Chapter 57 Principles of Drug Therapy

Jennifer A. Lowry, Bridgette L. Jones, Tracy Sandritter, Susanne Liewer, Gregory L. Kearns

Regulatory mandates and economic opportunities have positioned pediatric patients for inclusion as subjects in pediatric clinical drug trials, but the majority of drugs used to treat sick infants and children do not have complete, approved product labeling sufficient to guide their use. Thus, off-label (or off-license) use of drugs in pediatrics continues to be the rule as opposed to the exception. Nonetheless, any important therapeutic advances have been made in pediatrics because physicians most often do not prescribe drugs from an “off-knowledge” basis. Rather, scientific and technical information published in the peer-reviewed medical literature and distilled into compendia for pediatric therapeutics have been used to support prudent, safe, and effective drug prescribing. Much of this information has resulted from investigations in the field of pediatric clinical pharmacology, which have explored the association with development (most often represented by the surrogate of age) of both drug disposition and action.

The clinical pharmacology of a given drug reflects a multifaceted set of properties that pertain to the disposition and action of drugs and the response (e.g., adverse effects, therapeutic effects, therapeutic outcome) to their administration. The 3 most important facets of clinical pharmacology are pharmacokinetics, pharmacodynamics, and pharmacogenomics.

Pharmacokinetics describes the movement of a drug throughout the body and the concentrations (or amounts) of a drug that reach a given body space and/or tissue and the drug’s residence time therein. Pharmacokinetics of a drug are conceptualized by considering the characteristics that collectively are the determinants of the dose-concentration-effect relationship, namely, absorption, distribution, metabolism, and excretion (ADME).

Pharmacodynamics describes the relationship between drug dosage or drug concentration and response. The response may be desirable (effectiveness) or untoward (toxicity). Although in clinical practice the response to drugs in different patient populations is often described by a standard dosing or concentration range, response is best conceptualized along a continuum where the relationship between dosage and response(s) is not linear.

Pharmacogenetics is the study of how variant forms of human genes contribute to interindividual variability in drug response. The finding that drug responses can be influenced by the patient’s genetic profile has offered great hope for realizing individualized pharmacotherapy when the relationship between genotype and phenotype (disease and/or drug response) predicts drug response (Chapter 56). In the developing child, it is apparent ontogeny has the potential of modulating drug response through altering pharmacokinetics and pharmacodynamics.

General Principles of Pharmacokinetics and Pharmacodynamics

Drug effect is produced only when an exposure (amount and duration) occurs that is sufficient to produce a drug-receptor interaction capable of modulating the cellular milieu and inducing a physiologic response. Thus, exposure-response relationships for a given drug represent an interface between pharmacokinetics and pharmacodynamics that can be simply conceptualized by consideration of two profiles: plasma concentration vs. effect (Fig. 57-1) and plasma concentration vs. time (Fig. 57-2).

Figure 57-1 Plasma concentration vs. effect curve. The percent effect is measured as a function of increasing drug concentration in the plasma. The dosage at which no effect is seen in the population is E₀. The dosage required to produce a specified effect in 50% of the population is EC₅₀. The concentration associated with the maximal effect is E_max.

(From Abdel-Rahman SM, Kearns GL: The pharmacokinetic-pharmacodynamic interface: determinants of anti-infective drug action and efficacy in pediatrics. In Feigin RD, Cherry JD, Demmler-Harrison GJ, et al, editors: Textbook of pediatric infectious disease, ed 6, Philadelphia, 2009, Saunders/Elsevier, pp 3156–3178.)

Figure 57-2 Semilogarithmic plot of the plasma concentration vs. time curve for a hypothetical drug following extravascular administration. The area under the plasma level–time curve (AUC) is a concentration- and time-dependent measure of systemic drug exposure. After administration, the drug is absorbed and reaches the maximal concentration (C_max) at its peak time (T_max). Following completion of drug absorption and distribution, plasma drug concentrations decline in an apparent monoexponential fashion, whereby the slope of the apparent elimination phase represents the apparent elimination rate constant (ke).

