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Published on: April 18, 2019
Dose rationale for the use of meropenem/vaborbactam combination in paediatric patients with Gram-negative bacterial
Chiara Fornari1, Antonio Arrieta2, John S Bradley3,4
1Clinical Pharmacology, Pharmacometrics and Clinical DMPK Department, Stemline Therapeutics/Menarini Group, Pomezia, Italy.
Insights
This study determined optimal meropenem/vaborbactam dosing for children, recommending specific regimens for infants and older children to ensure effective treatment of Gram-negative infections.
Area of Science:
- Pharmacology
- Pediatric Infectious Diseases
- Pharmacokinetics
Background:
- Meropenem/vaborbactam is approved for complicated urinary tract infections in adults.
- Data on pediatric pharmacokinetics and dosing is limited.
Purpose of the Study:
- To characterize meropenem/vaborbactam pharmacokinetics in pediatric patients.
- To establish evidence-based dosing regimens for children using a model-based approach.
Main Methods:
- Population pharmacokinetic analysis of adult and pediatric data (414 adults, 39 children).
- Utilized adult pharmacokinetic model to inform pediatric parameter estimation.
- Simulations to determine dosing regimens for adequate probability of target attainment (PTA).
Main Results:
- Meropenem/vaborbactam disposition was modeled using two-compartment models.
- Body weight and creatinine clearance were significant covariates.
- Recommended 3.5-h IV infusion of 40 mg/kg Q8h for children ≥3 months and 20 mg/kg for neonates/infants <3 months.
Conclusions:
- Integrated adult and pediatric data accurately described meropenem/vaborbactam pharmacokinetics in children.
- Provided dosing recommendations for neonates, infants, and older children.
- Facilitated safe and effective use of meropenem/vaborbactam in pediatric populations.
Aims:
Meropenem/vaborbactam combination is approved in adults by FDA and EMA for complicated urinary tract infections and by EMA also for other Gram-negative infections. We aimed to characterise the pharmacokinetics of both moieties in an ongoing study in children and use a model-based approach to inform adequate dosing regimens in paediatric patients.
Methods:
Over 4196 blood samples of meropenem and vaborbactam (n = 414 subjects) in adults, together with 114 blood samples (n = 39) in paediatric patients aged 3 months to 18 years were available for this analysis. Data were analysed using a population with prior information from a pharmacokinetic model in adults to inform parameter estimation in children. Simulations were performed to assess the suitability of different dosing regimens to achieve adequate probability of target attainment (PTA).
Results:
Meropenem/vaborbactam PK was described with two-compartment models with first-order elimination. Body weight and CLcr were significant covariates on the disposition of both drugs. A maturation function was evaluated to explore changes in clearance in neonates. PTA ≥90% was derived for children aged ≥3 months after 3.5-h IV infusion of 40 mg/kg Q8h of both meropenem and vaborbactam and 2 g/2 g for those ≥50 kg. Extrapolation of disposition parameters suggest that adequate PTA is achieved after a 3.5-h IV infusion of 20 mg/kg for neonates and infants (3 months).
Conclusions:
An integrated analysis of adult and paediatric data allowed accurate description of sparsely sampled meropenem/vaborbactam PK in paediatric patients and provided recommendations for the dosing in neonates and infants (3 months).
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