Population Pharmacokinetic Model and Dosing Simulation of Meropenem Using Measured Creatinine Clearance for Patients with Sepsis

Fukumoto, Shiori; Ohbayashi, Masayuki; Okada, Akira; Kohyama, Noriko; Tamatsukuri, Tatsuro; Inoue, Hideki; Kotani, Toru; Sagara, Hironori; Dohi, Kenji; Kogo, Mari

doi:10.1097/ftd.0000000000001040

Cited by 3 publications

(2 citation statements)

References 23 publications

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“…Sjövall et al employed a Monte Carlo simulation to examine MEPM dosing in septic shock patients with potential augmented renal clearance [ 32 ]. They found that achieving a sufficient 100% f T >MIC against P. aeruginosa requires either a prolonged infusion of 1 g every 8 h with a 3 h infusion time or a continuous infusion of 3 g/day over 24 h. Fukumoto et al noted that in sepsis patients, with an MIC of MEPM set at 4 μg/mL, 1 g per dose (infusion time: 3–8 h), three times a day is necessary to achieve a 50% f T >MIC in patients with CLcr >85 mL/min [ 33 ]. Roberts et al used Monte Carlo simulation based on the PK parameters of MEPM in septic patients without renal dysfunction to compare the achievement rates of 50% f T >MIC among continuous, prolonged, and intermittent bolus infusions [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Relationship between Target Time above Minimum Inhibitory Concentration Achievement Rate of Meropenem Using Monte Carlo Simulation and In-Hospital Survival in Patients with Pseudomonas aeruginosa Bacteremia

Nakashima,

Miyazaki,

Kuwamura

et al. 2024

Antibiotics

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Pseudomonas aeruginosa bacteremia is associated with a high mortality rate, and meropenem (MEPM) is commonly used to treat it. However, the relationship between the time above the minimum inhibitory concentration (fT>MIC) of MEPM and its therapeutic efficacy in P. aeruginosa bacteremia has not been explored. This study aimed to investigate this relationship by defining the target % fT>MIC of MEPM as 75%. The retrospective study spanned 14 years and included hospitalized patients treated with MEPM for P. aeruginosa bacteremia. Monte Carlo simulation was used to calculate the probability of target attainment (PTA) for each patient, and the threshold for a PTA of 75% fT>MIC associated with in-hospital survival was determined using receiver operating characteristic (ROC) curves. The ROC curve-derived PTA associated with improved in-hospital survival was 65.0%, a significant finding in multivariate logistic regression analysis adjusted for patient background factors (odds ratio: 20.49, 95% confidence interval: 3.02–245.23, p = 0.005). This result suggests a dosing regimen that achieves a PTA of at least 65% when the target fT>MIC of MEPM for treating P. aeruginosa bacteremia is defined as 75%.

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Section: Discussionmentioning

confidence: 99%

Relationship between Target Time above Minimum Inhibitory Concentration Achievement Rate of Meropenem Using Monte Carlo Simulation and In-Hospital Survival in Patients with Pseudomonas aeruginosa Bacteremia

Nakashima,

Miyazaki,

Kuwamura

et al. 2024

Antibiotics

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“…Although only a few studies have investigated the population pharmacokinetics of carbapenems in septic patients, an increase in the volume of distribution is common. Fukumoto et al revealed the volume of distribution of meropenem V (V 1 +V 2 ) in patients with sepsis was 39.7L (Fukumoto et al, 2023), while Murínová et al reported an average V of 55L in patients with serious infection (Murínová et al, 2022), respectively. Both studies reported higher V of meropenem in patients with sepsis comparing with other patients, which may be caused by the increase in V of hydrophilic drugs, which is quite common in critically ill patients (Roberts and Lipman, 2006).…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics, dosing optimization and clinical outcomes of biapenem in patients with sepsis

Chen,

Wu,

Zhang

et al. 2024

Front. Pharmacol.

