Developmental Pharmacokinetics in Pediatric Populations

Abstract

Information on drug absorption and disposition in infants and children has increased considerably over the past 2 decades. However, the impact of specific age-related effects on pharmacokinetics, pharmacodynamics, and dose requirements remains poorly understood. Absorption can be affected by the differences in gastric pH and stomach emptying time that have been observed in the pediatric population. Low plasma protein concentrations and a higher body water composition can change drug distribution. Metabolic processes are often immature at birth, which can lead to a reduced clearance and a prolonged half-life for those drugs for which metabolism is a significant mechanism for elimination. Renal excretion is also reduced in neonates due to immature glomerular filtration, tubular secretion, and reabsorption. Limited data are available on the pharmacodynamic behavior of drugs in the pediatric population. Understanding these age effects provide a mechanistic way to identify initial doses for the pediatric population. The various factors that impact pharmacokinetics and pharmacodynamics mature towards adult values at different rates, thus requiring continual modification of drug dose regimens in neonates, infants, and children. In this paper, the age-related changes in drug absorption, distribution, metabolism, and elimination in infants and children are reviewed, and the age-related dosing regimens for this population are discussed.

Ontogeny-related pharmacogene changes in the pediatric liver transcriptome

“…Decreased expression of CYP3A7 between human fetal and postnatal liver, as well as, with increasing postnatal age is well recognized within the drug metabolism community. The fact that this trend was also observed in the limited number of samples investigated in this pilot study is consistent with previous investigations, and it suggests that genes showing association in both the three and four group analyses show promise to correspond to real associations that could potentially be relevant in pediatric pharmacodynamics 11 . FMO1 neither met the criterion nor showed a consistent trend between transcripts, even though a similar profile than for the former gene would be expected.…”

“…This subset of genes is known to play an important role in individual drug metabolisms in adults, and, as such, any of its genes that undergo developmental changes in activity should be relevant when assessing the pediatric setting. As these genes are, again, mostly based on studies on adult populations, two additional genes, CYP3A7 and FMO1 , were added to the set of VIPs, as expression of both is known to steadily decrease after birth and as both are involved in drug metabolism 11 . In addition to looking at the candidate genes, we also looked genome wide to determine novel genes that show differences in expression across childhood development, as these genes might be potential biomarkers that could aid in the drug dosing of children.…”

The role of oxidative stress, inflammation and acetaminophen exposure from birth to early childhood in the induction of autism

“…The therapeutic action of acetaminophen involves inhibition of prostaglandin synthesis, a surprisingly important biochemical process involved in development and neurological function, as shown in Figure 3 . Acetaminophen elimination from the body typically involves biochemical modification in the liver by phase II metabolism, which entails the addition of sulfate (or glucuronide more often in adults 130 ) to the molecule, facilitating its elimination ( Figure 3 ). However, the drug can also be modified via phase I metabolism, producing NAPQI, a highly toxic metabolite which is then processed via phase II metabolism to a non-toxic product by the addition of cysteine in a manner dependent on glutathione ( Figure 3 ).…”

Variability of efavirenz plasma concentrations among pediatric HIV patients treated with efavirenz based combination antiretroviral therapy in Dar es Salaam, Tanzania

“…Such wide inter-individual variabilities have also been seen by other studies [ 10 , 28 , 30 ]. The variability may be attributed to the growth and development processes which are still ongoing among pediatric patients impacting the maturity of metabolic organs such as liver and kidneys, feeding patterns affecting drug absorption and hence bioavailability, maturation of hepatic enzymes and variation in drug elimination [ 31 , 32 ]. Variability can furthermore be attributed to genetics, particularly single nucleotide genetic polymorphism of the gene for CYP2B6 enzyme responsible for efavirenz metabolism [ 33 ].…”