Infants pharmacodynamics

Effective and safe drug therapy for newborns, infants, and children depends on knowledge of pediatric pharmacokinetics and pharmacodynamics and knowledge of the drug formulation and delivery issues specific to this population. 

There has been tremendous progress in the identification of pharmacokinetic and pharmacodynamic parameters in chronically ill infants and children. 

Extensive medicinal chemistry optimization of potency, selectivity pharmacokinetic, and pharmacodynamic properties finally led to potent, selective, and orally bioavailable GSK-221149A, which is synthesized as shown on Scheme 17 [35, 37, 38]. Peptidic oxytocin receptor antagonists are currently used to treat preterm labor, the main reason for infant death. The peptide derivatives by their nature are not orally bioavailable but must be administered i.v. Surprisingly, the peptide derivatives are less potent and less selective against several related receptors than GSK-221149A with half the molecular weight [39]. 

Finally, developmental differences in pharmacodynamics can be observed in the absence of age-associated changes in the dose versus plasma concentration relationship. Marshall and Kearns demonstrated developmental differences in the pharmacodynamics of cyclosporin. In this study, the IC50 for interleukin-2 (IL-2) expression observed in peripheral blood monocytes obtained from infants less than 12 months of age and exposed in vitro to cyclosporin was approximately 50% of the value observed for older children. In this particular example, the pharmacodynamic differences appeared not to be the consequence of developmental dependence on pharmacokinetics but rather, in the true drug-receptor interaction. 

James LP, Marotti T, Stowe CD, Farrar HC, Taylor BJ, Kearns GL. Famotidine pharmacokinetics and pharmacodynamics in infant. Chn Pharmacol Ther... 

Changes in pharmacodynamics further complicate the pharmacology of many drugs in the neonate and infant. The blood-brain barrier is poorly developed, allowing more rapid transfer of drugs into the central nervous system (CNS). However, the response to higher brain concentrations may be tempered by an inadequate response due to lack of receptor maturation. 

Physiologic processes that influence pharmacokinetic variables in the infant change significantly in the first year of life, particularly during the first few months. Therefore, special attention must be paid to pharmacokinetics in this age group. Pharmacodynamic differences between pediatric and other patients have not been explored in great detail and are probably small except for those specific target tissues that mature at birth or immediately thereafter (eg, the ductus arteriosus). 

In situ pharmacokinetics and pharmacodynamics are essential issues in drug development. After metabolism, the drug and its metabolites are found in blood and urine at extremely low concentrations. Sometimes the amount of biological fluids is very low especially in infants and the cerebrospinal fluid. Therefore, development of microdevices have been a boon for drug discovery... 

Allegaert K, Daniels H, Naulaers G, Tibboel D, Devlieger H. Pharmacodynamics of chloral hydrate in former preterm infants. Eur J Pediatr 2005 164 403-7. 

Because clinical investigation of new agents is not uniformly performed in newbornS/ infantS/ and children/ we have a poor understanding of the effect of ontogeny on the pharmacokinetics and pharmacodynamics of most drugs. However/ we can often anticipate age-related differences in pharmacokinetics and... 

Fisher DM, O Keeffe C, Stanski DR, CronneUy R, Miller RD, Gregory GA. Pharmacokinetics and pharmacodynamics of d-tubocurarine in infants, children, and adults. Anesthesiology 1982 57(3) 203-8. 

Neonates, infants, and children are at risk of adverse effects of opioids, owing to pharmacokinetic and pharmacodynamic changes (SEDA-17, 78). Routine use of pulse oximetry is recommended in all children receiving opioids (SEDA-21, 85). 

Age-dependent differences in the incidence or severity of adverse effects, such as the increased hepatic toxicity of valproate in infants, may also be due to pharmacodynamic determinants. 

Huenseler C, Borucki D, Mueller C, Hering F, Kremer W, Theisohn M, Roth B. Prospective evaluation of the pharmacodynamics of piritramide in neonates and infants. Eur J Pediatr 2008 167 (8) 867-72. 

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