Gentamicin Pharmacokinetics in Preterm Infants with a Patent Ductus Arteriosus (PDA) 353

Touw, Daan; Stevens, Remi; Gianotten, Erno; Lafeber, Harry N; Weissenbruch, Mirjam M. van

doi:10.1203/00006450-199804001-00374

Cited by 4 publications

(5 citation statements)

References 21 publications

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“…It is highly probable that infants with hemodynamically significant PDA may have altered drug disposition. Presence of hemodynamically significant PDA may affect drug disposition 24 by causing reduced blood flow to drug‐metabolizing organs (i.e., liver) as well as introducing fluid overload since there are data available on the influence of physiologic changes induced by PDA on the pharmacokinetics of gentamicin 25,26 and indomethacin 27–29 . Moreover, the time after birth at which the drug was administered varies significantly among babies, which may also affect metabolism since advancing age has a maturational effect on the activity of several metabolizing enzymes.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Oral Ibuprofen in Premature Infants

Sharma

Garg

Narang

2003

The Journal of Clinical Pharma

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Patent ductus arteriosus (PDA) is a frequent complication in premature infants. So far, intravenous indomethacin is the standard mode of medical therapy in such patients but carries a risk of frequently occurring side effects. Ibuprofen, another nonsteroidal anti-inflammatory drug, has also been shown to be efficacious in closing ductus with lesser adverse effects after parenteral administration. However, limited data are available on the pharmacokinetics of intravenous ibuprofen in this population. Nonavailability of parenteral preparation and lack of information regarding pharmacokinetic disposition of ibuprofen in this subgroup of the population led the authors to conduct this pharmacokinetic study with oral ibuprofen. Twenty premature infants with a gestational age of 30.45 +/- 0.33 weeks and a birth weight of 1262.5 +/- 55.4 g (values given as mean +/- SEM) admitted to the neonatal unit were enrolled in this study. Ibuprofen was administered in a single oral dose of 10 mg/kg between 4 and 72 hours postnatally, and blood samples were collected through an indwelling vascular catheter at time 0 and 1, 2, 4, 8, 12, and 24 hours. Ibuprofen plasma concentrations were assayed by high-performance liquid chromatography. There was a large interindividual variability observed for plasma concentrations, elimination half-life (t1/2) (15.72 +/- 3.76 h), and area under the plasma concentration-time curve (AUC0-infinity) (402.60 +/- 79.67 micrograms.h/mL) in these babies. Variables such as gestational age, birth weight, and sex did not affect ibuprofen pharmacokinetics significantly (p > 0.05). Moreover, no correlation could be found between elimination half-life and gestational age (r = 0.02). Ibuprofen pharmacokinetics showed a wide variability in premature infants. The results of the present study warrant revising the oral dosage schedule to achieve comparable plasma concentrations of ibuprofen associated with successful closure of ductus, as reported in earlier studies.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Oral Ibuprofen in Premature Infants

Sharma

Garg

Narang

2003

The Journal of Clinical Pharma

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“…With the identification of covariates that notably influence Vd and Cl, gentamicin dosing can be adjusted to achieve maximum efficiency and minimum toxicity . The significant covariates in the paediatric population are body weight (BW), gestational age (GA) and post‐natal age (PNA) …”

Section: What Is Known and Objectivesmentioning

confidence: 99%

“…8 The significant covariates in the paediatric population are body weight (BW), gestational age (GA) and post-natal age (PNA). 9,10 Several studies have been performed to analyse the influence of various factors on inter-and intraindividual variability of gentamicin pharmacokinetic parameters. In most studies, the methodology of population data analysis was applied, and the methods most often used were Bayesian forecasting, nonparametric expectation maximization algorithm (NPEM) and non-linear mixed-effects modelling.…”

Section: What Is K Nown and Objec Tive Smentioning

confidence: 99%

A review of population pharmacokinetic models of gentamicin in paediatric patients

