Pharmacokinetics of Amikacin in
Neonates

E, Padovani; C, Pistolesi; Fanos, Vassilios; Messori, Andrea; Martini, Nello

doi:10.1159/000457558

Cited by 31 publications

(24 citation statements)

References 11 publications

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“…This may be because the age range of the population was not sufficiently large due to a lack of very premature neonates. These results are consistent with the results of previous studies on the pharmacokinetics of netilmicin (51), gentamicin (17), and amikacin (1,39,45) in neonates but not with the results of others suggesting that gestational age affects the clearance of gentamicin (43) and amikacin (45). The available data suggest that gestational age may have an effect only during the very first days of life (17,43,45).…”

Section: Discussionsupporting

confidence: 90%

Nonparametric Population Pharmacokinetic Analysis of Amikacin in Neonates, Infants, and Children

Tréluyer

Merlé

Tonnelier

et al. 2002

Antimicrob Agents Chemother

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The therapeutic and toxic effects of amikacin are known to depend on its concentration in plasma, but the pharmacokinetics of this drug in neonates, infants, and children and the influences of clinical and biological variables have been only partially assessed. Therapeutic drug monitoring data collected from 155 patients (49 neonates, 77 infants, and 29 children) receiving amikacin were analyzed by a nonparametric population-based approach, the nonparametric maximum-likelihood method. We assessed the effects of gestational and postnatal age, weight, Apgar score, and plasma creatinine and urea concentrations on pharmacokinetic parameters. There is no specific formulation of amikacin for neonates and infants. We therefore used an error model to account for errors due to dilution during preparation of the infusion. The covariates that reduced the variance of clearance from plasma and the volume of distribution by more than 10% were postnatal age (43 and 28%, respectively) and body weight (30.4 and 17.4%, respectively). The expected reduction of clearance was about 10% for the plasma creatinine concentration. The other covariates studied (Apgar scores, plasma urea concentration, gestational age, sex) were found to have little effect. Simulations showed that a smaller percentage of patients had a maximum concentration in plasma/MIC ratio greater than 8 with a regimen of 7.5 mg/kg of body weight twice daily than with a regimen of 15 mg/kg once a day for MICs of 1 to 8 mg/liter.Amikacin is widely used in neonates and infants, as well as in adults, for the treatment of severe infections caused by gramnegative bacteria. Previous studies have shown that both the therapeutic response and toxic effects depend on plasma amikacin concentrations. Achieving a therapeutic maximum concentration of amikacin in plasma is associated with a significant decrease in the rate of mortality due to infection in critically ill patients (2, 36, 37), and a relationship has also been found between the minimum plasma amikacin concentration and renal toxicity (20,49). Interindividual variability in the pharmacokinetics of amikacin may therefore make it difficult to achieve safe and effective treatment. The pharmacokinetics of aminoglycosides have been shown to be highly variable in neonates and children. Several factors account for the pharmacokinetic variabilities of other aminoglycosides in this population (50). The pharmacokinetics of netilmicin and gentamicin depend on gestational age, postnatal age, weight, renal clearance, and Apgar score (6,9,11,12,14,18,21,43,46,47,(51)(52)(53). Very few data are available concerning the effects of clinical and biological covariates on the pharmacokinetics of amikacin in neonates and the changes in the pharmacokinetic profile of amikacin that occur from birth into infancy. The lack of data on the pharmacokinetics of many drugs in neonates and children is related to blood sampling limitations for this population. One way around this problem is to collect a few samples from many individuals and analyze the...

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Section: Discussionsupporting

confidence: 90%

Nonparametric Population Pharmacokinetic Analysis of Amikacin in Neonates, Infants, and Children

Tréluyer

Merlé

Tonnelier

et al. 2002

Antimicrob Agents Chemother

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“…Amikacin pharmacokinetic parameters in our study are comparable to previously published values of Vd, CL, and t 1/2 (8,21). No statistical differences in the mean parameters values were observed between groups, as amikacin shows linear pharmacokinetics.…”

Section: Discussionsupporting

confidence: 90%

“…In pre-term neonates, weight and gestational and/or neonatal age significantly contributed to amikacin pharmacokinetic variability (9,10,23). However, in fullterm patients, there were only few studies on amikacin pharmacokinetics (8,21). The purpose of this study was to compare C peak and C trough amikacin after two dosing regimens in full-term neonates and to address amikacin pharmacokinetics and its variability.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic Variability of Amikacin After Once-Daily and Twice-Daily Dosing Regimen in Full-Term Neonates