The relationship between drug concentration and effect for most drugs is not linear (see Fig. 57-1). At a drug concentration of 0, the effect from the drug is generally 0 or not perceptible (E₀). Following administration of drug and/or escalation of dosage, the concentration increases as does the effect, first in an apparently linear fashion (at low drug concentrations) and then with a nonlinear increase in effect to an asymptotic point in the relationship where a maximal effect (E_max) is attained that does not perceptibly change with further increases in drug concentration. The point in the concentration-effect relationship where the observed effect represents 50% of the E_max is defined as EC₅₀, a common pharmacodynamics term used to compare concentration-effect relationships between patients (or research subjects) and between drugs that may be in a given drug class. In practice, E_max can be derived either from visual interpolation of the concentration-effect profile or via mathematical curve fitting of the relationship.

Because it is rarely possible to measure drug concentrations at or near the receptor, it is necessary to use a surrogate measurement to assess exposure-response relationships. In most instances, this surrogate is represented by the plasma drug concentration vs. time curve. For drugs whose pharmacokinetic properties are best described by first-order (as opposed to zero- or mixed-order) processes, a semilogarithmic plot of plasma drug concentration vs. time data for an agent given by an extravascular route of administration (e.g., intramuscular, subcutaneous, intracisternal, oral, transmucosal, transdermal, rectal) produces a pattern depicted in Figure 57-2. The ascending portion of this curve represents a time during which the liberation of a drug from its formulation, dissolution of the drug in a biologic fluid (e.g., gastric or intestinal fluid, interstitial fluid; a prerequisite for absorption) and absorption of a drug are rate-limiting relative to its elimination. After the time (T_max) where maximal plasma concentrations (C_max) are observed, the plasma concentration decreases as metabolism and elimination become rate limiting, the terminal portion of this segment of the plasma concentration vs. time curve being representative of drug elimination from the body. Finally, the area under the plasma concentration vs. time curve (AUC), a concentration- and time-dependent parameter reflecting the degree of systemic exposure from a given drug dosage, can be determined by integrating the plasma concentration data over time.

By being able to characterize the pharmacokinetics of a specific drug in a specific condition, the clinician can adjust the “normal” dosing regimens for patients who, by virtue of development and/or disease, do not demonstrate “normal” dose-concentration-response relationships, thereby individualizing the dosage to produce the degree of systemic exposure associated with desired pharmacologic effects. For drugs whose therapeutic plasma concentration range and/or “target” systemic exposure (i.e., AUC) is known, a priori knowledge of pharmacokinetic parameters for a given population or patient within a population can help in selecting a drug-dosing regimen. When linked with information regarding the pharmacodynamic behavior of a drug and the status of the patient (e.g., age, organ function, disease state, concomitant medications), the application of pharmacokinetics allows the practitioner to exercise some real degree of adaptive control over therapeutic decision making by enabling him or her to select a drug and dosing regimen with the greatest likelihood of efficacy and safety.

Definitions of Terms

A glossary of pharmacokinetic terms helps equip the reader with a working knowledge of pharmacokinetics as a tool that can enhance therapeutic success.

Absolute bioavailability (F) is the fraction of a drug dose administered by an extravascular route that is absorbed into the systemic circulation. It is determined within a given individual by comparing the AUC following administration of an oral dose of a drug with the AUC resulting from an intravenous dose (e.g., F = (AUC_po × dose_iv) ÷ (AUC_iv × dose_po), with corrections made for possible differences in the terminal elimination rate constant between the dosing periods used for evaluation.

Absorption of drugs describes the process of drug uptake from a site of extravascular administration (oral, intramuscular, subcutaneous, intraperitoneal, intraosseous, intratracheal, intravaginal, intraurethral, sublingual, buccal, rectal, or dermal) into the systemic circulation. A critical prerequisite for drug absorption is that it be in true solution. Thus, in the case of administration of solid dosage forms (e.g., preparations for oral use), the active drug must first be liberated from the formulation wherein it is contained. Drug absorption is most accurately conceptualized by considering rate (e.g., absorption half life, time to peak concentration) and extent (e.g., bioavailability), either of which can be influenced by biopharmaceutical (e.g., drug formulation), physicochemical (e.g., pH, solubility, hydrophilicity and lipophilicity, protein binding, complexation characteristics with food or drugs), and physiologic factors (e.g., barrier integrity, motility, volume and pH of body fluids at absorptive site, protein binding capacity, or degradation or biotransformation potential).

