dosing guidelines were mostly derived from the non-critically ill, findings from this study suggest that the licensed "one-dose-fits-all" dosing for doripenem is unlikely to achieve optimal exposures in critically ill patients. Empirical use of PI dosing should be considered to account for PK and illness severity differences, particularly when less-susceptible pathogens are involved.ii Chapter 3 incorporates a published systematic review which compares the PK/PD data and clinical outcomes between CI and IB dosing to describe any potential merits supporting either of the two dosing approaches for critically ill patients. The findings suggest that beta-lactam CI may not be advantageous for all critically ill patients and may be beneficial in patients with severe infections.Chapter 4 describes the findings of a post hoc analysis on the Defining...

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Population Pharmacokinetics of Doripenem in Critically Ill Patients with Sepsis in a Malaysian Intensive Care Unit

Cited by 13 publications

References 52 publications

Pharmacokinetic/Pharmacodynamic Analysis for Doripenem Regimens in Intensive Care Unit Patient

Pharmacokinetic/Pharmacodynamic Analysis for Doripenem Regimens in Intensive Care Unit Patient

Population Pharmacokinetic Analysis of Doripenem after Intravenous Infusion in Korean Patients with Acute Infections

Optimizing beta-lactam antibiotic dosing in critically ill patients: Prolonged infusion versus intermittent bolus administration

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