Vučićević¹,

Rakonjac

Miljković³

et al. 2014

J Pharmacol Sci

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Abstract. The purpose of the study was to compare peak (C peak ) and trough (C trough ) amikacin levels after twice-daily (TD) or once-daily dosing (OD) in full-term neonates. Additionally, the study aimed to address amikacin pharmacokinetics and its variability. Data included 31 patients born on term. Amikacin daily dose was 15 or 20 mg/kg depending on the neonate's age. Patients randomly received amikacin every 12 or 24 h. In all patients corresponding C peak and C trough were taken. Volume of distribution (Vd), clearance (CL) and half-life (t 1/2 ) were calculated. Mean C peak of 21.79 mg/ml in the TD group was statistically different from C peak of 36.39 mg/ml in the OD group. Average C trough in TD (5.67 mg/ml) was statistically different from the corresponding 3.99 mg/ml in the OD group. Mean amikacin Vd, CL, and t 1/2 were 0.78 ± 0.38 l/kg, 86.99 ± 48.22 ml/h•kg, and 6.81 ± 2.51 h, respectively. High interindividual pharmacokinetic variability was observed. Further analysis showed that neonatal age contributed to the pharmacokinetic parameters' values. Statistically significant difference in CL and t 1/2 was observed between patients age ≤ 2 and > 2 days on therapy initiation. As expected, amikacin given OD achieved higher C peak and lower C trough than TD. Based on the results, observed variability in amikacin pharmacokinetics was possibly due to the renal maturation process.

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“…There is a remarkable variation in the pharmacokinetic parameters of gentamicin [21,50], netilmicin [30][31][32]38], tobramycin [39,40] and amikacin [51,52]. Such a variation is due to renal maturation [50] as aminoglycosides are fairly water soluble and are eliminated with the urine.…”

Section: Discussionmentioning

confidence: 99%

“…The variability in t 1/ 2 and Cl of gentamicin could be due to variability in the glomerular filtration rate [54]. Another source of variability is the gestational age [52]. Other factors generating variability are malnutrition, disease, developmental stage or genetics.…”

Section: Discussionmentioning

confidence: 99%

Clinical pharmacokinetics of aminoglycosides in the neonate: a review

Pacifici

2008

Eur J Clin Pharmacol

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Background Sepsis is common in neonates and is a major cause of morbidity and mortality. Sixty percent of preterm neonates receive at least one antibiotic, and 43% of the antibiotics administered to these neonates are aminoglycosides. The clearance (Cl), serum half-life (t 1/2 ), and volume of distribution (Vd) of aminoglycosides change during the neonatal life, and the pharmacokinetics of aminoglycosides need to be studied in neonates in order to optimise therapy with these drugs. Objective The aim of this work is to review the published data on the pharmacokinetics of aminoglycosides in order to provide a critical analysis of the literature that can be a useful tool in the hands of physicians. Methods The bibliographic search was performed electronically using PubMed, as the search engine, through July 11th, 2008. Firstly, a Medline search was performed with the keywords "pharmacokinetics of aminoglycosides in neonates" with the limit of "human". Other Medline searches were performed with the keywords "pharmacokinetics of … in neonates" followed by the name of the aminoglycosides: amikacin, gentamicin, netilmicin and tobramycin. In addition, the book Neofax: A Manual of Drugs Used in Neonatal Care by Young and Mangum (Thomson Healthcare, 2007) was consulted. Results The aminoglycosides are mainly eliminated by the kidney, and their elimination rates are reduced at birth. As a consequence Cl is reduced and t 1/2 is prolonged in the neonate as compared to more mature infants. The high body-water content of the neonate results in a large Vd of aminoglycosides as these drugs are fairly water soluble. Postnatal development is an important factor in the maturation of the neonate, and as postnatal age proceeds, Cl of aminoglycosides increases. Conclusion The maturation of the kidney governs the pharmacokinetics of aminoglycosides in the infant. Cl and t 1/2 are influenced by development, and this must be taken into consideration when planning a dosage regimen with aminoglycosides in the neonate. Aminoglycosides are fairly water soluble, and the larger water content of neonates yields a larger Vd in these patients.

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Pharmacokinetics of Amikacin in Neonates

Cited by 31 publications

References 11 publications

Nonparametric Population Pharmacokinetic Analysis of Amikacin in Neonates, Infants, and Children

Nonparametric Population Pharmacokinetic Analysis of Amikacin in Neonates, Infants, and Children

Pharmacokinetic Variability of Amikacin After Once-Daily and Twice-Daily Dosing Regimen in Full-Term Neonates

Clinical pharmacokinetics of aminoglycosides in the neonate: a review

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