Area under the curve (AUC) is, conceptually, a measure of both the extent of drug absorbed and its persistence in the body. Thus, it is both concentration- and time-dependent. Mathematically, AUC represents the integral of blood drug levels over time from 0 to either a predetermined postdose time point (AUC_0→tx) or extrapolated to infinity (AUC_0→∞), which is calculated by using the apparent terminal elimination rate constant (similarly calculated from the observed plasma concentration vs. time plot; see Fig. 57-2).

Bioequivalence of a drug product is achieved if its extent and rate of absorption are not significantly different (within 80-125%) from those of a reference standard drug product when administered at the same molar dose. The determination of bioequivalence does not entail a relative comparison of drug action and efficacy but rather is simply an assessment of whether one drug formulation (e.g., a generic drug) produces a rate and extent of absorption that is comparable to that of the reference formulation. It assumes that effect and toxicity profiles of the two drugs are virtually identical if the systemic exposures (as determined from AUC) are comparable.

Clearance of a drug is conceptually represented by the volume of blood from which a certain amount of unmetabolized drug is removed (cleared) per unit time by any and all pathways capable of drug removal (e.g., renal, hepatic, biliary, pulmonary, breast milk, sweat). In pharmacokinetics, clearance (Cl) is generally represented as either total body (or plasma) clearance, renal clearance (Cl_ren) or nonrenal clearance (Cl_nr). Clearance is easily determined from knowledge of the drug dosage and AUC and can be calculated as follows:

where AUC can either represent the AUC_0→∞ for single dose administration or the AUC from time zero to the end of the dosing interval at steady state (i.e., AUCss_0→τ). Calculation of Cl_ren requires a complete, quantitative collection of urine (usually over 24 hr) to determine the amount of drug excreted unchanged (Ae). Cl_nr is generally determined as the difference between Cl and Cl_ren. For drug administration by any extravascular route, the calculation of Cl yields an “apparent” value (e.g., Cl/F) which must be corrected for bioavailability.

A compartment in pharmacokinetics represents a hypothetical space that is helpful in quantitating the relationship between drug dosage and the amount of drug in the body at a given time. A simple 1-compartment open model treats all body fluids and tissues as 1 space with definable rates of drug ingress and egress and thus it greatly oversimplifies physiology. More complex models (2- and 3-compartment open models; physiologic models) separate fluid, organ, and/or tissue spaces into discrete spaces and therefore can be more precise in describing relationships between drug concentration and effect. Because of their mathematical complexity, the use of multicompartment models is largely limited to research settings. In all instances, compartmental models oversimplify the true processes of ADME. However, they have been repeatedly demonstrated to be useful as a means to reliably predict the relationship between drug dosage and concentration in plasma and tissue.

Disposition refers collectively to the processes of drug absorption, distribution, metabolism and elimination, all of which occur simultaneously following drug administration, as opposed to being discrete pharmacologic events.

Elimination half-life (T_1/2) of a drug represents the time for postabsorption blood or plasma concentrations to be reduced by 50%. The apparent elimination rate constant (ke) can be reliably estimated from two drug concentrations obtained on the elimination phase of the concentration vs. time curve (see Fig. 57-2). The T_1/2 is then determined as the natural logarithm of 2 divided by the elimination rate constant (T_1/2 = 0.693/ke). T_1/2 reflects the elimination of parent drug by all of the routes involved in its clearance. Although T_1/2 is often considered a surrogate indicator of drug clearance, this should be done cautiously because it depends upon the clearance and the apparent volume of distribution (Vd), as illustrated by the following equation:

Practically speaking, T_1/2 is an important pharmacokinetic parameter, because it can be used to determine the time required for a dosing regimen to produce steady-state plasma concentrations (e.g., 5 × T_1/2 elimination) and the time required for most of a drug to be completely eliminated from the body (e.g., 10 × T_1/2).

First-pass effect describes a phenomenon whereby a drug may be metabolized and/or chemically degraded following extravascular administration before it reaches the systemic circulation. It is generally a consideration for drugs given by the oral or rectal routes. Examples include biotransformation of selected drugs in the enterocyte, the transport or drugs from the enterocyte back into the lumen of the gastrointestinal (GI) tract, and the hydrolysis of active drug in the lumen of the GI tract. Drugs subject to first-pass effect generally have a reduced rate and/or extent of relative bioavailability when compared to that achieved with parenteral administration.

