Human development is described by the various anatomic and physiologic changes that occur as the single-celled zygote matures into an adult human being. Concomitant with bodily maturation are changes in the complex interactions between pharmacologic agents and the biologic matrix that is the human body. Profound changes in the manner by which drugs traverse the body during development can have significant implications in drug efficacy and toxicity. Although not a replacement for well-conducted, pediatric, pharmacokinetic studies, an understanding of developmental biology and the mechanisms for drug disposition invariably assists the pediatric clinician with the judicious use of medications in children.
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Drug disposition is dynamic and can be attributed to developmental physiologic changes.
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An understanding of the anatomic and physiologic changes during development is paramount in predicting age-dependent changes in drug disposition.
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Without a complete understanding of how biology drives drug disposition, pediatric clinical pharmacokinetic studies are a necessity for rational drug use in children.
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Future studies are needed to understand the ontogeny of drug disposition pathways, including the importance of drug transporters, in pediatric clinical pharmacokinetics.
Introduction
The efficacious use of therapeutic agents is often guided by an understanding of the relationship between dose and exposure (ie, pharmacokinetics [PK]). These relationships vary based on the demographic, genetic, anthropomorphic, and pathologic constitution of the patient being treated. As such, the clinical practitioner is required to understand how these patient-specific factors influence the disposition of drugs in the body. For pediatric practitioners, the process of growth and development overlays these patient-specific factors adding complexity to therapeutic management. In the absence of pediatric PK studies to guide the safe and effective use of medications, pediatric dosing can be guided by knowledge of the anatomic and physiologic factors that govern drug disposition and the developmental patterns that influence these factors.
This article links understanding of anatomic and physiologic changes observed during human development to their impact on drug disposition. It discusses developmental changes that can affect the absorption, distribution, metabolism, and excretion (ADME) of therapeutic agents in children. Relevant examples from the literature are discussed and attention is drawn to developmental changes that have yet to be described. Where human data are unavailable, animal data are supplemented to allude to the potential role of ontogeny in drug disposition.
Absorption
Drugs administered by extravascular routes must overcome multiple barriers to reach the systemic circulation. In addition to the physical and chemical processes that affect drug absorption (ie, stability, solubility, permeability), mechanical barriers such as transporter-mediated uptake and efflux are being found to play an important role in regulating the absorption of many drugs. All of these processes are influenced by development, thus influencing the PK profiles of many drugs in children.
Peroral Absorption
Following oral administration, there are several ontogenic factors that influence systemic drug absorption. One of the most prominent is the period of relative achlorhydria observed shortly after birth. Gastric pH influences absorption by 2 mechanisms: permeation and stability. Although the stomach is not a principal site of drug absorption, the decrease in ionization of weakly acidic drugs in the low-pH environment of the stomach can theoretically enhance permeation across the epithelial lining of the stomach. In contrast, a decrease or delay in absorption could be expected for weakly acidic drugs (eg, phenobarbital, phenytoin) under conditions of increased gastric pH in the newborn. More importantly, the stomach is an important site of pH-dependent drug degradation, ultimately affecting the amount of intact drug that reaches the small intestine. Perhaps the best-documented example of the impact of development on gastric pH arises with the acid-labile β-lactam antibiotic penicillin, with which plasma concentrations in the neonate reach levels 5 to 6 times those seen in infants and children owing to protection from decomposition ( Fig. 1 A).
