Pediatric Formulations: Knowledge Gaps Limiting the Expedited Preclinical to Clinical Translation in Children

Abstract

Traditionally, drug discovery and development research have been primarily focused on the mitigation of disease treatment for the general adult population, often overlooking the medical needs of pediatric patients. While remarkable progress toward the discovery of better medicines has been made, the pharmacological differences between children and adults are often neglected as part of the translation process. In fact, until recently, children have been considered therapeutic orphans due to the lack of significant drug discovery, formulation development, and dosage form design specifically tailored for pediatric patients. Perhaps the least understood is the significant physiological changes that occur during the maturation process from birth to adulthood. It requires careful considerations to achieve age-specific-desired therapeutic outcomes with minimal toxicity. This introduces considerable risk into the preclinical and clinical testing of new medicaments, which until recently, was avoided based on the conventional approach where a demonstration of safe and efficacious use in adults over several years potentially would minimize the chance of adverse juvenile responses. However, the lack of appropriate drug products for children has led to off-label use of adult medicines with potential life-threatening adverse reactions and health complications. Recent developments and future considerations regarding pediatric drug discovery and development using a patient-centric approach in the context of ontogenic biopharmaceutical considerations are discussed below.

Navigating off‐label and unlicensed medicines use in obstetric and paediatric clinical practice

“…In the paediatric setting, significant physiological changes occur from the time of birth to adulthood . The expression of drug‐metabolising enzymes and transporters differs from adults and changes as children develop and approach puberty . Developmental pharmacokinetics also affect the susceptibility of children and neonates to adverse medicine reactions .…”

“…Developmental pharmacokinetics also affect the susceptibility of children and neonates to adverse medicine reactions . Life‐threatening adverse events have occurred when adult formulations, previously used safely, are used off‐label in children . Adapting population approaches to paediatric and neonatal groups allows for dosage adjustment and differences in drug responses to avoid toxicity …”

“…[40][41][42] The expression of drug-metabolising enzymes and transporters differs from adults and changes as children develop and approach puberty. [40][41][42] Developmental pharmacokinetics also affect the susceptibility of children and neonates to adverse medicine reactions. 43 Lifethreatening adverse events have occurred when adult formulations, previously used safely, are used off-label in children.…”

“…43 Lifethreatening adverse events have occurred when adult formulations, previously used safely, are used off-label in children. 42 Adapting population approaches to paediatric and neonatal groups allows for dosage adjustment and differences in drug responses to avoid toxicity. [40][41][42] Children are not small adults; rather, they experience patterns of growth and adaptation that require frequent dosage iterations.…”

“…42 Adapting population approaches to paediatric and neonatal groups allows for dosage adjustment and differences in drug responses to avoid toxicity. [40][41][42] Children are not small adults; rather, they experience patterns of growth and adaptation that require frequent dosage iterations. 44 Linear extrapolation of adult dosages cannot substitute pharmacokinetic and pharmacodynamic studies in specific age groups.…”