Protein binding results when a drug combines with plasma or with extracellular or tissue proteins to form a reversible drug-protein complex. Binding of drug and protein is usually nonspecific and depends on the drug’s affinity for the protein molecule (i.e., binding site), the number of protein binding sites, and the drug and protein concentrations. With few exceptions, drugs that are bound to proteins are pharmacologically inactive and cannot be readily metabolized or excreted. There are pharmacokinetic consequences of drug-protein binding that can influence the disposition profile. Drugs with extensive tissue binding have a Vd that is far in excess of the total body water space. Generally, these drugs have long elimination half-lives (e.g., phenothiazines, digoxin). Conditions where intravascular proteins escape to extravascular sites (e.g., nephrotic syndrome, severe burns, ascites) can increase the Vd and T_1/2 of drugs that are extensively (>70%) bound to albumin. Also, for drugs that have extensive binding to circulating plasma proteins, the concentration-effect profiles can differ as a consequence of altered unbound (free) drug concentrations in patients with normal vs. abnormal plasma protein concentrations (e.g., phenytoin neurotoxicity in a patient who has an apparently therapeutic total plasma drug concentration and hypoalbuminemia).

Relative bioavailability reflects the extent of drug absorbed from one dosage form given by an extravascular route of administration in comparison with a dosage of a “standard” drug formulation administered by the same route. Generally, it reflects the relative extent of systemic availability (F) and is calculated by a comparison of the AUC of the test article relative to the standard formulation (e.g., F = (AUC_test × dose_standard) ÷ (AUC_standard × dose_test).

Steady state reflects a level of drug accumulation in blood and tissue upon multiple dosing when the rate of input (the amount of drug placed into the systemic circulation) and output (drug clearance) are at equilibrium. When drugs are given at fixed doses and dosing intervals, the steady-state concentrations in blood or plasma fluctuate between a maximum (C_max) and minimum (C_min) within a given dosing interval. The interdose values of C_max and C_min should be identical provided that dose size, method of administration, dosing interval, and drug pharmacokinetics do not change between doses. For drugs that follow first-order pharmacokinetics, steady-state plasma concentrations are attained in a period corresponding to 4-5 times the T_1/2 after institution of treatment and/or a change in a given dosing regimen. In general, the pharmacokinetics of a drug at steady state provides the most accurate means to assess the drug’s effect(s).

Therapeutic range represents a range of plasma drug concentrations where the drug has desirable therapeutic effects in the majority of subjects receiving a drug at an age-appropriate “normal” (recommended) dosage. Consequent to interindividual differences in pharmacodynamics, some patients with plasma drug concentrations within a recommended therapeutic range exhibit either no discernable drug effect or concentration-related adverse drug effects. The therapeutic index (also known as therapeutic ratio) is a comparison of the amount of a drug that causes the desired therapeutic effect to the amount that causes death: Therapeutic index = LD₅₀/ED₅₀, where LD₅₀ and ED₅₀ represent the lethal and effective dosages, respectively, for 50% of the normal population receiving a drug.

Volume of distribution (apparent volume of distribution) represents a hypothetical volume of body fluid that would be required to dissolve the total amount of drug at the same concentration as that found in the blood and is illustrated by the equation

where Cp₀ represents the highest attainable plasma concentration following administration of a single dose. As a proportionality constant, Vd is a determinant of plasma drug concentrations attained following administration of a given drug dose. For drugs that do not distribute extensively or associate with great affinity to proteins and tissue, the Vd may dimensionally correspond to a physiologic or anatomic body space: Vd < 0.1 L/kg ≅ intravascular space, 0.1-0.3 L/kg ≅ extracellular space, 0.6-0.7 L/kg ≅ total body water space. Disease and development can influence the Vd, and thus the achievable concentration, for a given drug. Following extravascular drug administration, the apparent Vd is affected by the extent of drug absorbed (Vd/F). In instances in which a drug has incomplete absorption, plasma concentration can underestimate the true value of the Vd.

A working knowledge of these pharmacokinetic definitions makes it possible to understand the relationship among drug dose, concentration, and effect.

