Population pharmacokinetics and dosing optimization of latamoxef in neonates and young infants

Qi, Hui; Kou, Chen; Qi, Yuan; Tang, Bo‐Hao; Wu, Yue‐E; Jin, Fei; Luo, Xiao-Jing; Shen, Yifan; Guo, Yinlong; Qi, Xue; Wang, Yacui; Chen, Xing-Kai; Shi, Haiyan; Zheng, Yi; Zhao, Wei; Shen, Adong

doi:10.1016/j.ijantimicag.2018.11.017

Cited by 11 publications

(17 citation statements)

References 18 publications

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“…According to our preliminary PPK study and dose simulation for latamoxef in neonates ( Qi et al, 2019 ), 60.2% of neonates using conventional treatment regimen (30 mg/kg q12 h) reached 70% fT > MIC and 80.1% of neonates using model treatment regimen (20 mg/kg q8h) reached 70% fT > MIC with MIC of 2 mg/L, respectively. We conducted sample size estimation for superiority design by using PASS 15.0 (NCSS, Kaysville, Utah, United States).…”

Section: Methods and Designmentioning

confidence: 99%

“…To assess the PK features of latamoxef in neonates, we performed a population pharmacokinetics (PPK) study of latamoxef in Chinese neonates and established a PPK model for them ( Carmine et al, 1983 ). Current body weight, birth weight, and postnatal age have been identified as significant covariates influencing latamoxef clearance ( Qi et al, 2019 ). Moreover, to develop a rational dosing regimen for latamoxef, we conducted dose simulation and found that ascending administration frequency could improve the target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval (70% fT > MIC) ( Qi et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

“…Current body weight, birth weight, and postnatal age have been identified as significant covariates influencing latamoxef clearance ( Qi et al, 2019 ). Moreover, to develop a rational dosing regimen for latamoxef, we conducted dose simulation and found that ascending administration frequency could improve the target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval (70% fT > MIC) ( Qi et al, 2019 ). Based these findings, to provide more pharmacodynamics (PD) data for generalizing this PPK model-based regimen, we plan to conduct a single-blind, multicenter randomized controlled trial (RCT) and compare the 70%fT > MIC, efficacy and safety between conventional regimen and PPK model regimen for latamoxef in EONS treatment for the first time.…”

Section: Introductionmentioning

confidence: 99%

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Latamoxef for Neonates With Early-Onset Neonatal Sepsis: A Study Protocol for a Randomized Controlled Trial

Liu

et al. 2021

Front. Pharmacol.

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Early-onset neonatal sepsis (EONS), a bacterial infection that occurs within 72 h after birth, is associated with high likelihood of neonatal mortality. Latamoxef, a semi-synthetic oxacephem antibiotic developed in 1980s, has been brought back into empirical EONS treatment in recent years. In the preliminary work, we established a population pharmacokinetics (PPK) model for latamoxef in Chinese neonates. Moreover, in order to better guide clinical treatment, we conducted dose simulation and found that ascending administration frequency could improve the target rate of 70% of patients having a free antimicrobial drug concentration exceeding the MIC during 70% of the dosing interval (70% fT > MIC). Accordingly, this study is aimed to compare the 70% fT > MIC, efficacy and safety between conventional regimen and PPK model regimen for rational use of latamoxef in EONS treatment. A single-blind, multicenter randomized controlled trial (RCT) for latamoxef will be conducted in Chinese EONS patients. Neonates (≤3 days of age, expected number = 114) admitted to the hospital with the diagnosis of EONS and fulfilling inclusion and exclusion criteria will be randomized (ratio of 1:1) to either a conventional regimen (30 mg/kg q12h) or model regimen (20 mg/kg q8h) latamoxef treatment group for at least 3 days. Primary outcome measure will be 70% fT > MIC and secondary outcome indicators will be the latamoxef treatment failure, duration of antibiotic therapy, changes of white blood cell count (WBC), C-reactive protein (CRP) and procalcitonin (PCT), blood culture results during administration and incidence of adverse event (AE)s. Assessments will be made at baseline, initial stage of latamoxef treatment (18–72 h) and before the end of latamoxef treatment. Ethical approval of our clinical trial has been granted by the ethics committee of the Beijing Children’s Hospital (ID: 2020-13-1). Written informed consent will be obtained from the parents of the participants. This trial is registered in the Chinese Clinical Trial Registry (ChiCTR 2000040064).It is hoped that our study will provide a clinical basis for the rational clinical use of latamoxef in EONS treatment.

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Section: Methods and Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Latamoxef for Neonates With Early-Onset Neonatal Sepsis: A Study Protocol for a Randomized Controlled Trial

Liu

et al. 2021

Front. Pharmacol.

