Determination of population pharmacokinetic parameters for amikacin in neonates using mixed-effect models

Botha, Julia; Preez, M. J. Du; Miller, Raymond; Adhikari, Miriam

doi:10.1007/s002280050389

Cited by 25 publications

(19 citation statements)

References 19 publications

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“…(34) did find more individuals with an impaired GFR (Ͻ90 ml/min per 1.73 m 2 ) in the IUGR group. We found a positive correlation between amikacin clearance and GA, as has been described for aminoglycosides (18,20,(35)(36)(37)(38)(39). The absolute value of amikacin clearance (0.61 ml/kg per min) is comparable to previously reported values (0.52 to 0.6 ml/kg per min (17)(18)(19)40).…”

Section: Discussionsupporting

confidence: 88%

Impact of Gestational Age and Birth Weight on Amikacin Clearance on Day 1 of Life

Schreuder

Wilhelm²,

Bökenkamp

et al. 2009

Clinical Journal of the American Society of Nephrology

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Background and objectives: Intrauterine growth restriction (IUGR) and prematurity are associated with a low nephron endowment. It can therefore be expected that neonates who are born premature and/or after IUGR have a lower GFR. Measurement of GFR in neonates is difficult, but the clearance of amikacin has been proven to be a reliable marker. We hypothesized that amikacin clearance is lower after IUGR or premature birth as a marker of low nephron endowment.Design, setting, participants, & measurements: Amikacin clearance was retrospectively analyzed in 161 neonates who received amikacin within the first 24 h of life. Using the MW/Pharm computer program, a population one-compartment model was calculated. The mean population pharmacokinetic parameters were individualized for each patient according to the maximum a posteriori Bayesian fitting method and provided the amikacin clearance.Results: Our results show that birth weight z score and gestational age are correlated with the clearance of amikacin (partial correlation coefficient 0.159, P ‫؍‬ 0.046, and 0.396, P < 0.001, respectively), after correction for other factors.Conclusions: We conclude that renal clearance on the first day of life is lower in neonates with a lower gestational age and/or birth weight z score. This indicates that both prematurity and IUGR impair GFR on the first day of life.

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Section: Discussionsupporting

confidence: 88%

Impact of Gestational Age and Birth Weight on Amikacin Clearance on Day 1 of Life

Schreuder

Wilhelm²,

Bökenkamp

et al. 2009

Clinical Journal of the American Society of Nephrology

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“…This is consistent with other studies that have reported a 1-compartment model for amikacin disposition in neonates,[3], [4], [5] but different from others that reported a 2-compartment model for amikacin disposition among neonates 15 . The differences in compartmentalization between the present and other studies may be due to differences in sample schedules or postnatal age differences.…”

Section: Discussionsupporting

confidence: 88%

“…However, near-ubiquitous resistance of common pathogenic organisms to gentamicin has necessitated the increasing use of amikacin as first-line treatment 2 . Amikacin exhibits wide interindividual variability in pharmacokinetic (PK) parameters during the neonatal period[3], [4], [5], [6] and with unique PK characteristics among preterm neonates. The wide interindividual variability in amikacin concentrations in heterogeneous neonatal populations require amikacin therapeutic monitoring; however, such data rarely exist in most low-resource settings.…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetic Characteristics of Amikacin in Suspected Cases of Neonatal Sepsis in a Low-Resource African Setting: A Prospective Nonrandomized Single-Site Study

Amponsah

Adjei

Enweronu‐Laryea

et al. 2017

Current Therapeutic Research

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BackgroundAmikacin exhibits marked pharmacokinetic (PK) variability and is commonly used in combination with other drugs in the treatment of neonatal sepsis. There is a paucity of amikacin PK information in neonates from low-resource settings.ObjectivesTo determine the PK parameters of amikacin, and explore the influence of selected covariates, including coadministration with aminophylline, on amikacin disposition in neonates of African origin.MethodsNeonates with suspected sepsis admitted to an intensive care unit in Accra, Ghana, and treated with amikacin (15 mg/kg loading followed by 7.5 mg/kg every 12 hours), were recruited. Serum amikacin concentration was measured at specified times after treatment initiation and analyzed using a population PK modeling approach.ResultsA total of 419 serum concentrations were available for 247 neonates. Mean (SD) trough amikacin concentration (from samples collected 30 minutes before the fourth dose) among term (n = 25), and preterm (<37 weeks’ gestation n = 36) neonates were 6.2 (3.4) and 9.2 (5.7) µg/mL, respectively (P = 0.02). A 1-compartment model best fitted amikacin disposition, and birth weight was the most important predictor of amikacin clearance (CL) and distribution (V). The population CL and V of amikacin were related as CL (L/h) = 0.153 (birth weight/2.5)1.31, V (L) = 2.94 (birth weight/2.5)1.18. There was a high between-subject variability (58.9% and 50.7%) in CL and V, respectively. CL and V were 0.058 L/h/kg and 1.15 L/kg, respectively, for a mean birth weight of 2.1 kg, and the mean half-life (based on 1-compartment model), was 13.7 hours.ConclusionsThe V and half-life of amikacin in this cohort varied from that reported in non-African populations, and the high trough and low peak amikacin concentrations in both term and preterm neonates suggest strategies to optimize amikacin dosing are required in this population.

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“…As a result, the preliminary nonlinear regressions for each patient, carried out whenever possible with a two-compartment model, produced inaccurate second elimination constants. We therefore used a one-compartment model to describe our kinetic data, as already proposed by Botha et al (4) and Padovani et al (39) for a previously studied pediatric population. The two parameters were clearance (CL) and the volume of distribution (V), from which the elimination half-life (t 1/2 ) was derived.…”

Section: Methodsmentioning

confidence: 99%

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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Determination of population pharmacokinetic parameters for amikacin in neonates using mixed-effect models

Abstract: Birth weight was an important determinant of both CL and V and, in this data set, gender was also found to influence CL. Mean population pharmacokinetic values were within the range of those previously derived for other neonatal populations using traditional methods.

Cited by 25 publications

References 19 publications

Impact of Gestational Age and Birth Weight on Amikacin Clearance on Day 1 of Life

Impact of Gestational Age and Birth Weight on Amikacin Clearance on Day 1 of Life

Population Pharmacokinetic Characteristics of Amikacin in Suspected Cases of Neonatal Sepsis in a Low-Resource African Setting: A Prospective Nonrandomized Single-Site Study

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

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