In contrast with the permeation-limited absorption of many water-soluble drugs, oral absorption of many lipophilic drugs is limited by their poor solubility in the aqueous digestive fluids. Absorption of drugs in this category often shows significant food effects (eg, enhanced absorption in the fed state). Stimulation of bile acid secretion into the alimentary canal by food results in micellar solubilization of many lipophilic drugs rendering their absorption dependent on biliary function. Despite an increase in circulating bile acid levels in young infants, concentrations of the major bile salts in the intestinal lumen are reduced, likely the result of a decrease in transporter-mediated secretion of bile acids into the biliary canaliculi. As a result, clinically significant changes in drug absorption are possible for solubility-limited drugs. This possibility is shown by data on the antiviral pleconaril, a highly lipophilic compound that, in adults, shows a 2-fold increase in exposure with food. Although dose escalation studies in adults revealed a dose-proportional increase in exposure, dose escalation in neonates resulted in no increase in exposure. This failure to increase neonatal drug exposure may reflect restricted bioavailability caused by limited micellar solubilization. If so, then other solubility-limited, lipophilic drugs may have similar saturable absorption profiles in neonates.
In addition to the impact of the gastrointestinal fluid composition on the solubility and permeability of drugs, the rate of gastric emptying (GE) influences the speed at which drugs are presented to the absorptive surfaces of the small intestine. The rate of GE is prolonged in the first week of life and approaches adult values by 6 to 8 months of age. There exists a significant level of developmental variation in GE, in part because a variety of newborn disorders can significantly affect GE rates, among them prematurity, respiratory disease, gastroesophageal reflux disease, and congenital heart disease. Intestinal motility further affects the drug’s residence time, thereby serving as another important determinant of the rate and extent of drug absorption. In the young infant, intestinal contractile frequency and amplitude are reduced and highly variable. The overall impact of decreased emptying and motility on drug absorption depends on the dissolution and permeation properties of the formulation. For drugs that are rapidly and completely absorbed within the small intestine, absolute bioavailability in young infants is expected to remain mostly unchanged, although the rate of absorption, and consequently the maximum drug concentration (C max ), may be significantly reduced and the time to C max (T max ) delayed. Age-dependent changes in the absorption rate constant (k a ) and T max for numerous drugs and nutrients (eg, l (+)-arabinose, phenobarbital, sulfonamides, digoxin, cisapride) support this hypothesis. Attempts to enhance absorption rates in young infants via administration of a prokinetic agent can increase k a ; however, absolute differences in the absorption rate constants between neonates (<30 days of life) and infants (>30 days of life) remain unchanged despite pharmacologic stimulation. These results suggest that additional developmental factors influence the rate of drug absorption in the neonate.
Apart from physicochemical and mechanical forces, phase I and phase II drug metabolizing enzymes (DME) residing in the intestinal tract influence drug absorption. Although only limited data exist on the age-dependent expression of most intestinal DMEs, existing data support a developmental component for at least some of the enzymes. Duodenal biopsies have shown increases in intestinal CYP1A1 and CYP3A with increasing age. Thus, drugs metabolized by these pathways are expected to undergo less presystemic intestinal clearance in young children. Among the intestinal phase II enzymes evaluated to date, glutathione S-transferase (GST)–mediated conjugating capacity of the antineoplastic agent busulfan was highest in distal duodenal biopsies from children less than 5 years of age compared with children older than 8 years of age and adolescents. These findings are in accordance with age-dependent changes in the presystemic clearance of this drug, implying that young children may require higher oral doses of drugs that are subject to clearance via glutathione conjugation. With the paucity of data on the ontogeny of intestinal DMEs, further studies are needed to fully examine the influence of development on intestinal drug metabolism.
One of the newest and still emerging fields is the study of the impact of drug transporters on absorption. Transporter proteins expressed along the intestinal tract not only facilitate the uptake of nutrients and drugs across the intestinal epithelium but also limit their absorption by actively pumping them back into the intestinal lumen. As with intestinal DMEs, very few data have been generated on developmental changes in transporter expression, and the studies that have been completed are primarily restricted to the transport of nutrients (ie, SGLT1, GLUT2, PEPT1) in animal models, many of which seem to be maximally expressed shortly after birth. By contrast, the acquisition of iron absorption capacity (mediated by DMT1) increases linearly after birth, reaching adult levels by early childhood (see Fig. 1 B).
