By: Narasimha Midde, PhD, Associate Director, Pharmacokinetics, KinderPharm
One in ten babies in the United States are born prematurely (CDC) and they are at greater risk of death or disability for life. Over the last two decades, more than 700 drug labels were updated to direct safe drug use in children. An examination of these revisions shows that only 7% of drugs that are used in the Neonatal Intensive Care Units (NICU) were investigated in both preterm and term neonates. Importantly, only 7 (Ranitidine, Acetaminophen, Lansoprazole, Nitric oxide, Meropenem, Phenylephrine, and Naloxone) out of 100 most routinely used medication in NICU have been studied for their use in this population. In other words, the majority of prescribed medications in NICU are still being used off-label and require adequate assessment. There are several reasons for omitting or conducting minimal studies in neonates that including immature systems, rapid developmental changes, high risk adverse outcomes, gaps in regulations for studying drugs in preterm infants, and relatively small market etc. Because of these dynamic features, this smallest and most vulnerable population require a tailor-made study design to investigate each individual drug.
Defining clear treatment goals early in the planning and carefully considering preclinical and juvenile toxicology data is a key to achieve better outcomes from neonatal studies. “Clinical pharmacology gap analysis” that helps identifying potential knowledge gaps in the available data and assessing possible ways to fill these gaps through other reliable sources is an important early step in the study design. Modeling and simulations can serve as a good source in this regard. Modeling and simulations approach is a learn and confirm process. Incorporating new data as they become available into the modeling efforts can increase confidence in the generated knowledge.
Pharmacokinetic (PK) data is heavily dependent on size and maturation levels of the subject. Therefore, age groups should be selected based on developmental biology, pharmacology of the drug and intended treatment age groups. Concomitant medication exposure or organ specific dysfunction should also be taken into consideration. For instance, premature babies often have multiple concomitant conditions and therefore are exposed to a combination of drugs. Hence, it is essential to be mindful of these situations while designing a study. Dosing and sampling strategies are the other challenges to need to be overcome for conducting studies in this population. Physiologically based pharmacokinetic (PBPK) modeling can be leveraged to project initial doses, to explore limited sampling schemes or to evaluate potential drug-drug interactions. Additionally, microdose, sparse sampling, dried blood spot sampling and microtrace approaches that require very little sample volumes may be exploited in the neonatal study.
Neonatal drug metabolic and elimination processes show tremendous variability due to development changes. Special attention should be given to neonatal specific enzyme isoforms or transporters that do not appear in older children or in adults. The adult pharmacodynamic markers that are well validated may not be meaningful in preterm neonates. Hence, choosing right biomarker or clinical endpoint and understanding its relationship with PK is pivotal to the success of the study. Integration of pharmacogenetic markers analysis into study design is also important if the drug is primarily eliminated by known biomarker (e.g., CYP2D6). It is important to keep in mind that phenotype-genotype relationship in perinatal life may be completely different from adults or even from older children.
In summary, neonatal clinical pharmacology studies are complex and ethically challenging. Therefore, careful evaluation of existing data through “Gap analysis” and leveraging pharmacometric approaches throughout the study design and conduct will help understanding the drug as efficiently as possible in this unique population.
- Laughon MM, et al. Drug labeling and exposure in neonates. JAMA Pediatr 168 130-136. (2014)
- Hsieh EM, et al. Medication use in the neonatal intensive care unit. Am J Perinatol 31 811-821. (2014)
- FDA-Guidance. General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and Biological Products – Draft Guidance for Industry (2014)
- EMA-Guideline. Guideline on the investigation of medicinal products in the term and preterm neonate (2009)
- Ward RM, et al. Safety, dosing, and pharmaceutical quality for studies that evaluate medicinal products (including biological products) in neonates. Pediatr Res 81 692-711. (2017)
- Dueker SR, Vuong le T, Lohstroh PN, Giacomo JA, Vogel JS. Quantifying exploratory low dose compounds in humans with AMS. Adv Drug Deliv Rev 63 518-531. (2011)
- Evans C, et al. Implementing dried blood spot sampling for clinical pharmacokinetic determinations: considerations from the IQ Consortium Microsampling Working Group. AAPS J 17 292-300. (2015)