Population Pharmacokinetics of Meropenem in Preterm Infants

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Abstract

Background. Meropenem, a broad spectrum carbapenem antibiotic, is often used for newborns despite of limited data available on neonatal pharmacokinetics. Due to pharmacokinetic and pharmacodynamic differences as well as to significant changes in the human body related to growth and maturation of organs and systems, direct scaling and dosing extrapolation from adults or older children with adjustment on patient’s weight can result in increased risk of toxicity or treatment failures. Aims — to evaluate the pharmacokinetics of meropenem in premature neonates based on therapeutic drug monitoring data in real clinical settings. Materials. Of 53 pre-term neonates included in the pharmacokinetic/pharmacodynamic analysis, in 39 (73.6%) patients, gestational age ranged from 23 to 30 weeks. Population and individual pharmacokinetic parameter values were estimated by the NPAG program from the Pmetrics package based on peak-trough therapeutic drug monitoring. Samples were assayed by high-performance liquid chromatography. One-compartment pharmacokinetic model with zero-order input and first-order elimination was used to fit concentration data and to predict pharmacokinetic parameter (%T > MIC of free drug) for virtual “patients” with simulated fast, moderate and slow meropenem elimination “received” different dosage by minimum inhibitory concentration (MIC) level. Univariate and multivariate regression analysis was used to evaluate the influence of patient’s covariates (gestational age, postnatal age, postconceptual age, body weight, creatinine clearance calculated by Schwartz formula, etc) on estimated meropenem pharmacokinetic parameters. Results. The identified population pharmacokinetic parameters of meropenem in pre-term newborns (elimination half-lives T1/2 = 1.93 ± 0.341 h; clearance CL = 0.26 ± 0.085 L/h/ kg; volume of distribution V = 0.71 ± 0.22 L/h) were in good agreement with those published in the literature for adults, neonates and older children. Pharmacokinetic/pharmacodynamic modeling demonstrated that a meropenem dosage regimen of 90 mg/kg/day administered using prolonged 3-hour infusion every 8 hours should be considered as potentially effective therapy if nosocomial infections with resistant organisms (MIC ≥ 8 mg/L) are treated. Conclusions. Neonates and especially pre-term neonates have a great pharmacokinetic variability. Meropenem dosing in premature newborns derived from population pharmacokinetic/pharmacodynamic model can partly overcome the variability, but not all pharmacokinetic variability can be explained by covariates in a model. Further personalizing based on Bayesian forecasting approach and a patient’s therapeutic drug monitoring data can help to achieve desired pharmacodynamic target.

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About the authors

Irina B. Bondareva

Peoples’ Friendship University of Russia

Author for correspondence.
Email: i_bondareva@yahoo.com
ORCID iD: 0000-0002-8436-8931
SPIN-code: 1631-3470

PhD in Biology, Professor

Russian Federation, 6, Miklukho-Maklaya st., 117198, Moscow

Sergey K. Zyryanov

Peoples’ Friendship University of Russia; City Clinical Hospital No. 24

Email: zyryanov-sk@rudn.ru
ORCID iD: 0000-0002-6348-6867
SPIN-code: 2725-9981

MD, PhD, Professor

Russian Federation, 6, Miklukho-Maklaya st., 117198, Moscow; Moscow

Aleksandra M. Kazanova

Peoples’ Friendship University of Russia

Email: kazanova.alex@yandex.ru
ORCID iD: 0000-0003-2324-0069
SPIN-code: 6277-6484

PhD in Pharmacy, Assistant

Russian Federation, 6, Miklukho-Maklaya st., 117198, Moscow

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Supplementary files

Supplementary Files
Action
1. Fig 1. Marginal distributions of the values of the pharmacokinetic parameters of meropenem (linear single-chamber model) in the population of premature newborns, estimated using the Bayesian approach (NPAG program)

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2. Fig 2. The ratio of the concentration values of meropenem predicted by the model based on population mean values (A) and estimated individual values (B) (NPAG program)

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3. Fig 3. Modeled values of the pharmacodynamic index -% T> MIC - for different levels of MIC, depending on the dosage regimens and values of the clearance of meropenem in the patient: A - MIC = 2 mg / l; B - MIC = 8 mg / l. Dosing modes: 1, 2 - 40 mg / kg / day, 2 hours, interval 8 hours (1), 12 hours (2); 3, 4 - 40 mg / kg / day, 3 hours, interval 8 hours (3), 12 hours (4); 5, 6 - 60 mg / kg / day, 2 hours, interval 8 hours (5), 12 hours (6); 7, 8 - 60 mg / kg / day, 3 hours, interval 8 hours (7), 12 hours (8); 9 - 90 mg / kg / day, 3 hours, interval 8 hours

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4. Fig 4. Simulated values of the pharmacodynamic index -% T> MIC - for a dosing regimen of 90 mg / kg / day with an injection interval of 8 hours and a 3-hour infusion, depending on different values of the patient's clearance of meropenem and different levels of BMD

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