LAUSR

Most immunosuppressants are critical dose drugs with a narrow ther‐ apeutic index.1 While pharmacokinetic monitoring is well‐established and always accompanies the phase I‐III studies of new immunosup‐ pressants or formulations in adult solid organ transplantation, chil‐ dren remain understudied.2 This is despite the fact that, particularly in younger children, there are substantial developmental changes including changes in metabolic capacity, integumental development, distribution sites, acquisition of renal and gastrointestinal function in the first 18 months of life, and other factors beyond the genetic variability of drug disposition.3 This entire line of research is entitled “ontogeny of drug disposition.” These differences between adults and children warrant more extensive research relating to drug disposition in children compared to adults. For example, children do not form 39‐ desmethyl sirolimus, which is the main sirolimus metabolite in adults. Instead, children make hydroxylated metabolites which result in dra‐ matic changes in the sirolimus half‐life from 7 hours in a preschool child to 72 hours in adults.4 Even when switching formulations of the same drug, there may be substantial variability which may lead to over‐ or underimmunosuppression.5 For tacrolimus, it is known that there is a biphasic change with age and bone maturation. Tacrolimus has been characterized as having a high and stable drug clearance until a specific phase in pubertal development around the age of ~14 years. This is followed by an important decline in relative dose requirements thereafter, while pharmacogenetic variation demon‐ strated an age/puberty‐independent effect.6 In that context, we are delighted to see a new study in this edition of Pediatric Transplantation from a multicenter clinical trial that compared two innovator tacroli‐ mus formulations in actual transplant patients. Vondrak et al estab‐ lished that the exposure from a prolonged‐tacrolimus formulation was comparable to the standard immediate‐release tacrolimus which we all use after pediatric solid organ transplantation.