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Introduction: Biapenem is a carbapenem antibiotic widely used in Asia, can be used for the treatment of adults and children with infections due to susceptible bacteria. Although biapenem is utilized in the treatment of a diverse range of bacterial infections, current pharmacokinetic data in the context of septic populations remain limited. Consequently, our research aims to evaluate the pharmacokinetics and efficacy of biapenem within a septic population to optimize biapenem therapy.Methods: In this study, we characterized the pharmacokinetics of biapenem in septic patients using a population pharmacokinetic (PPK) approach. The clinical PK data to develop the PPK model were obtained from 317 septic patients admitted to Nanjing Drum Tower Hospital between 2018 and 2022. All patients were randomized to the modeling and validation cohorts at a 3:1 ratio, with PPK modeling and validation performed utilizing the NONMEM software.Results: The model found to best describe the available data was a two-compartment PPK model with first-order elimination characterized by the parameters clearance (CL), central volume (V1), peripheral volume (V2), and intercompartmental clearance (Q). A covariate analysis identified that creatinine clearance (CLCR) was a significant covariate influencing biapenem CL, while blood urea nitrogen (BUN) was a significant covariate influencing biapenem Q. Accoding to the clinical outcome analyses, 70% of the time that the free antimicrobial drug concentration exceeds the MIC (fT>MIC) is associated with favourable clinical outcomes. The PPK model was then used to perform Monte Carlo simulations to evaluate the probability of attaining 70% fT>MIC.Conclusions: A final PPK model of biapenem was established for patients with sepsis. The current daily dosage regimen of 1.2 g may insufficient to achieve 70% fT>MIC in septic patients. The dosage regimen of 600 mg every 6 h appears to be the optimal choice.

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Improvement of Statistical Models by Considering Correlations among Parameters: Local Anesthetic Agent Simulator for Pharmacological Education

Ara,

Kitamura

2024

BioMedInformatics

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Background: To elucidate the effects of local anesthetic agents (LAs), guinea pigs are used in pharmacological education. Herein, we aimed to develop a simulator for LAs. Previously, we developed a statistical model to simulate the LAs’ effects, and we estimated their parameters (mean [μ] and logarithm of standard deviation [logσ]) based on the results of animal experiments. The results of the Monte Carlo simulation were similar to those from the animal experiments. However, the drug parameter values widely varied among individuals, because this simulation did not consider correlations among parameters. Method: In this study, we set the correlations among these parameters, and we performed simulations using Monte Carlo simulation. Results: Weakly negative correlations were observed between μ and logσ (rμ−logσ). In contrast, weakly positive correlations were observed among μ (rμ) and among logσ (rlogσ). In the Monte Carlo simulation, the variability in duration was significant for small rμ−logσ values, and the correlation for the duration between two drugs was significant for large rμ and rlogσ values. When parameters were generated considering the correlation among the parameters, the correlation of the duration among the drugs became larger. Conclusions: These results suggest that parameter generation considering the correlation among parameters is important to reproduce the results of animal experiments in simulations.

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Population Pharmacokinetic Model and Dosing Simulation of Meropenem Using Measured Creatinine Clearance for Patients with Sepsis

Abstract: Supplemental Digital Content is Available in the Text.

Cited by 3 publications

References 23 publications

Relationship between Target Time above Minimum Inhibitory Concentration Achievement Rate of Meropenem Using Monte Carlo Simulation and In-Hospital Survival in Patients with Pseudomonas aeruginosa Bacteremia

Relationship between Target Time above Minimum Inhibitory Concentration Achievement Rate of Meropenem Using Monte Carlo Simulation and In-Hospital Survival in Patients with Pseudomonas aeruginosa Bacteremia

Population pharmacokinetics, dosing optimization and clinical outcomes of biapenem in patients with sepsis

Improvement of Statistical Models by Considering Correlations among Parameters: Local Anesthetic Agent Simulator for Pharmacological Education

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