The Impact of Ontogeny on Drug Disposition

Development represents a continuum of biologic events that enable adaptation, somatic growth, neurobehavioral maturation, and eventually reproduction. The impact of development on the pharmacokinetics of a given drug is determined, to a great degree, by age-related changes in body composition and the acquisition of function in organs and organ systems that are important in determining drug metabolism and excretion. Although it is often convenient to classify pediatric patients on the basis of postnatal age for providing drug therapy (e.g., neonate ≤1 mo of age; infant = 1-24 m of age; child = 2-12 yr of age; adolescent = 12-18 yr of age), it is important to recognize that the changes in physiology are not linearly related to age and might not correspond to these age-defined breakpoints. The most dramatic changes in drug disposition occur during the first 18 mo of life, when the acquisition of organ function is most dynamic. Additionally, the pharmacokinetics of a given drug may be altered in pediatric patients consequent to intrinsic (e.g., gender, genotype, ethnicity, inherited diseases) or extrinsic (e.g., acquired disease states, xenobiotic exposure, diet) factors that can occur during the first 2 decades of life.

Selection of an appropriate drug dosage for a neonate, infant, child, or adolescent requires an understanding of the basic pharmacokinetic properties of a given compound and how the process of development affects each facet of drug disposition. Accordingly, it is most useful to conceptualize pediatric pharmacokinetics by examining the impact of development on the physiologic variables that govern drug ADME.

Dramatic pharmacokinetic, pharmacodynamic, and psychosocial changes occur as preterm infants mature toward term, as infants mature through the first few years of life, and as children reach puberty and adolescence (Fig. 57-3). To meet the needs of these different pediatric groups, different formulations are needed for drug delivery that can influence drug absorption and disposition, and different psychosocial issues influence compliance, timing of drug administration, and reactions to drug use. These additional factors must be considered in conjunction with known pharmacokinetic and pharmacodynamic influences of age when developing an optimal patient-specific drug therapy strategy.

Figure 57-3 Developmental changes in physiologic factors that influence drug disposition in infants, children, and adolescents. Physiologic changes in multiple organ systems during development are responsible for age-related differences in drug disposition. A, the activity of many cytochrome P450 (CYP) isoforms and a single glucuronsyltransferase (UGT) isoform is markedly diminished during the first 2 mo of life. In addition, the acquisition of adult activity over time is enzyme- and isoform-specific. B, Age-dependent changes in body composition, which influence the apparent volume of distribution of drugs. Infants in the first 6 mo of life have markedly expanded total body water and extracellular water, expressed as a percentage of total body weight, as compared with older infants and adults. C, Age-dependent changes in both the structure and function of the gastrointestinal tract. As with hepatic drug-metabolizing enzymes (A), the activity of CYP1A1 in the intestine is low during early life. D, The effect of postnatal development on the processes of active tubular secretion, represented by the clearance of p-aminohippuric acid and the glomerular filtration rate, both of which approximate adult activity by 6 to 12 mo of age. E, Age dependence in the thickness, extent of perfusion, and extent of hydration of the skin and the relative size of the skin surface area (reflected by the ratio of body surface area to body weight). Although skin thickness is similar in infants and adults, the extent of perfusion and hydration diminishes from infancy to adulthood.

(From Kearns GL, Abdel-Rahman SM, Alander SW, et al: Developmental pharmacology—drug disposition, action, therapy in infants and children, N Engl J Med 349:1157–1167, 2003.

Drug Absorption

Largely, absorption occurs via passive diffusion, but active transport or facilitated diffusion might also be necessary for drug entry into cells. Several physiologic factors affect this process, one or more of which may be altered in the face of certain disease states (e.g., inflammatory bowel disease, diarrhea) and consequently produce changes in drug bioavailability. The rate and extent of absorption can be significantly affected as a consequence of a child’s normal growth and development.

Peroral Absorption

The most important factors that influence drug absorption from the GI tract are related to the physiology of the stomach, intestine, and biliary tract (see Fig. 57-3C and Table 57-1). The rate and extent of peroral absorption of drugs depends primarily on the pH-dependent passive diffusion and motility of the stomach and intestinal tract because both of these factors influence transit time of the drug. Gastric pH changes significantly throughout development, and the highest (alkaline) values occur during the neonatal period. In the fully mature neonate, the gastric pH ranges from 6 to 8 at birth and drops to 2 to 3 within a few hours of birth. However, after the first 24 hr of life, the gastric pH increases due do the immaturity of the parietal cells. As the parietal cells mature, the gastric acid secretory capacity increases (pH decreases) over the first few months of life to reach adult levels by 3-7 yr of age. As a result, the peroral bioavailability of acid-labile drugs, such as penicillin or ampicillin, is increased. In contrast, the absorption of weak organic acids (e.g., phenobarbital and phenytoin) is relatively decreased, a condition that can necessitate administering larger doses in the very young to achieve therapeutic plasma levels.

