Retinopathy of prematurity (ROP), characterized by abnormal postnatal retinal vascular growth, is a common comorbidity of extreme prematurity. Despite improvements in disease management, infants with ROP remain at risk of lifelong visual impairments, and there is an unmet need for a preventive therapy.
Historically, pharmacokinetic (PK) analyses have not been routinely conducted in newborns, with dosing typically extrapolated from PK data obtained in older children and adults. However, newborns undergo rapid developmental changes, which often alter the PK properties of a drug and we believe that PK analyses specific to the neonatal population are essential from an ethical perspective in order to establish optimal dosing, and to ensure the greatest potential therapeutic benefit and safety of drug usage in these infants. Early clinical studies have been conducted that aimed (among other objectives) to evaluate PK and optimize dosing of rhIGF-1/rhIGFBP-3 in extremely preterm infants.
Since very few therapeutic indications are unique to infants, dosing is typically derived from adult dosing regimens, a common practice that results in the widespread off-label use of drugs within the neonatal population. A prospective study conducted in 70 infants (including preterm), over 13 wk in the NICU showed that 90% were given a drug that was either unlicensed or used in an off-label way. However, PK properties of a drug are frequently age dependent, and may be particularly variable between a neonatal population (undergoing rapid developmental changes) and an older population. As an example, half-life for IGF-1 following administration of rhIGF-1/rhIGFBP-3 in preterm infants has been shown to be significantly shorter than in older children and adults, highlighting the importance of PK analysis and dose optimization specifically in this population. We believe the work undertaken in this study is unique in its approach and in ensuring optimization of drug dosing at an early stage of clinical development.
The study was carefully designed in several stages, first compiling information from published literature and prior clinical trials in order to estimate IGF-1 levels in utero and in preterm infants and determine IGF-1 target levels, followed by population PK modeling and dose simulations to predict optimal dosing, and finally, verification of the predicted dose regimen within a clinical trial. We would urge a similar level of study for other investigational agents in development for use in the neonatal preterm population. Generally, optimal dosing and PK are not well characterized before medicines are introduced to the neonatal population. We believe this work will help to establish a new standard for testing of drugs for utilization in infants.
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