2019

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What is known and objectives Gentamicin is often used for the treatment of Gram‐negative infections. Due to pharmacokinetic variability in paediatric patients, appropriate dosing of gentamicin in the paediatric population is challenging. This article reviews published population pharmacokinetic models of gentamicin in paediatric patients, identifies covariates that significantly influence gentamicin pharmacokinetics, and determines whether there is a consensus on proposed dosing for intravenous gentamicin in this population. Methods The PubMed database was searched for articles published until the end of 2017. If the articles described population pharmacokinetic models of gentamicin in the paediatric population (after intravenous administration of gentamicin), the following data were extracted: type of study, year of publication, population characteristics and number of patients, gentamicin dosing, total number of gentamicin (serum and/or plasma) concentrations, type of population modelling approach, developed model with pharmacokinetic parameters and covariates included. Results and discussion In most of the studies, one‐ or two‐compartment modelling was applied. The mean estimated gentamicin clearance for newborns, infants and the complete paediatric population was 0.048, 0.13 and 0.067 L/h/kg, respectively, and the mean predicted volume of distribution was 0.475, 0.35 and 0.33 L/kg, respectively. The values reflect differences in body composition and kidney maturation within the different paediatric populations. Gentamicin pharmacokinetics were most influenced by age, body size and renal function. What is new and conclusion Based on our review, the authors agree on a prolonged dosing interval for preterm and term newborns (up to 48 hours). However, there was no agreement on proposed dosing with respect to gestational age. In general, the proposed daily doses were lower compared to those initially applied for preterm newborns and comparable to those for term newborns. For infants and children, the dosing interval remained unchanged (24 hours), but the proposed daily doses were higher than actually applied. When differences in the paediatric population are considered and an appropriate population PK model with applicable covariates is applied, dosing can be individualized. In the future, studies of gentamicin pharmacokinetics in paediatric patients should focus on currently underestimated covariates, such as fat‐free mass, concomitantly administered drugs, body temperature and critical illness because these can change gentamicin PK considerably. Consequently, different dosing is required and TDM becomes even more important.

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“…Touw et al 28 studied gentamicin pharmacokinetics in 12 neonates with patent ductus arteriosus and 12 infants with closed ductus arteriosus. A patent ductus arteriosus may influence renal and hepatic blood flow and hence the pharmacokinetics of drugs.…”

Section: Pharmacokinetics Of Gentamicin In Neonatesmentioning

confidence: 99%

Clinical pharmacology of gentamicin in neonates: regimen, toxicology and pharmacokinetics

Pacifici¹

2015

Medical Express

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Gentamicin is an aminoglycoside antibiotic. It kills bacteria by inhibiting protein synthesis and to some extent by lysing the cell envelope. Gentamicin is frequently the first choice drug because of its reliability, but also because of the long experience with its use. In combination with β-lactam antibiotics it is recommended for the treatment of sepsis or pneumonia and is active against P. aeruginosa, Enterobacter, Klebsiella and Serratia. However, gentamicin is ototoxic and nephrotoxic. The human mitochondrial genetic variant m.1555A > G has been reported to be an important cause of non-syndromic hereditary hearing dysfunction and may cause permanent hearing loss. Even short courses of gentamicin therapy in healty newborn infants can lead to abnormalities of auditory function. It is active against very resistant bacteria at peak concentrations (> 10 mg/l) that are high enough to be potentially toxic. For safe therapeutic efficacy, peak plasma concentrations of gentamicin should range from 4 to 10 mg/l; but trough concentrations, immediately before a new drug administration, must be lower that 2 mg/L to avoid toxic effects. Pharmacokinetic parameters vary considerably in infants. Half-life ranges from 5.4 to 10.0 hours, clearance 0.50 to 1.71 ml/h/kg and distribution volume from 0.4 to 0.7 l/kg. Preterm infants have a longer half-life than full-term infants. Thus, it is mandatory to monitor gentamicin serum concentrations whenever infants are treated for 48 hours or more.

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Gentamicin Pharmacokinetics in Preterm Infants with a Patent Ductus Arteriosus (PDA) 353

Cited by 4 publications

References 21 publications

Pharmacokinetics of Oral Ibuprofen in Premature Infants

Pharmacokinetics of Oral Ibuprofen in Premature Infants

A review of population pharmacokinetic models of gentamicin in paediatric patients

Clinical pharmacology of gentamicin in neonates: regimen, toxicology and pharmacokinetics

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