Modification in the pharmacokinetics of amikacin during development

Lanao, J. M.; Domínguez-Gil, A; S, Málaga; Crespo, Manuel; Nuño, F.

doi:10.1007/bf00545971

Cited by 7 publications

(4 citation statements)

References 15 publications

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“…For infants and children, the manufacturer recommends a dose of 15 mg/kg/day administered intravenously or intramuscularly and divided into two or three doses. For neonates, a loading dose of 10 mg/kg followed by a maintenance dose of 7.5 mg/kg every 12 h administered intravenously over 1 to 2 h has been recommended by the manufacturer, as V of amikacin is higher in neonates than in infants and children (26,45). However, many other regimens have been proposed (23,41,45).…”

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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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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“…Although this was a relatively minor model adjustment for fosfomycin, amikacin required a more significant model modification to capture the change in neonatal V d seen from observed data. This change in amikacin V d as neonates age is well‐documented, 45 but the mechanism is not understood. Further characterization of this mechanism is required in order to incorporate this more generally in pediatric PBPK models.…”

Section: Discussionmentioning

confidence: 99%

Development and application of neonatal physiology‐based pharmacokinetic models of amikacin and fosfomycin to assess pharmacodynamic target attainment

Darlow,

Parrott,

Peck

et al. 2024

CPT Pharmacom & Syst Pharma

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Antimicrobial resistance increasingly complicates neonatal sepsis in a global context. Fosfomycin and amikacin are two agents being tested in an ongoing multicenter neonatal sepsis trial. Although neonatal pharmacokinetics (PKs) have been described for these drugs, the physiological variability within neonatal populations makes population PKs in this group uncertain. Physiologically‐based pharmacokinetic (PBPK) models were developed in Simcyp for fosfomycin and amikacin sequentially for adult, pediatric, and neonatal populations, with visual and quantitative validation compared to observed data at each stage. Simulations were performed using the final validated neonatal models to determine drug exposures for each drug across a demographic range, with probability of target attainment (PTA) assessments. Successfully validated neonatal PBPK models were developed for both fosfomycin and amikacin. PTA analysis demonstrated high probability of target attainment for amikacin 15 mg/kg i.v. q24h and fosfomycin 100 mg/kg (in neonates aged 0–7 days) or 150 mg/kg (in neonates aged 7–28 days) i.v. q12h for Enterobacterales with fosfomycin and amikacin minimum inhibitory concentrations at the adult breakpoints. Repeat analysis in premature populations demonstrated the same result. PTA analysis for a proposed combination fosfomycin‐amikacin target was also performed. The simulated regimens, tested in a neonatal sepsis trial, are likely to be adequate for neonates across different postnatal ages and gestational age. This work demonstrates a template for determining target attainment for antimicrobials (alone or in combination) in special populations without sufficient available PK data to otherwise assess with traditional pharmacometric methods.

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“…To evaluate the predictivity of the preterm PBPK model, two model drugs were selected based on the (i) the availability of clinical data in preterm neonates and (ii) differences in drug distribution and elimination behavior. While amikacin is a renally cleared antibiotic with relatively low distribution volume (approximately 0.25 -0.50 L/kg in adults [55]), the analgesic drug paracetamol mainly undergoes hepatic metabolization and distributes to a greater extent to peripheral compartments (distribution volume in adults around 1 L/kg [56]). The comparison of predicted plasma levels with TDM data obtained in the clinic for both drugs indicated that the physiologically-based model is indeed able to accurately predict the pharmacokinetics in preterm neonates.…”

Section: Discussionmentioning

confidence: 99%

Development of a Physiologically-Based Pharmacokinetic Model for Preterm Neonates: Evaluation with In Vivo Data

Claassen¹,

Thelen²,

Coboeken³

et al. 2015

CPD

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Among pediatric patients, preterm neonates and newborns are the most vulnerable subpopulation. Rapid developmental changes of physiological factors affecting the pharmacokinetics of drug substances in newborns require extreme care in dose and dose regimen decisions. These decisions could be supported by in silico methods such as physiologically-based pharmacokinetic (PBPK) modeling. In a comprehensive literature search, the physiological information of preterm neonates that is required to establish a PBPK model has been summarized and implemented into the database of a generic PBPK software. Physiological parameters include the organ weights and blood flow rates, tissue composition, as well as ontogeny information about metabolic and elimination processes in the liver and kidney. The aim of this work is to evaluate the model's accuracy in predicting the pharmacokinetics following intravenous administration of two model drugs with distinct physicochemical properties and elimination pathways based on earlier reported in vivo data. To this end, PBPK models of amikacin and paracetamol have been set up to predict their plasma levels in preterm neonates. Predicted plasma concentration-time profiles were compared to experimentally obtained in vivo data. For both drugs, plasma concentration time profiles following single and multiple dosing were appropriately predicted for a large range gestational and postnatal ages. In summary, PBPK simulations in preterm neonates appear feasible and might become a useful tool in the future to support dosing decisions in this special patient population.

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Modification in the pharmacokinetics of amikacin during development

Cited by 7 publications

References 15 publications

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

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

Development and application of neonatal physiology‐based pharmacokinetic models of amikacin and fosfomycin to assess pharmacodynamic target attainment

Development of a Physiologically-Based Pharmacokinetic Model for Preterm Neonates: Evaluation with In Vivo Data

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