Population Pharmacokinetics and Dosing Optimization of Amoxicillin in Neonates and Young Infants

Abstract

Amoxicillin is widely used to treat bacterial infections in neonates. However, considerable intercenter variability in dosage regimens of antibiotics exists in clinical practice. The pharmacokinetics of amoxicillin has been described in only a few preterm neonates. Thus, we aimed to evaluate the population pharmacokinetics of amoxicillin through a large sample size covering the entire age range of neonates and young infants and to establish evidence-based dosage regimens based on developmental pharmacokinetics-pharmacodynamics. This is a prospective, multicenter, pharmacokinetic study using an opportunistic sampling design. Amoxicillin plasma concentrations were determined using high-performance liquid chromatography. Population pharmacokinetic analysis was performed using NONMEM. A total of 224 pharmacokinetic samples from 187 newborns (postmenstrual age range, 28.4 to 46.3 weeks) were available for analysis. A two-compartment model with first-order elimination was used to describe population pharmacokinetics. Covariate analysis showed that current weight, postnatal age, and gestational age were significant covariates. The final model was further validated for predictive performance in an independent cohort of patients. Monte Carlo simulation demonstrated that for early-onset sepsis, the currently used dosage regimen (25 mg/kg twice daily [BID]) resulted in 99.0% of premature neonates and 87.3% of term neonates achieving the pharmacodynamic target (percent time above MIC), using a MIC breakpoint of 1 mg/liter. For late-onset sepsis, 86.1% of premature neonates treated with 25 mg/kg three times a day (TID) and 79.0% of term neonates receiving 25 mg/kg four times a day (QID) reached the pharmacodynamic target, using a MIC breakpoint of 2 mg/liter. The population pharmacokinetics of amoxicillin was assessed in neonates and young infants. A dosage regimen was established based on developmental pharmacokinetics-pharmacodynamics.

Population pharmacokinetic models of first choice beta-lactam antibiotics for severe infections treatment: What antibiotic regimen to prescribe in children?

“…For amoxicillin, our review showed that the median clearance in the pediatric population are in accordance with previously reported values in critically ill adults (0.10 L/h/kg vs 0.13 L/kg) (63). Whereas for amoxicillin and cefotaxime, we observed a value of clearance divided by 2.0 for cefotaxime and 3.0 for ampicillin in the pediatric population (21,22,24,31,39,41,47,50). But if we looked at each amoxicillin studies in detail, we observed a large variability on amoxicillin clearance values as for piperacillin, explained by the same maturation process described previously (61) since numerous studies have been conducted in preterms and neonates (22,24,47,50).…”

“…Whereas for amoxicillin and cefotaxime, we observed a value of clearance divided by 2.0 for cefotaxime and 3.0 for ampicillin in the pediatric population (21,22,24,31,39,41,47,50). But if we looked at each amoxicillin studies in detail, we observed a large variability on amoxicillin clearance values as for piperacillin, explained by the same maturation process described previously (61) since numerous studies have been conducted in preterms and neonates (22,24,47,50). For imipenem, our review showed increased median clearance (0.36 L/h/kg vs 0.16 L/h/kg in adults) and volume of distribution (0.57 L/kg vs 0.16 L/kg in adults) in the pediatric population (32,53).…”

“…There is increasing evidence that targeting 100% of the dosing interval for these time dependent antibiotics further increases the probability for improved bacteriologic and clinical outcomes, especially in populations such as the critically ill, whose unpredictable PK increase their risk for inadequate dosing. In these 34 studies we observed six different percentage of time interval objectives (40,50,70,75, 80 and 100% of time interval) for fT>MIC or fT>4xMIC and various MIC breakpoints according the pathogens. There is still debate regarding what the clinical pharmacodynamic target(s) should be and it is unlikely that a single pharmacodynamic target would be appropriate for all drugs, all pathogens, and all indications.…”

Initial Dosage Recommendation for Sirolimus in Children With Tuberous Sclerosis Complex

“…Fortunately, the combination of population pharmacokinetics and Monte Carlo simulation can successfully predict and recommend the best initial dosing regimen, the method has been widely used in clinical practice (Niu et al, 2019;Ren et al, 2019;Tang et al, 2019;Wang et al, 2019b). For example, Ren et al (2019) reported population pharmacokinetics of voriconazole and optimization of dosage regimens based on Monte Carlo simulation in patients with liver cirrhosis, Niu et al (2019) reported that population pharmacokinetics and dosing regimen optimization of lopinavir in Chinese adults infected with HIV, Wang et al (2019b) reported population pharmacokinetics and initial dosing regimen optimization of cyclosporin in pediatric hemophagocytic lymphohistiocytosis patients, Tang et al (2019) reported population pharmacokinetics and dosing optimization of amoxicillin in neonates and young infants. Based on these studies, the present study was to establish a population Partial concentration values were collected in a previous study (Wang et al, 2018).…”

Amoxicillin Dosing Regimens for the Treatment of Neonatal Sepsis: Balancing Efficacy and Neurotoxicity

“…In vitro amoxicillin efficacy is time-dependent and the key pharmacokinetic/pharmacodynamic (PKPD) index is the fraction of time during which the antibiotic concentration remains above the minimal inhibitory concentration (MIC) of the targeted pathogen (% f T > MIC) [4]. Most studies have not investigated amoxicillin pharmacokinetics (PK) across the entire age and disease spectrum of premature and term infants cared for in neonatal units [4-9]. This limits the identification of optimal dosing approaches in a population that is subject to short-term maturational changes in drug clearance during the postnatal period.…”