Population pharmacokinetics and pharmacodynamics of teicoplanin in neonates: making better use of C-reactive protein to deliver individualized therapy

The aim of this study was to develop a population pharmacokinetic (PK) model for teicoplanin across childhood age ranges to be used as Bayesian prior information in the software constructed for individualized therapy. We developed a nonparametric population model fitted to PK data from neonates, infants, and older children. We then implemented this model in the BestDose multiple-model Bayesian adaptive control algorithm to show its clinical utility. It was used to predict the dosages required to achieve optimal teicoplanin predose targets (15 mg/liter) from day 3 of therapy. We performed individual simulations for an infant and a child from the original population, who provided early first dosing interval concentration-time data. An allometric model that used weight as a measure of size and that also incorporated renal function using the estimated glomerular filtration rate (eGFR), or the ratio of postnatal age (PNA) to serum creatinine concentration (SCr) for infants <3 months old, best described the data. The median population PK parameters were as follows: elimination rate constant (Ke) = 0.03 · (wt/70)−0.25 · Renal (h−1); V = 19.5 · (wt/70) (liters); Renal = eGFR0.07 (ml/min/1.73 m2), or Renal = PNA/SCr (μmol/liter). Increased teicoplanin dosages and alternative administration techniques (extended infusions and fractionated multiple dosing) were required in order to achieve the targets safely by day 3 in simulated cases. The software was able to predict individual measured concentrations and the dosages and administration techniques required to achieve the desired target concentrations early in therapy. Prospective evaluation is now needed in order to ensure that this individualized teicoplanin therapy approach is applicable in the clinical setting. (This study has been registered in the European Union Clinical Trials Register under EudraCT no. 2012-005738-12.)

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“…The pharmacokinetics (PK) of teicoplanin are highly variable in children and neonates ( 1 , 2 ). Weight-based dosing is advocated ( 3 ).…”

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confidence: 99%

Tools for the Individualized Therapy of Teicoplanin for Neonates and Children

Ramos-Martín

Neely

Padmore

et al. 2017

Antimicrob Agents Chemother

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“…3 Teicoplanin is administered by the parenteral route (intravenously or intramuscularly) and is mainly excreted via the renal route. 5, 6 Matsumoto et al suggested a target AUC 24 /MIC ratio of ࣙ900. 4 The clinical benefit of teicoplanin is associated with the ratio of the area under the drug concentrationtime curve (AUC) to the minimum inhibitory concentration (MIC).…”

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confidence: 99%

“…21,22 Although the CRP concentration is an indirect index for infections and its threshold levels for efficacy are not clearly known, it is widely used because monitoring variations in the CRP concentration provides information on the sequential efficacy of antibacterial agents. 24 A population PKPD model for predicting sequential variations of teicoplanin and CRP concentration that can be applied to a wide range of patients including the elderly, the obese, and those with renal insufficiency could provide physicians with useful information for setting individual dosing regimens. 21 For the population pharmacokinetics and pharmacodynamics (PKPD) model of teicoplanin and CRP, there has only been a report of 18 cases of neonates.…”

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confidence: 99%

“…4 The clinical benefit of teicoplanin is associated with the ratio of the area under the drug concentrationtime curve (AUC) to the minimum inhibitory concentration (MIC). 5,6 Matsumoto et al suggested a target AUC 24 /MIC ratio of ࣙ900. 6 The use of therapeutic drug monitoring has been recommended with a target minimum concentration (C min ) range of 15-30 mg/L, 7 but the optimal dosing regimen is not yet known.…”

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confidence: 99%

“…21 For the population pharmacokinetics and pharmacodynamics (PKPD) model of teicoplanin and CRP, there has only been a report of 18 cases of neonates. 24 A population PKPD model for predicting sequential variations of teicoplanin and CRP concentration that can be applied to a wide range of patients including the elderly, the obese, and those with renal insufficiency could provide physicians with useful information for setting individual dosing regimens. 14,15,25 However, there has been no study that has evaluated the population PKPD of teicoplanin and CRP based on data from a large-scale population.…”