Table 57-1 DEVELOPMENTAL ALTERATION IN INTESTINAL DRUG ABSORPTION

Gastric emptying time is prolonged throughout infancy and childhood consequent to reduced motility, which can retard drug passage into the intestine, where the majority of absorption takes place. Gastric emptying rates reach or exceed adult values by 6 to 8 mo of life. Thus, intestinal motility is important to the rate of drug absorption and, like other factors, depends on the age of the child. Consequently, the rate of absorption of drugs with limited water solubility (e.g., phenytoin, carbamazepine) can be dramatically altered consequent to changes in GI motility. In older infants and young children, more-rapid rates of intestinal drug transit can reduce the bioavailability for some drugs (e.g., phenytoin) and/or drug formulations (e.g., sustained-release) by reducing their residency at the absorptive surfaces in the small intestine.

Neonates, particularly premature neonates, have a reduced bile acid pool and biliary function, resulting in a decreased ability to solubilize and absorb lipophilic drugs. Although biliary function develops in the first few months of life, it may be difficult for the neonate and young infant to absorb fat-soluble vitamins because low concentrations of bile acids are necessary for their absorption.

Extravascular Drug Absorption

Intravenous drug administration is assumed to be the most dependable and accurate route for drug delivery, with a bioavailability of 100%. Absorption of drugs from tissues and organs (e.g., intramuscular, transdermal, and rectal) can also be affected by development (Table 57-2). Intramuscular blood flow changes with age, which can result in variable and unpredictable absorption. Reduced muscular blood flow in the first few days of life, the relative inefficiency of muscular contractions (useful in dispersing an IM drug dose), and an increased fraction of water per unit of muscle mass can delay the rate and/or extent of drugs given intramuscularly to the neonate. Muscular blood flow increases into infancy, and consequently the bioavailability of drugs given by the IM route is comparable to that seen in children and adolescents.

Table 57-2 INFLUENCE OF ONTOGENY ON DRUG ABSORPTION

In contrast, mucosal permeability (rectal and buccal) in the neonate is increased and thus can result in enhanced absorption by this route. Transdermal drug absorption in the neonate and very young infant is increased due to the thinner and more hydrated stratum corneum (see Fig. 57-3E). In addition, the ratio of body surface area to body weight is greater in infants and children than in adults. Collectively, these developmental differences can predispose the child to increased exposure and risk for toxicity for drugs or chemicals placed on the skin (e.g., silver sulfadiazine, topical corticosteroids, benzocaine, diphenhydramine), and such toxicity is more likely during the first 8 to 12 mo of life.

Normal developmental differences in drug absorption from almost all extravascular routes of administration can influence the dose-plasma concentration relationship in a manner sufficient to alter pharmacodynamics. The presence of disease states that alter a physiologic barrier for drug absorption and/or the time that a drug spends at a given site of absorption can further alter drug bioavailability and effect.

Drug Distribution

Drug distribution is influenced by a variety of drug-specific physiochemical factors, including the role of drug transporters and protein binding, pH, and perfusion in blood and tissue. However, age-related changes to drug distribution are primarily related to developmental changes in body composition and the quantity of plasma proteins capable of drug binding. Age-dependent changes in the relative sizes of body water (total body water [TBW] and extracellular water [ECW]) and fat compartments can alter the apparent Vd for a given drug. The absolute amounts and distribution of body water and fat depend on a child’s age and nutritional status. In addition, certain disease states (e.g., ascites, dehydration, burn injuries, disruption of the integument involving a large surface area) can influence body water compartment sizes and thereby further affect the Vd for certain drugs.