Among established drug transporters, it seems that P-glycoprotein (P-gp) is present in the intestine by 1 month of age. Other PK studies provide circumstantial evidence supporting developmental changes in intestinal drug transporter activity. For example, the H 2 -receptor antagonist nizatidine (a substrate for intestinal transporters whose activity can be modified by the coadministration of apple juice) shows an age-dependent decrease in apparent oral clearance despite no age dependence on terminal elimination rate constant. Even transporters whose expression seems to mature shortly after birth can show age effects. Drugs whose transport is mediated by the intestinal peptide transporter 1 (PEPT1) compete with milk peptides for uptake, and infants on a milk-based diet with condensed feeding frequency likely have milk peptides continuously distributed along the intestinal lumen. Thus, the magnitude of drug-nutrient interactions may be more pronounced in the young infant. An advanced understanding of developmental changes in intestinal transporter activity will facilitate understanding of the potential for drug-drug and drug-nutrient interactions in young children.
Extraoral Absorption
Despite conventional preferences to deliver drugs orally, nonoral routes of administration may be preferred in some settings. As with peroral administration, the absorption of extraorally administered drugs is also subject to developmental variation. The absorption of rectally administered drugs depends in part on drug dissolution profiles within the lower intestinal tract. Rectal formulations with delayed release characteristics (ie, erythromycin, acetaminophen) may experience decreased residence times in young infants owing to an increase in the number of high-amplitude pulsatile contractions of the lower intestine. Preterm neonates have enhanced rectal acetaminophen bioavailability, possibly caused by reductions in presystemic metabolism, intestinal motility, or temperature instability.
Although infrequently used, percutaneous administration can be an efficient means of delivering drugs to children. The increased systemic exposure experienced by children is a product of developmental differences in the neonate and young infant that result in enhanced percutaneous absorption, namely an increased body surface area/mass ratio, higher rates of tissue perfusion, and a higher degree of skin hydration. These differences can increase a child’s risk of toxicity to topically applied agents even when systemic exposure is not the goal of treatment. Unintended consequences of topical agents have been shown for numerous agents, such as antihistamines, steroids, sulfadiazine, talcum powder, and laundry detergent.
In addition, absorption following intramuscular (IM) injection is considered. Although IM absorption of some drugs in children is reported as erratic, others are efficiently absorbed by this route, which may be explained by increases in capillary density (25%–50%) experienced by the young infant to assist with the metabolic demands of growth and development. Peak plasma concentrations for some drugs (eg, cephalosporins, aminoglycosides) are consequently significantly higher in neonates compared with young children, presumably reflecting a change in the rate of absorption from the site of administration.
Distribution
Once absorbed into the systemic circulation, the extent to which a drug penetrates extravascular tissues is described by the drug’s volume of distribution (V d ). The underlying determinants of drug distribution include the physiologic characteristics of the tissue and the physicochemical and transport properties of the drug. Thus, physiologic changes observed throughout development can have a sizable impact on the distribution properties of a drug.
One of the more prominent changes that influence drug distribution is the fluid composition of the body. Water comprises approximately 80% of a newborn infant’s body weight, with fractional decreases over the first 4 months of life to adult levels (approximately 60%) ( Fig. 2 A). Hydrophilic drugs that are mainly restricted to the aqueous fluid compartments (eg, gentamicin, linezolid) consequently have a larger apparent V d and decreased plasma concentrations in the young infants. In conjunction with developmental changes in drug clearance, these children can experience circulating concentrations that fail to adequately meet pharmacodynamic criteria if dose and dosing interval are not adjusted for age.