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confidence: 99%

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Population Pharmacokinetics and Pharmacodynamics of Teicoplanin and C‐Reactive Protein in Hospitalized Patients With Gram‐Positive Infections

Ogami

Tsuji

Mizoguchi

et al. 2019

Clinical Pharm in Drug Dev

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Teicoplanin is an antibiotic agent used for the treatment of Gram-positive infections. The clinical benefit of teicoplanin is associated with its blood concentrations, but the optimal dosing regimen is not yet known. To explore the optimal individual dosing regimen, we performed a population pharmacokinetic (PK) and pharmacodynamic (PD) analysis targeting a large-scale population, including patients with a wide range of ages, body weights, and renal functions. The PK of teicoplanin was described with a 2-compartment model, and the PD of C-reactive protein (CRP) concentrations was described with a turnover maximum inhibition model. The elimination half-life of teicoplanin calculated from the final estimated parameters was 169 hours, and renal function was a significant covariate of teicoplanin clearance. The teicoplanin concentration producing 50% of the maximum inhibition of CRP production was estimated to be 2.66 mg/L. The minimum concentration of teicoplanin in patients with higher loading doses (15 mg/kg) reached the target range (15-30 mg/L) with a probability of >50% in the dosing simulation. We described the influence of body size, body composition, and renal function on the PK of teicoplanin. The population PKPD model of teicoplanin and CRP in this study should provide useful information for development of a dosing strategy including the sequential clinical benefit of teicoplanin. KeywordsC-reactive protein, pharmacodynamics, pharmacokinetics, teicoplanin, therapeutic drug monitoring Teicoplanin, a glycopeptide antibiotic agent first approved in France and Italy in 1988, is currently available and used in over 60 countries for the treatment of Gram-positive infections including methicillinresistant Staphylococcus aureus. 1 Teicoplanin has a structure and a mechanism similar to those of vancomycin, another glycopeptide antibacterial agent, and exhibits bactericidal activity by inhibiting the synthesis of cell wall peptidoglycan. 2 A meta-analysis study comparing the efficacy and toxicity of teicoplanin and vancomycin revealed no significant differences in efficacy between these 2 drugs, but adverse events (eg,

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Biomarker‐Guided Individualization of Antibiotic Therapy

Aulin

Lange

Saleh

et al. 2021

Clin Pharma and Therapeutics

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Treatment failure of antibiotic therapy due to insufficient efficacy or occurrence of toxicity is a major clinical challenge, and is expected to become even more urgent with the global rise of antibiotic resistance. Strategies to optimize treatment in individual patients are therefore of crucial importance. Currently, therapeutic drug monitoring plays an important role in optimizing antibiotic exposure to reduce treatment failure and toxicity. Biomarker-based strategies may be a powerful tool to further quantify and monitor antibiotic treatment response, and reduce variation in treatment response between patients. Host response biomarkers, such as CRP, procalcitonin, IL-6, and presepsin, could potentially carry significant information to be utilized for treatment individualization. To achieve this, the complex interactions among immune system, pathogen, drug, and biomarker need to be better understood and characterized. The purpose of this tutorial is to discuss the use and evidence of currently available biomarker-based approaches to inform antibiotic treatment. To this end, we also included a discussion on how treatment response biomarker data from preclinical, healthy volunteer, and patient-based studies can be further characterized using pharmacometric and system pharmacology based modeling approaches. As an illustrative example of how such modeling strategies can be used, we describe a case study in which we quantitatively characterize procalcitonin dynamics in relation to antibiotic treatments in patients with sepsis.

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Population pharmacokinetics and pharmacodynamics of teicoplanin in neonates: making better use of C-reactive protein to deliver individualized therapy

Cited by 23 publications

References 38 publications

Tools for the Individualized Therapy of Teicoplanin for Neonates and Children

Tools for the Individualized Therapy of Teicoplanin for Neonates and Children

Population Pharmacokinetics and Pharmacodynamics of Teicoplanin and C‐Reactive Protein in Hospitalized Patients With Gram‐Positive Infections

Biomarker‐Guided Individualization of Antibiotic Therapy

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