Pharmacokinetic–pharmacodynamic target attainment analysis of doripenem in infected patients

Ikawa, Kazuro; Morikawa, Norifumi; Uehara, Shuichiro; Monden, Koichi; Yamada, Yoshiaki; Honda, Nobuaki; Kumon, Hiromi

doi:10.1016/j.ijantimicag.2008.08.031

Cited by 48 publications

(46 citation statements)

References 10 publications

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“…Typical V (V 1 ϩ V 2 ) of doripenem in our cohort was 0.47 liters/kg (range, 0.14 to 1.7 liters/kg), which is generally consistent with other reports in critically ill patients with conserved renal function (0.30 to 0.54 liters/kg) (7,9,18,33). This estimate is considerably larger than that previously described in healthy volunteers (0.22 to 0.24 liters/kg) (34,35) and noncritically ill patients (0.18 to 0.24 liters/kg) (17,(36)(37)(38). This was anticipated, as the V of hydrophilic antibiotics, such as aminoglycosides (39,40) and beta-lactams (12), is often reported to be 2-fold greater in critically ill patients.…”

Section: Discussionsupporting

confidence: 91%

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

Abdul‐Aziz

Rahman

Mat-Nor

et al. 2016

Antimicrob Agents Chemother

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g 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.

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Section: Discussionsupporting

confidence: 91%

“…However, this estimate is notably lower than that previously described in healthy volunteers (0.22 to 0.25 liters/kg/h) (34,35) and noncritically ill patients (0.16 to 0.25 liters/kg/h) (8,(36)(37)(38). The differences were expected, as the noncritically ill population would presumably have better end-organ function than our patient cohort.…”

Section: Discussioncontrasting

confidence: 79%

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

Abdul‐Aziz

Rahman

Mat-Nor

et al. 2016

Antimicrob Agents Chemother

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“…2). These values were higher than the PK/PD breakpoints (1, 2 µg/mL) reported previously for patients with urinary tract infection and prostatitis 12) (Table 5). In patients with 60>Ccr≥30 and 30>Ccr, the mean PK/PD breakpoints for standard and higher regimens were 1-2 and 2 µg/mL, respectively, which tended to be higher than the PK/PD breakpoints (1, 2 µg/mL) reported in previous study.…”

Section: Resultscontrasting

confidence: 65%

“…However, the population mean parameters estimated using a previously reported population PK model for Japanese subjects 21) were comparable to those estimated by the population PK model reported by Nandy et al 15) Hence, the difference in ethnicity in the development of two population PK models established by Nandy et al or Ikawa et al may have little influence on our results. 12,15) In conclusion, the current PK/PD study found that the PK/PD breakpoint of DRPM for ICU patients tended to be higher compared to non-ICU patients, suggesting that the dosage regimens described in the Japanese package insert may be sufficient to achieve effective treatment in ICU patients.…”

Section: Discussionmentioning

confidence: 71%

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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“…MIC target of 50% against P. aeruginosa. In a recent study by Ikawa et al 91 prolonging the doripenem infusion time was shown to be a more effective strategy than dose escalation to increase the break point (i.e. defined as the highest MIC value at which the target attainment probabilities were $90%).…”

Section: Population Pharmacokinetic Analysismentioning

confidence: 99%

A Review of Doripenem for the Treatment of Serious Bacterial Infections

Redman

Flamm²,

Cirillo³

2010

Clinical Medicine Reviews in Therapeutics

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Doripenem is a carbapenem bactericidal agent that demonstrates in vitro activity against a wide variety of Gram-negative and Gram-positive pathogens. In vitro data show that doripenem combines the intrinsic activity of meropenem against Gram-negative pathogens with the intrinsic activity of imipenem against Gram-positive pathogens. The availability of doripenem is particularly welcome in the current setting of increased resistance among Gram-negative pathogens including Pseudomonas aeruginosa, Acinetobacter species, and extended-spectrum β-lactamase-producing Enterobacteriaceae. Characteristic of doripenem is its potent activity against P. aeruginosa with a minimum inhibitory concentration (MIC) necessary for the inhibition of 90% of all isolates (MIC 90 ) of 4 µg/mL, a value that is 2 to 4 times lower than the corresponding MIC 90 values of meropenem and imipenem. Doripenem was shown to be noninferior to other commonly used antibiotics in phase 3 clinical trials and is currently approved for the treatment of complicated intra-abdominal infection and complicated urinary tract infection, and in some countries for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia. Intravenous (IV) infusions of doripenem can be either 1 hour or for longer durations of 4 hours. Overall, IV doripenem is safe and well tolerated, with a limited propensity to induce seizures compared with other carbapenems. Doripenem may represent a valuable option when carbapenem therapy is warranted for the treatment of serious infection, particularly in cases in which the etiology is a drug-resistant, Gram-negative pathogen.

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Pharmacokinetic–pharmacodynamic target attainment analysis of doripenem in infected patients

Cited by 48 publications

References 10 publications

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

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

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

A Review of Doripenem for the Treatment of Serious Bacterial Infections

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