Ontogeny and Cross-species Comparison of Pathways Involved in Drug Absorption, Distribution, Metabolism, and Excretion in Neonates (Review): Kidney

Abstract

The kidneys play an important role in many processes, including urine formation, water conservation, acid-base equilibrium, and elimination of waste. The anatomic and functional development of the kidney has different maturation time points in humans versus animals, with critical differences between species in maturation before and after birth. Absorption, distribution, metabolism, and excretion (ADME) of drugs vary depending on age and maturation, which will lead to differences in toxicity and efficacy. When neonate/ juvenile laboratory animal studies are designed, a thorough knowledge of the differences in kidney development between newborns/ children and laboratory animals is essential. The human and laboratory animal data must be combined to obtain a more complete picture of the development in the kidneys around the neonatal period and the complexity of ADME in newborns and children. This review examines the ontogeny and cross-species differences in ADME processes in the developing kidney in preterm and term laboratory animals and children. It provides an overview of insights into ADME functionality in the kidney by identifying what is currently known and which gaps still exist. Currently important renal function properties such as glomerular filtration rate, renal blood flow, and ability to concentrate are generally well known, while detailed knowledge about transporter and metabolism maturation is growing but is still lacking. Preclinical data in those properties is limited to rodents and generally covers only the expression levels of transporter or enzyme-encoding genes. More knowledge on a functional level is needed to predict the kinetics and toxicity in neonate/juvenile toxicity and efficacy studies. SIGNIFICANCE STATEMENTThis review provides insight in cross-species developmental differences of absorption, distribution, metabolism, and excretion properties in the kidney, which should be considered in neonate/juvenile study interpretation, hypotheses generation, and experimental design.dependent on the specialized subcellular structural and functional properties of renal tubule epithelium, including their various transporters, metabolic activity, and membrane integrity. Therefore, the development and maturation of these processes in pediatric patients or in animals can have a profound effect on the disposition and fate of administered drug therapies that depend on the kidney for filtration, uptake, secretion, and/or metabolism.

Safety Testing of an Antisense Oligonucleotide Intended for Pediatric Indications in the Juvenile Göttingen Minipig, including an Evaluation of the Ontogeny of Key Nucleases

“…In the present study, the safety, exposure, and pharmacological effect of a model LNA gapmer, RTR5001, were assessed in a limited number of juvenile Göttingen Minipigs after repeated subcutaneous dosing. The rapid growth and development of the pediatric population can influence the pharmacokinetics and pharmacodynamics of therapeutic agents, leading to potential adverse effects [ 65 , 66 , 67 ]. RTR5001 was previously tested in adult minipigs, in which the liver and kidney were the main target organs of distribution/toxicity, and its pharmacologic effect (i.e., reduced total and LDL cholesterol) was demonstrated [ 31 ].…”

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“…166 Finding preclinical (animal) models that display physiology and development comparable to human models is challenging. 167 The growth plate (physis) is a hierarchic organized complex system and can be described as an organ. It is the site where elongation of the long bones occurs in longitudinal growth during development.…”

A Review of Specific Biomarkers of Chronic Renal Injury and Their Potential Application in Nonclinical Safety Assessment Studies

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