[R01] Impact of maturation on the pharmacokinetic and physiologic response to furosemide in very preterm infants (IMPPROVE-furosemide)
Ente: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Scadenza: 2030-08-31
Importo max: $3,203,539
Paese: US
Descrizione
PROJECT SUMMARY/ABSTRACT
Preterm infants are a clinical population in great need of precision therapeutics. Their high morbidity
and mortality stem from an immature physiology that requires intensive medical support for survival, and also
results in many medication exposures. Rapid postnatal changes in drug absorption, distribution, metabolism,
and elimination make preterm infants uniquely susceptible to pharmacologic knowledge gaps. Despite
this, population-specific pharmacology data are sparse, medication dosing rarely adjusts for maturation, and
precision therapeutics in preterm infants lags behind older populations.
This proposal addresses a critical knowledge gap in neonatal pharmacology: uncertainty in how
furosemide clearance changes as very preterm (VP) infants (birth gestational age < 32 weeks) mature.
Furosemide is prominent in preterm lung disease despite weak evidence of safety and efficacy, and rapid
postnatal maturation in furosemide clearance is supported by existing literature, preliminary data and biologic
plausibility rooted in the ontogeny of organic anion transporters. In current clinical practice, furosemide use in
prominent over a broad postmenstrual age (PMA) range without maturational dosing adjustments.
This proposal will enroll hospitalized very preterm infants prescribed furosemide for clinical indications
in a prospective longitudinal observational cohort study measuring furosemide blood concentrations and
physiologic response measures up to 16 times over the first year of life. Innovations is blood sampling
strategies will be applied to overcome limitations in neonatal pharmacology, and population pharmacokinetic
modeling with PMA evaluated as a Hill function will be used to determine the association between maturation
and clearance (Aim 1). Innovations in critical care health informatics will be applied to obtain time-granular
longitudinal real-world data to measure the acute physiologic renal (Aim 2) and direct pulmonary (Aim 3)
response to furosemide, and flexible multivariable piece-wise linear mixed effects will characterize the
relationship between PMA and response. A significant association between increasing PMA and each outcome
is hypothesized, with the rate of change most pronounced between 32-40 weeks PMA, a period suspected of
dynamic maturational change.
This proposal’s findings will impact clinical practice by informing furosemide dose adjustments with
maturation, guide dosing for needed phase 3 neonatal clinical trials, and further developmental biology insights
into renal organic anion transporter ontogeny. Moreover, this proposal will underscore the relevance of
developmental pharmacology in preterm infants and highlight the importance of neonatal precision
therapeutics.
Istituzione: CHILDREN'S HOSP OF PHILADELPHIA
PI: Nicolas Augusto Bamat
Progetto: 1R01HD120423-01
Settori: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.