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“…19 Given all this, the 70% fT > MIC in at least 70% patients was selected as the target based on a balance between maximal efficacy and minimal toxicity, which was consistent with the value used in other studies in neonates. [20][21][22] The proportion of free piperacillin was set at 70%. 23,24 The MIC of 16 mg/L was selected as the PK-PD breakpoint which covered common pathogens for EOS (e.g., Escherichia coli) in China.…”

Section: Model-based Dosing Regimenmentioning

confidence: 99%

Clinical utiliy of a model‐based piperacillin dose in neonates with early‐onset sepsis

Hou

Fang

et al. 2021

Brit J Clinical Pharma

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AimsEarly‐onset sepsis (EOS) is a common disease in neonates with a high morbidity and mortality rate. Piperacillin/tazobactam has been used extensively and empirically for EOS treatment without clinically validated dosing regimens, although the population pharmacokinetics (PPK) of piperacillin in neonates has been reported. Therefore, we wanted to study the effectiveness and tolerance of a PPK model‐based dosing regimen of piperacillin/tazobactam in EOS patients.MethodsA prospective, single‐centre, phase II clinical study of piperacillin/tazobactam in neonates with EOS was conducted. The dosing regimen (90 mg·kg−1, q8h) was determined based on a previous piperacillin PPK model in young infants using NONMEM v7.4. The pharmacodynamics (PD) target (70%fT > MIC, free drug concentration above MIC during 70% of the dosing interval) attainment was calculated using NONMEM combined with an opportunistic sampling design. The clinical treatment data were collected.ResultsA total of 52 neonates were screened and 49 neonates completed their piperacillin/tazobactam treatment course and were included in this analysis. The median (range) values of postmenstrual age were 33.57 (range 26.14–41.29) weeks. Forty‐seven (96%) neonates reached their PD target. Eight (16%) neonates experienced treatment failure clinically. The mean (SD, range) duration of treatment and length of hospitalization were 100.1 (62.2, 36.2–305.8) hours and 31 (30, 5–123) days. There were no obvious adverse events and no infection‐related deaths occurred in the first month of life.ConclusionsA model‐based dosing regimen of piperacillin/tazobactam was evaluated clinically, was tolerated well and was determined to be effective for EOS treatment.

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“…Basing on a balance between maximal efficacy and minimal toxicity, as well as reduction of resistance, the desired target was that the free drug concentration of more than 70% of patients was above the MIC during 70% of the dosage interval. 17,38,39 The neonatal dosage simulation of azlocillin was on a mg/kg basis. Monte Carlo simulations were performed using parameter estimates obtained from the final model.…”

Section: Simulation and Dosage Regimen Optimizationmentioning

confidence: 99%

Population pharmacokinetics and dosing optimization of azlocillin in neonates with early-onset sepsis: a real-world study

Wang

Yang

et al. 2020

Journal of Antimicrobial Chemotherapy

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Objectives Nowadays, real-world data can be used to improve currently available dosing guidelines and to support regulatory approval of drugs for use in neonates by overcoming practical and ethical hurdles. This proof-of-concept study aimed to assess the population pharmacokinetics of azlocillin in neonates using real-world data, to make subsequent dose recommendations and to test these in neonates with early-onset sepsis (EOS). Methods This prospective, open-label, investigator-initiated study of azlocillin in neonates with EOS was conducted using an adaptive two-step design. First, a maturational pharmacokinetic-pharmacodynamic model of azlocillin was developed, using an empirical dosing regimen combined with opportunistic samples resulting from waste material. Second, a Phase II clinical trial (ClinicalTrials.gov: NCT03932123) of this newly developed model-based dosing regimen of azlocillin was conducted to assure optimized target attainment [free drug concentration above MIC during 70% of the dosing interval (‘70% fT>MIC’)] and to investigate the tolerance and safety in neonates. Results A one-compartment model with first-order elimination, using 167 azlocillin concentrations from 95 neonates (31.7–41.6 weeks postmenstrual age), incorporating current weight and renal maturation, fitted the data best. For the second step, 45 neonates (30.3–41.3 weeks postmenstrual age) were subsequently included to investigate target attainment, tolerance and safety of the pharmacokinetic-pharmacodynamic model-based dose regimen (100 mg/kg q8h). Forty-three (95.6%) neonates reached their pharmacokinetic target and only two neonates experienced adverse events (feeding intolerance and abnormal liver function), possibly related to azlocillin. Conclusions Target attainment, tolerance and safety of azlocillin was shown in neonates with EOS using a pharmacokinetic-pharmacodynamic model developed with real-world data.

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Population pharmacokinetics and dosing optimization of latamoxef in neonates and young infants

Cited by 11 publications

References 18 publications

Latamoxef for Neonates With Early-Onset Neonatal Sepsis: A Study Protocol for a Randomized Controlled Trial

Latamoxef for Neonates With Early-Onset Neonatal Sepsis: A Study Protocol for a Randomized Controlled Trial

Clinical utiliy of a model‐based piperacillin dose in neonates with early‐onset sepsis

Population pharmacokinetics and dosing optimization of azlocillin in neonates with early-onset sepsis: a real-world study

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