As opposed to total body water, total body fat stores are reduced in infants and approach adult values in the first years of life, with age-dependent fluctuations throughout childhood (see Fig. 2 B). Based on these changes, it theoretically could be expected that lipophilic drugs would show a lower V d in infants and young children; however, this is largely not observed, because these drugs tend to freely associate with cellular components in tissues other than adipose. The failure to observe a lower V d for lipophilic agents in young children may also indicate that additional tissue retention mechanisms compensate for the changes in body composition. A variety of retention mechanisms can facilitate the partitioning and accumulation of drugs in tissue. For example, a subset of drugs with extremely large V d accumulate in tissues through their affinity for acidic subcellular compartments (ie, lysosomes), which are enriched in the liver, lung, heart, brain, and kidneys. Thus, age-dependent changes in the mass of these organs relative to total body mass would result in V d differences with age (see Fig. 2 B), particularly when blood flow/volume to these tissues is comparable with or greater than that of adults. Although speculative, these changes in fractional organ mass may contribute to changes in the V d , and future studies addressing the impact of development on tissue retention mechanisms are needed to more thoroughly evaluate their relevance to pediatric pharmacotherapy.
A drug must exist in its free, unbound form to distribute out of the central compartment and into extravascular tissues. Therefore, the apparent V d of a drug depends not only on its ability to enter and accumulate in tissue but also on the free fraction of the circulating drug. Protein binding depends on the quantity of circulating plasma proteins (eg, α-1-acid glycoprotein [AAG] and albumin), the drug’s binding affinity for these proteins, and the presence of endogenous or exogenous substances that compete for binding sites, including free fatty acids, bilirubin, and other drugs. Development influences each of these factors, with neonates and young infants experiencing reduced concentration of albumin and AAG, protein isoforms for which drugs have a reduced affinity, and increased circulating concentrations of ligands that can displace drugs from their binding sites. Compared with older children and adults, young infants experience increased free fractions, and thus increased V d , of many drugs (eg, barbiturates, opioid analgesics). The clinical importance of developmental changes in the fractional protein binding of drugs ultimately depends on the therapeutic agent under consideration and its therapeutic index.
Although limited data are available describing the ontogeny of transmembrane proteins responsible for the cellular uptake and efflux of drugs, there is strong biologic evidence to support the assertion of a developmental expression profile. The endogenous substrates for these transport proteins include a variety of substances that are crucial to normal human growth and development (eg, metals, electrolytes, amino acids, nucleotides, lipids, carbohydrates, steroids). Realizing that these substrates are used by different tissues to different extents throughout development, adaptive mechanisms that control transporter expression and activity are likely involved. To date, only limited data from postmortem brain tissue are available, suggesting that P-gp, MRP1 (multidrug resistance protein 1), and BCRP (breast cancer resistance protein) all show distinct anatomic and cellular expression patterns that are developmentally dependent. Such differences may explain changes in the central nervous system (CNS) penetration of drugs that are substrates for these transport proteins; however, other studies suggest that changes in pore density and regional blood flow may account for age-dependent differences in CNS drug penetration.
Metabolism
In addition to the liver functioning in a variety of life-sustaining synthetic and digestive processes, it also serves as the predominant organ of metabolism for exogenously administered drugs. Hepatic clearance pathways are usually divided into phase I (eg, oxidation, reduction, hydrolysis) and phase II (eg, covalent conjugation) reactions. The DMEs responsible for drug bioconversion are found in multiple tissues other than the liver; however, these extrahepatic sites (with the exception of the intestine) are of minimal significance in overall drug clearance and this article only discusses the liver. As alluded to earlier, an understanding of the ontogeny of DMEs helps to appreciate the potential for drug-drug, drug-nutrient, and drug-gene interactions in children.
Phase I Metabolism
Phase I drug metabolism is typically performed by a group of mixed-function oxidases referred to as the cytochromes P450 (CYPs). These enzymes are highly expressed in the liver; CYP3A4 being the most clinically relevant followed by CYP2D6 > CYP2C > CYP2E1 > CYP1A2. Although the fetus expresses a high level of CYP3A7, humans undergo an isoform switch shortly after birth and CYP3A7 rapidly decreases coincident with a steady increase in CYP3A4 expression and activity through the first year of life ( Fig. 3 A). The clinical implications of this profile can be shown for numerous CYP3A substrates (eg, sildenafil, cisapride) that show marked reductions in half-life during infancy.
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