Limited predictability of amikacin clearance in extreme premature neonates at birth

Allegaert, Karel; Anderson, Brian J.; Cossey, Veerle; Holford, Nicholas H. G.

doi:10.1111/j.1365-2125.2005.02530.x

Cited by 65 publications

(64 citation statements)

References 43 publications

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“…The administration of ibuprofen, to enhance closure of a symptomatic patent ductus arteriosis (PDA), was associated with a reduction of vancomycin clearance by 18%. This reduction is similar to that reported for an NSAID effect on amikacin clearance at birth [26]. This observation in the current cohort with a mean PNA of 11.9 days (SD 5.9) suggests an effect attributable to the NSAID and not the PDA and that this effect is not restricted to the first few days of life.…”

Section: Discussionsupporting

confidence: 72%

Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance

Anderson

Allegaert

Anker

et al. 2006

Brit J Clinical Pharma

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What is already known about this subject• Effects of size, renal function, age (postnatal age, gestational age and postmenstrual age) as predictors of vancomycin clearance in premature neonates are established, but the relative contribution of each component remains poorly quantified, largely because these variables are closely correlated.• We have quantified the covariates contributing to vancomycin clearance population parameter variability in order to establish the major covariates required for dosing predictions. Size, standardized using allometric models, was the primary covariate used in our analysis. What this study adds• Size explained 49.8%, postmenstrual age 18.2% and renal function 14.1% of clearance variability.• Descriptors of the relationship between age and clearance in premature neonates vary.• The use of a variable slope sigmoidal model to describe the relationship between clearance and postmenstrual age predicted an adult clearance of 3.79 l h − 1 70 kg − 1 (95% confidence interval 2.76, 4.98) from premature neonatal data. AimTo identify and quantify factors describing the variability of vancomycin clearance in premature neonates. MethodsPopulation pharmacokinetics were estimated (NONMEM) in 214 neonates [postmenstrual age (PMA) 30.4 weeks, range 24-34 weeks; postnatal age 11.9 days, range 1-27 days; weight 1.30 kg, range 0.42-2.6 kg] using therapeutic drug monitoring data. Covariate analysis included weight, PMA, serum creatinine, use of inotropes or ibuprofen, positive blood culture and respiratory support. A one-compartment linear disposition model with zero order input and first-order elimination was used to describe the data (604 observations). ResultsThe population estimate for volume of distribution ( V ) was 39 l 70 kg − 1 (coefficient of variation 19.4%). Clearance (CL) increased from 0.897 l h − 1 70 kg − 1 at 24 weeks PMA to 2.02 l h − 1 70 kg − 1 by 34 weeks PMA. The between-subject variability for CL was 18.6% and the between-occasion variability was 12.2%. The use of ibuprofen reduced clearance, but this effect was attributable to reduced renal function. Overall, 82% of the variability of CL was predictable. Size explained 49.8%, P MA 18.2% and renal function 14.1%. The use of a variable slope sigmoidal model to describe the relationship between clearance and PMA predicted an adult clearance of 3.79 l h − 1 70 kg − 1 (95% confidence interval 2.76, 4.98). ConclusionsSize, renal function and PMA are the major contributors to clearance variability in premature neonates. The small (18%) unexplained variability in clearance suggests target concentration intervention is unnecessary if size, age and renal function are used to predict the dose. Extrapolation to an adult clearance from neonatal data is possible using allometric size models and a function describing clearance maturation.B. J. Anderson et al.

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Section: Discussionsupporting

confidence: 72%

Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance

Anderson

Allegaert

Anker

et al. 2006

Brit J Clinical Pharma

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147

151

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“…Vd showed an opposite trend; the highest values were found in neonates and then Vd decayed up to 80 months of age. A remarkable interindividual variability in Cl was also observed in extremely premature neonates [48].…”

Section: Amikacinmentioning

confidence: 82%

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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“…The findings of other authors confirm that variability in amikacin elimination was caused by gestation age or birth weight which correlates to gestation age. However, in these studies, pre-and full-term neonates were included (10,18,30). There were as well conflicting data if postmenstrual (sum of gestational and neonatal) age was a good predictor of aminoglycoside CL (12,17,23,31).…”

Section: Discussionmentioning

confidence: 99%

“…High interindividual variability in amikacin pharmacokinetics was previously observed, and it was described in detail in pre-term neonates (9,11,22). 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).…”

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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Limited predictability of amikacin clearance in extreme premature neonates at birth

Cited by 65 publications

References 43 publications

Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance

Vancomycin pharmacokinetics in preterm neonates and the prediction of adult clearance

Clinical pharmacokinetics of aminoglycosides in the neonate: a review

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

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