The developmental continuum between birth and adolescence is a very dynamic, complex period of life. The effects of development can be applied to all steps of drug disposition and response. These effects range from differences in gastric pH [34
] and gastric emptying (affecting the absorption of compounds) [36
], to changes in circulating plasma proteins with age, potentially affecting drug distribution [37
]. Developmental changes in phase I drug biotransformation and phase II conjugating enzyme expression have the potential to alter drug metabolism [38
]. In addition, developmental differences in glomerular filtration rates will affect drug excretion in children [39
]. Common drug biotransformation pathways are also known to be shared with endogenous compounds involved in growth and development, a nonexhaustive list including: testosterone, progesterone, prostaglandins, cortisol and vitamin D3 [16
]. Therefore, it may not be surprising that some of these drug biotrans-formation pathways may be affected by rapid growth and maturation, for example, during infancy and puberty. The developmental expression of these pathways at different rates may also lead to further variability in drug disposition and response.
Age-dependent predisposition to ADRs may also be a function of developmental changes in the expression of drug targets, including transporters, ion channels, receptors and downstream signal transduction pathways [40
]. For example, the serotonergic system plays an important role in postnatal brain development, a period of considerable plasticity. However, very little research has actually been conducted in the area of ontogeny of the response to medications targeting the serotonergic pathway. In fact, the ontogeny of many important drug targets for medications widely used in human adults, such as warfarin (vitamin K oxido-reductase complex 1 [VKORC1]), HMG Co-A reductase inhibitors, angiotensin-converting enzyme inhibitors and atypical antipsychotics (dopaminergic pathway) remains virtually unknown.
Based on available in vitro
data and in vivo
pediatric pharmacokinetic studies, drug clearance pathways are known to undergo dramatic changes throughout the maturation process [37
]. The activities of many enzymes involved in drug biotransformation are absent or very limited at birth, raising the possibility that there may be periods of relatively increased vulnerability to concentration-dependent drug toxicity. Cardiovascular collapse from chloramphenicol, associated with delayed maturation of glucuronidation and accumulation of the parent drug, is a classic example of this phenomenon [41
]. The specific UGT isoform responsible for glucuronidation of chloramphenicol has now been identified as UGT2B7 [44
]. The ontogeny of UGT2B7, both in vitro
and in vivo
, is reasonably well understood owing to the considerable number of studies on the ontogeny of morphine, a CYP2B7 substrate, in newborns, infants and young children [45
]. Thus, delayed development of chloramphenicol glucuronidation is consistent with the ontogeny of UGT2B7 as inferred from the morphine data. However, genetic variation also contributes to variability in UGT2B7 activity and morphine glucuronidation [46
], which may account for the apparent dose-dependent toxicity of chloramphenicol reported in adults [47
Another example of the potential role of ontogeny in pediatric ADRs is the syndrome of irritability, tachypnea, tremors, jitteriness, increased muscle tone and temperature instability in neonates born to mothers receiving SSRIs during pregnancy. Controversy currently exists as to whether these symptoms reflect a neonatal withdrawal (hyposerotonergic) state [48
], or whether they represent manifestations of serotonin toxicity [49
] analogous to the hyperserotonergic state attributed to SSRI-induced serotonin syndrome in adults [51
]. Currently available data reveals that CYP2D6 and CYP3A4 are acquired in the first weeks of life. They support a hyperserotonergic state owing to delayed clearance of paroxetine and fluoxetine (CYP2D6), or sertraline (CYP3A4) in neonates exposed to these compounds in utero
. Furthermore, decreases in plasma SSRI concentrations and resolution of symptoms would be expected to be present with increasing postnatal age and maturation of these pathways. In addition, genetic variation, especially in CYP2D6
, may contribute to susceptibility to these reactions [52
]. Given that treatment of a ‘withdrawal’ reaction may include administration of an SSRI, there is considerable potential for increased toxicity in affected neonates if this course of action is taken when they are at risk for delayed clearance. However, the relative contribution of ontogeny and genetic variation in genes involved in serotonin biosynthesis, catabolism, transport and response for risk of SSRI-induced neonatal adaptation syndrome and its appropriate management is less well understood. Initial data from a study investigating the role of genetic variation in the serotonin reuptake pump, SLC6A4, implies a complex interaction between genotype and adverse neonatal outcomes following maternal SSRI exposure [53
Genotyping an individual for variations that affect function is an important step in understanding variability in outcomes. However, knowing if and when that gene is expressed at a given point in the developmental continuum is a concept specific to genotype–phenotype relationships in children [54
]. An approach to investigating hypotheses related to drug outcomes in children can be guided by the following questions [54
- What gene products are quantitatively important in the disposition (absorption, distribution, metabolism and excretion) of the drug in question?
- For each gene product, what is the ontogeny for the acquisition of functional activities?
- Is allelic variation in the gene(s) of interest associated with any functional consequences in vivo?
- Does allelic variation affect the ontogeny of the drug disposition phenotype?
- What is the developmental context in which the gene(s) of interest is/are operating?
It may be impossible to address all of these questions simultaneously, and there may be several unknown areas requiring further investigation to fill a specific knowledge deficit. However, by keeping these questions in mind, one can systematically investigate many of the potential sources of variability in drug responses experienced in children. From this, additional new research opportunities may arise. The entire process results in a more global approach to investigating outcomes, such as drug response and toxicity. Several examples of investigative approaches evaluating drug responses in children in various stages of development are discussed in the next section.