Pharmacokinetic–pharmacodynamic target attainment analysis of meropenem in Japanese adult patients

Ikawa, Kazuro; Morikawa, Norifumi; Ohge, Hiroki; Ikeda, Kayo; Sueda, Taijiro; Kurisu, Kaoru

doi:10.1007/s10156-009-0022-3

Cited by 24 publications

(20 citation statements)

References 17 publications

(22 reference statements)

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“…However, the possibility of ethnic differences in doripenem clearance was already raised in a previous study, in spite of the difficulty with the interpretation of the results (17). From our point of view, physiological differences, such as body size, may contribute to interethnic differences in the pharmacokinetics of carbapenems (42)(43)(44)(45), which would help to explain the results of our study. 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.…”

Section: Discussionmentioning

confidence: 55%

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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Section: Discussionmentioning

confidence: 55%

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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“…Ikawa et al have reported that age and BW should not both be used to estimate MEPM clearance, in order to avoid a collinearity effect, as age and BW are both highly correlated with CCR. 10) In our study, we considered that, in critical situations, it may be more important to estimate a patient's BW without delay, in order to determine the correct starting dose and administration interval of the appropriate drug. When weighing patients is impossible, an incorrect visual approximation of BW may lead to adverse effects or lack of therapeutic effectiveness.…”

Section: Discussionmentioning

confidence: 99%

Development and Assessment of a Nomogram to Propose the Initial Dosage Regimen of a Meropenem Infusion Based on Serum Creatinine and Age Using a Monte Carlo Simulation

Shino

Uchida

Yoshida

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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A conventional nomogram, based on serum creatinine (sCr) and age, was developed in order to determine the correct initial dosage regimen for meropenem (MEPM) infusions in elderly patients with severe community-acquired pneumonia (CAP), using a target minimum inhibitory concentration (MIC) of 2 mg/L. A correlation between age and actual bodyweight (BW) in a development cohort of 44 males and 45 females was performed by linear regression using the least-squares method (male: y 0.4676x 80.281, R 2 0.4888; female: y 0.4373x 77.502, R 2 0.3194). There were no significant differences between actual BW and the BW (e-BW) estimated using this equation in this cohort (male: e-BW 41.6 3.1 kg, BW 41.7 3.5 kg, p 0.93; female: e-BW 39.5 2.1 kg, BW 39.5 3.7 kg, p 0.20). By integrating these equations using the Monte Carlo simulation method, a dosage regime was calculated which would have an 80% probability of maintaining plasma drug levels above the MIC for more than 40% of the time (>40%TAM), using only the age and sCr of individual patients. This relationship was summarized as a nomogram. The nomogram was validated using an independent validation cohort (n 28) of patients. An optimized dosage regimen could be predicted in 84 patients (94.4%) in the development cohort and 25 patients (89.3%) in the validation cohort. This nomogram may be a useful tool for clinicians and pharmacists in determining an initial MEPM regimen in elderly patients with severe CAP, based only on age and sCr.

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“…Second, infected patients often have renal dysfunction, which causes lower clearance, leading to the persistence of higher meropenem and biapenem concentrations in plasma (the T MIC will consequently be longer in bile) because both drugs are eliminated predominantly renally, with a 24-h urinary recovery of 60% to 70% (2,18). The mean estimate for clearance from the central compartment was higher for the study patients (Table 3) (8.98 liters/h for meropenem and 7.18 liters/h for biapenem) than for infected patients with a creatinine clearance of 30 ml/min (4.75 liters/h for meropenem [10] and 4.24 liters/h for biapenem [11]). The creatinine clearance of the study patients was within a restricted range (71.9 Ϯ 19.0 ml/min for meropenem and 78.9 Ϯ 26.7 ml/min for biapenem), and there was only a small number of patients (n ϭ 8 for each drug).…”

mentioning

confidence: 84%

“…Using the set of seven i values, the drug concentration-time curves (48 to 72 h after the start of the regimen) were created. For bile, the total concentration was employed because bile contains water, bile salts, mucus, and pigments but not protein; for plasma, the free fraction concentration was employed using protein binding values (2.4% for meropenem [10] and 3.0% for biapenem [11]). Next, the time point at which the drug concentration coincided with a specific MIC (0.031 to 64 mg/liter) was determined, and the percentages of a 24-h period that the drug concentrations remained above the MIC (free fraction %T MIC in plasma and %T MIC in bile) were finally calculated.…”

Section: Methodsmentioning

confidence: 99%

Clinical Pharmacokinetics of Meropenem and Biapenem in Bile and Dosing Considerations for Biliary Tract Infections Based on Site-Specific Pharmacodynamic Target Attainment

Ikawa

Nakashima

Morikawa

et al. 2011

Antimicrob Agents Chemother

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The present study investigated the pharmacokinetics of meropenem and biapenem in bile and estimated their pharmacodynamic target attainment at the site. Meropenem (0.5 g) or biapenem (0.3 g) was administered to surgery patients (n ‫؍‬ 8 for each drug). Venous blood samples and hepatobiliary tract bile samples were obtained at the end of infusion (0.5 h) and for up to 5 h thereafter. Drug concentrations in plasma and bile were analyzed pharmacokinetically and used for a Monte Carlo simulation to predict the probability of attaining the pharmacodynamic target (40% of the time above the MIC). Both drugs penetrated similarly into bile, with mean bile/plasma ratios of 0.24 to 0.25 (maximum drug concentration) and 0.30 to 0.38 (area under the drug concentration-time curve). The usual regimens of meropenem (0.5 g every 8 h [q8h]) and biapenem (0.3 g q8h) (0.5-h infusions) achieved similar target attainment probabilities in bile (>90%) against Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae isolates. However, against Pseudomonas aeruginosa isolates, meropenem at 1 g q8h and biapenem at 0.6 g q8h were required for values of 80.7% and 71.9%, respectively. The biliary pharmacodynamic-based breakpoint (the highest MIC at which the target attainment probability in bile was >90%) was 1 mg/liter for 0.5 g q8h and 2 mg/liter for 1 g q8h for meropenem and 0.5 mg/liter for 0.3 g q8h and 1 mg/liter for 0.6 g q8h for biapenem. These results help to define the clinical pharmacokinetics of the two carbapenems in bile while also helping to rationalize and optimize the dosing regimens for biliary tract infections based on site-specific pharmacodynamic target attainment.

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Pharmacokinetic–pharmacodynamic target attainment analysis of meropenem in Japanese adult patients

Cited by 24 publications

References 17 publications

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

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

Development and Assessment of a Nomogram to Propose the Initial Dosage Regimen of a Meropenem Infusion Based on Serum Creatinine and Age Using a Monte Carlo Simulation

Clinical Pharmacokinetics of Meropenem and Biapenem in Bile and Dosing Considerations for Biliary Tract Infections Based on Site-Specific Pharmacodynamic Target Attainment

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