Newborns have a much higher proportion of body mass in the form of water (approximately 75% TBW) than older infants and children (see Fig. 57-3B). Also, the percentage of ECW decreases from the newborn stage (∼45%) into adulthood (∼20-30%). In fact, the increase of TBW in the neonate is attributable to ECW. The reduction in TBW is rapid in the first year of life, with adult values (55%) achieved by approximately 12 years of age. In contrast, the percentage of intracellular water (ICW) as a function of body mass remains stable from the first months of life through adulthood. The impact of developmental changes in body water spaces is exemplified by drugs such as the aminoglycoside antibiotics, compounds that distribute predominantly throughout the extracellular fluid space and have a higher Vd (0.4-0.7 L/kg) in neonates and infants than in adults (0.2-0.3 L/kg).

Body fat percentage and composition increase during normal development. The neonate’s percentage of body fat is approximately 16% (57% water and 35% lipid). Despite the relatively low body fat content in the neonate, the lipid content in the developing central nervous system (CNS) is high, which has implications for the distribution of lipophilic drugs (e.g., propranolol) and their CNS effects during this time period. The body fat percentage tends to increase up to about 10 years of age and then changes composition during puberty with respect to sex to approach adult body fat composition (26% water and 71% lipid). In addition, a sex difference exists as the child ages into adolescence. Whereas the total body fat in boys is reduced by 50% of body mass between 10 and 20 yr of life, the reduction in girls is not as dramatic and decreases from about 28% to 25% of body mass during this same developmental stage.

Albumin, total proteins, and total globulins (e.g., α₁-acid glycoprotein) are the most important circulating proteins responsible for drug binding in plasma. The absolute concentration of these proteins is influenced by age, nutrition, and disease (Table 57-3). The concentrations of most all circulating plasma proteins are reduced in the neonate and young infant (about 80% of adult) and reach adult values by 1 year of age. A similar pattern of maturation is observed with α₁-acid glycoprotein (an acute phase reactant capable of binding basic drugs) where neonatal plasma concentrations are approximately 3 times lower than in maternal plasma and attain adult values by approximately 1 year of age.

Table 57-3 FACTORS INFLUENCING DRUG BINDING IN PEDIATRICS

The extent of drug binding to proteins in the plasma can influence distribution characteristics. Only free, unbound, drug can be distributed from the vascular space into other body fluids and, ultimately, to tissues where drug-receptor interaction occurs. Drug protein binding depends on a number of age-related variables, which can include the absolute amount of proteins and their available binding sites, the conformational structure of the binding protein (e.g., reduced binding of acidic drugs to glycated albumin in patients with poorly controlled diabetes mellitus), the affinity constant of the drug for the protein, the influence of pathophysiologic conditions that either reduce circulating protein concentrations (e.g., ascites, major burn injury, chronic malnutrition, hepatic failure) or alter their structure (e.g., diabetes, uremia), and the presence of endogenous or exogenous substances that compete for protein binding (protein displacement interactions).

Developmentally associated changes in drug binding can occur as a consequence of altered protein concentrations and/or binding affinity. For example, circulating fetal albumin in the neonate has significantly reduced binding affinity for acid drugs such as phenytoin, which is extensively (94-98%) bound to albumin in adults as compared to 80-85% in the neonate. The resultant 6- to 8-fold difference in the free fraction can result in CNS adverse effects in the neonate when total plasma phenytoin concentrations are within the generally accepted therapeutic range (10-20 mg/L). The importance of reduced drug-binding capacity of albumin in the neonate is exemplified by interactions between endogenous ligands (e.g., bilirubin, free fatty acids) and drugs with greater binding affinity (e.g., the ability of sulfonamides to produce kernicterus).

Drug transporters, such as P-glycoprotein, MDR1, and MDR2 (multidrug resistance 1 or 2) can influence drug distribution. These drug transporters can markedly influence the extent to which drugs cross membranes in the body and whether drugs can penetrate or are secreted from the target sites (inside cancer cells or microorganisms, or crossing the blood-brain barrier). Thus, drug resistance to cancer chemotherapy, antibiotics, or epilepsy may be conferred by these drug transport proteins and their effect on drug distribution. Although there are limited data on the ontogeny of drug transport proteins, available information demonstrates their presence as early as 22 weeks of gestation, and low levels in the neonatal period rapidly increase to adult values by 1-2 y of age.

