Pediatric pharmacokinetic considerations and implications for drug dosing

Abstract

Optimizing the dosing of medicines for pediatric patients in routine clinical practice and determining the dose for clinical trials is still a challenging task. Children differ from adults in their response to drugs due to inherent differences in pharmacokinetics and/or pharmacodynamics, and responses may also vary among pediatric patients of different ages. However, the greatest disparities compared to adult pharmacokinetic profiles are observed in children below 2 years of age. The maturation of the liver and the kidneys, as well as the variation in body composition, are considered to be the main sources of pharmacokinetic variability. Hence, besides specific pharmacodynamic features, understanding age-related changes in drug absorption, distribution, and elimination is fundamental for optimizing drug efficacy and avoiding toxicity. This paper summarizes the pharmacokinetic changes throughout the childhood, along with the effect of developmental changes on drug dosage calculation. In clinical practice, age and body weight-based dosing regimens are usually used. In spite of dosing recommendations based on age and/or body weight, variabilities in pharmacokinetics and pharmacodynamic response remain, implying a need to monitor patients and optimize the dosing regimen according to physiological characteristics, disease characteristics and therapy.

Optimizacija doziranja lekova kod pedijatrijskih pacijenata u rutinskoj kliničkoj praksi i procena doze pre započinjanja kliničkih studija je i dalje značajan izazov. Pedijatrijska populacija se razlikuje od odraslih pacijenata u odgovoru na lekove, što je uzrokovano izmenjenom farmakokinetikom i/ili farmakodinamikom, a odgovor može varirati i među decom različitog uzrasta. Međutim, najveće razlike u odnosu na farmakokinetičke profile odraslih pacijenata primećuju se kod dece mlađe od 2 godine. Sazrevanje jetre i bubrega, kao i promene u udelu telesnih tečenosti i masnog tkiva u odnosu na ukupnu telesnu masu, smatraju se glavnim izvorima farmakokinetičke varijabilnosti. Dakle, pored specifičnih farmakodinamičkih karakteristika, razumevanje razvojnih promena u resorpciji, raspodeli i eliminaciji leka je fundamentalno za optimizaciju efikasnosti i bezbednosti terapije. Ovaj rad sumira farmakokinetičke promene tokom detinjstva, zajedno sa uticajem razvojnih promena na izračunavanje doze leka. U kliničkoj praksi se obično koriste režimi doziranja zasnovani na starosti i telesnoj masi. Uprkos preporukama za doziranje na osnovu godina i/ili telesne mase, i dalje se uočava varijabilnost u farmakokinetici i farmakodinamičkom odgovoru, što ukazuje na potrebu za praćenjem pacijenata i optimizacijom režima doziranja prema fiziološkim karakteristikama, karakteristikama bolesti i terapiji.