Plasma and CSF pharmacokinetics of meropenem in neonates and young infants: results from the NeoMero studies

Abstract

BackgroundSepsis and bacterial meningitis are major causes of mortality and morbidity in neonates and infants. Meropenem, a broad-spectrum antibiotic, is not licensed for use in neonates and infants below 3 months of age and sufficient information on its plasma and CSF disposition and dosing in neonates and infants is lacking.ObjectivesTo determine plasma and CSF pharmacokinetics of meropenem in neonates and young infants and the link between pharmacokinetics and clinical outcomes in babies with late-onset sepsis (LOS).MethodsData were collected in two recently conducted studies, i.e. NeoMero-1 (neonatal LOS) and NeoMero-2 (neonatal meningitis). Optimally timed plasma samples (n = 401) from 167 patients and opportunistic CSF samples (n = 78) from 56 patients were analysed.ResultsA one-compartment model with allometric scaling and fixed maturation gave adequate fit to both plasma and CSF data; the CL and volume (standardized to 70 kg) were 16.7 (95% CI 14.7, 18.9) L/h and 38.6 (95% CI 34.9, 43.4) L, respectively. CSF penetration was low (8%), but rose with increasing CSF protein, with 40% penetration predicted at a protein concentration of 6 g/L. Increased infusion time improved plasma target attainment, but lowered CSF concentrations. For 24 patients with culture-proven Gram-negative LOS, pharmacodynamic target attainment was similar regardless of the test-of-cure visit outcome.ConclusionsSimulations showed that longer infusions increase plasma PTA but decrease CSF PTA. CSF penetration is worsened with long infusions so increasing dose frequency to achieve therapeutic targets should be considered.

Development of a physiologically-based pharmacokinetic pediatric brain model for prediction of cerebrospinal fluid drug concentrations and the influence of meningitis

“…Since quantitative data on membrane permeability of meropenem were not available from literature, the brain permeability parameter was obtained for the adult population by empirical optimization. The value we derived this way (0.003 L/h) is in the same order of magnitude as intercompartmental clearances that have been described in population PK models for adults and children (0.0017 and 0.0007 L/h, respectively) [17, 20]. This estimated permeability was subsequently applied in simulations with the pediatric model, which is also in accordance with studies in which a correlation between TNFα and blood-brain barrier damage was found, but not between TNFα and age [21].…”

A Physiology-Based Pharmacokinetic Framework to Support Drug Development and Dose Precision During Therapeutic Hypothermia in Neonates

“…Another example of nonmaturational factors for drug disposition is disease condition. As part of the NeoMero trials in neonates with late onset sepsis (NeoMero-1) and/or meningitis (NeoMero-2), Germovsek et al reported a (model-based) penetration of meropenem, a broad-spectrum carbapenem, into the cerebrospinal fluid (CSF) of 8% in neonates (Germovsek et al, 2018). This overall low value was attributed to the absence of meningeal inflammation in many of the NeoMero-1 patients without meningitis.…”

“…However, this percentage rose with increasing CSF protein, with even 40% penetration predicted at a protein concentration of 6 g/L, i.e. when inflammation of the meninges is present (Germovsek et al, 2018). For asphyxiated neonates treated with TH, both the underlying pathophysiology as well as the hypothermia treatment are considered as nonmaturational factors impacting drug disposition.…”

Approaches to Dose Finding in Neonates, Illustrating the Variability between Neonatal Drug Development Programs

“…In a very small study using an opportunistic sampling strategy with 9 cerebrospinal fluid (CSF) samples in 6 patients, CSF penetration of meropenem was estimated [ 24 ]. More recently, two large studies on meropenem use in neonates (NeoMero1 and NeoMero2) supported by the European Funded Program 7 reported on plasma and CSF PK of meropenem in neonates and young infants [ 27 , 28 ]. This much larger study collected 78 CSF samples in 56 patients and demonstrated that CSF penetration was low (8%).…”