Drug Metabolism

Metabolism reflects the biotransformation of an endogenous or exogenous molecule by one or more enzymes to moieties that are more hydrophilic and thus can be more easily eliminated by excretion, secretion, or exhalation. Although metabolism of a drug generally reduces its ability to produce a pharmacologic action, it can result in metabolites that have significant potency and thereby contribute to the overall pharmacodynamic profile of a drug (e.g., biotransformation of the tricyclic antidepressant amitriptyline to nortriptyline; codeine to morphine; cefotaxime to desacetylcefotaxime; theophylline to caffeine). In the case of prodrugs (e.g., zidovudine, enalapril, fosphenytoin) or some drug salts or esters (e.g., cefuroxime axetil, clindamycin phosphate), biotransformation is required to produce a pharmacologically active moiety. For some drugs, cellular injury and associated adverse reactions are the result of drug metabolism, such as acetaminophen hepatotoxicity or Stevens-Johnson syndrome associated with sulfamethoxazole.

The primary organ responsible for drug metabolism is the liver, although the kidneys, intestines, lungs, adrenals, blood (phosphatases, esterases), and skin can also biotransform certain compounds. Drug metabolism occurs primarily in the endoplasmic reticulum of cells via two general classes of enzymatic processes: phase I, or nonsynthetic, and phase II, or synthetic, reactions. Phase I reactions include oxidation, reduction, hydrolysis, and hydroxylation reactions, and phase II reactions primarily involve conjugation with an endogenous ligand (e.g., glycine, glucuronide, glutathione, or sulfate). As illustrated by Figure 57-3A, many drug-metabolizing enzymes demonstrate an ontogenic profile, with generally low activity present at birth and maturation over a period of months to years (Table 57-4).

Table 57-4 IMPACT OF DEVELOPMENT ON DRUG METABOLISM

Although there are many enzymes that are capable of catalyzing the biotransformation of drugs and xenobiotics, the quantitatively most important are represented by the cytochrome P450 (CYP450) supergene family, which has at least 16 primary enzymes. The specific CYP450 isoforms responsible for the majority of human drug metabolism are represented by CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 (Chapter 56). These enzymes represent the products of genes that in some instances are polymorphically expressed, with allelic variants producing enzymes generally resulting in either no or reduced catalytic activity (a notable exception being the *17 allele of CYP2C19, which conveys increased activity). At birth, the concentration of drug-oxidizing enzymes in fetal liver (corrected for liver weight) appears similar to that in adult liver. However, the activity of these oxidizing enzyme systems is reduced, which results in slow clearance (and prolonged elimination) of many drugs that are substrates for them, including phenytoin, caffeine, diazepam, and many others. After birth, the hepatic CYP450s appear to mature at different rates. Within hours after birth, CYP2E1 activity increases rapidly, and CYP2D6 is detectable soon thereafter. CYP2C (CYP2C9 and CYP2C19) and CYP3A4 are present within the first month of life, a few months before CYP1A2. CYP3A4 activity in young infants can exceed that observed in adults as reflected by the clearance of drugs that are substrates for this enzyme, such as cyclosporine and tacrolimus.

Compared to phase I drug-metabolizing enzymes, the impact of development on the activity of phase II enzymes (acetylation, glucuronidation, sulfation) is not characterized as well. Generally speaking, phase II enzyme activity is decreased in the newborn and increases into childhood. For example, conjugation of compounds metabolized by isoforms of glucuronosyltransferase (UGT) (e.g., morphine, bilirubin, chloramphenicol) is reduced at birth but can exceed adult values by 3-4 yr of age. Also, the ontogeny of UGT expression is isoform specific. Newborns and infants primarily metabolize the commonly used analgesic acetaminophen by sulfate conjugation because the UGT isoforms responsible for its glucuronidation (UGT1A1 and UGT1A9) have markedly reduced activity. As children age, the glucuronide conjugate becomes predominant in the metabolism of therapeutic dosages of acetaminophen. In contrast, the glucuronidation of morphine (a UGT2B7 substrate) can be detected as early as 24 weeks’ gestation.

The activity of certain hydrolytic enzymes, including blood esterases, is also reduced during the neonatal period. Blood esterases are important for the metabolic clearance of cocaine, and the reduced activity of these plasma esterases in the newborn might account for the delayed metabolism (prolonged effect) of local anesthetics in the neonate. In addition, this might account for the prolonged effect that cocaine has on the fetus with prenatal exposures. Adult esterase activity is achieved by 10-12 mo of age.

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