Persistent pharmacokinetic challenges to pediatric drug development

Abstract

The development of new therapeutic agents for the mitigation of pediatric disorders is largely hindered by the inability for investigators to assess pediatric pharmacokinetics (PK) in healthy patients due to substantial safety concerns. Pediatric patients are a clinical moving target for drug delivery due to changes in absorption, distribution, metabolism and excretion (ADME) and the potential for PK related toxicological (T) events to occur throughout development. These changes in ADMET can have profound effects on drug delivery, and may lead to toxic or sub-therapeutic outcomes. Ethical, economical, logistical, and technical barriers have resulted in insufficient investigation of these changes by industrial, regulatory, and academic bodies, leading to the classification of pediatric patients as therapeutic orphans. In response to these concerns, regulatory agencies have incentivized investigation into these ontogenic changes and their effects on drug delivery in pediatric populations. The intent of this review is to briefly present a synopsis of the development changes that occur in pediatric patients, discuss the effects of these changes on ADME and drug delivery strategies, highlight the hurdles that are still being faced, and present some opportunities to overcome these challenges.

Adverse Events in Pediatric Patients Receiving Long-term Oral and Intravenous Antibiotics

“…10 However, children vary in drug absorption, distribution, pharmacokinetics, immunologic response, and prevalence and type of comorbidities, all of which are likely to contribute to differences in the rates and variety of complications observed in pediatric patients. 11 Current literature supports that 19% to 51% of children experience adverse drug events (ADEs) and 27% to 41% experience venous access complications (VACs) while receiving OPAT. [12][13][14][15][16][17][18][19][20][21][22][23][24] Most studies, however, are limited in size, often exclude children with premorbid conditions, evaluate a single clinical diagnosis, and exclude patients treated with oral antibiotics.…”

Age‐Related Changes in MicroRNA Expression and Pharmacogenes in Human Liver

“…Developmental changes in drug disposition create the need for age‐appropriate pharmacotherapy . Although there have been many approaches for estimating pediatric drug dosing (e.g., extrapolation from adult data), these approaches are not adequate for many children, particularly for the very young patients (infants vs. children) . Developmental changes in drug response are difficult to predict at the individual patient level, in part due to our poor understanding of the mechanisms that regulate these developmental changes.…”

Theoretical pharmacokinetic drug alterations in pediatric celiac disease

“…In children of 1 year of age, the glomerular filtration rate (GFR) is nearly twice that of adults [16]. A higher dose per weight equation can compensate for this increase; however, as children age, additional adjustments are needed to accommodate for the gradual normalization to adult levels over time [15]. One study identified inadequate levels of efavirenz, an HIV drug, in 40% of children receiving weight-based doses recommended by the manufacturer [17].…”

“…Weight-based dosing in children assumes weight increases proportionally to age. Consequently, larger children are prone to overdose with this strategy unless maximum doses are predefined [15]. In children of 1 year of age, the glomerular filtration rate (GFR) is nearly twice that of adults [16].…”

“…Changes in the pH environment of the gastrointestinal tract can affect the degree of ionization and stability of drugs influencing the amount of drug available for absorption [20]. The gastric pH is neutral at birth and decreases to 2.3 to 3.6 within 48 h following birth for full-term newborns [15]. Milk feeds can neutralize gastric pH in the neonate [21,22].…”