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.

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.

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).

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.

The development of presystemic clearance or first-pass metabolism is unclear given the involvement of multiple enzymes and transporters in the small intestine, many of which have patterns of developmental expression that may be more or less concordant. However, given that the activity of almost all drug metabolizing enzymes is markedly reduced in the neonate, the extent of bioavailability of drugs given by the oral route that may be subjected to significant presystemic clearance in older children and adults would appear to be markedly increased during the first days to weeks of life. It is important for the clinician to recognize that estimates of bioavailability for a host of drugs available in reference texts and therapeutic compendia are most often derived from studies conducted in young adults. Thus, estimates of the rate and/or extent of absorption (including a propensity to be effected by presystemic clearance) from adults cannot be accurately used to extrapolate how a peroral drug dose may need to be age-adjusted for a neonate or infant.

With regard to the impact of development on drug metabolism, most therapeutic drugs are polyfunctional substrates for a host of enzymes and/or transporters. The isoform-specific ontogenic profile (see Fig. 57-3) must be considered in the context of deducing how development can affect the metabolic portion of drug clearance. True developmental dependence of drug clearance (CL) must also consider the role of pharmacogenetic constitution on the activity of enzymes and transporters (Chapter 56) and the impact of ontogeny on the nonmetabolic routes (e.g., renal drug excretion, salivary and biliary drug excretion, pulmonary drug excretion) that contribute to the overall drug clearance (Total CL = CL_hepatic + CL_renal + CL_nonrenal).

Renal Drug Elimination

The kidney is the primary organ responsible for the excretion of drugs and their metabolites. The development of renal function begins during early fetal development and is complete by early childhood (see Fig. 57-3D; Table 57-5). Total renal drug clearance (CL_renal) can be conceptualized by considering the following equation:

where glomerular filtration (GFR), active tubular secretion (ATS), and active tubular reabsorption (ATR) of drugs can contribute to overall clearance. As is true for hepatic drug metabolism, only free (unbound) drug and/or metabolite can be filtered by a normal glomerulus and/or either secreted or reabsorbed via a renal tubular transport protein.

Renal clearance is limited in the newborn owing to anatomic and functional immaturity of the nephron unit. In term and preterm neonates, GFR averages 2-4 mL/min/1.73 m² at birth. During the first few days of life, a drop in renal vascular resistance occurs, which results in a net increase in renal blood flow and a redistribution of intrarenal blood flow from a predominantly medullary to a cortical distribution. All of these changes are associated with a commensurate increase in GFR. In term neonates, GFR increases rapidly over the first few months of life and approaches adult values by 10-12 mo of life (see Fig. 57-3D). The rate of GFR acquisition is blunted in preterm neonates, consequent to continued nephrogenesis, which occurs in the early postnatal period. In children 2 to 5 yr of age, GFR can exceed adult values, especially during periods of increased metabolic demand (e.g., during a fever).

In addition, there is a relative glomerular:tubular imbalance due to a more advanced maturation of glomerular function. Such an imbalance can persist up to 6 mo of age and might account for the observed decrease in the ATS of drugs commonly used in neonates and young infants (e.g., β-lactam antibiotics). Finally, there is some evidence that ATR is reduced in neonates and that it appears to mature at a slower rate than the GFR.

Altered renal drug clearance in neonates and infants result in the different dosing recommendations commonly seen in pediatrics. The aminoglycoside antibiotic gentamicin provides an illustrative example. In adolescents and young adults with normal values for GFR (85-130 mL/min/1.73 m²), the recommended dosing interval for the drug is 8 hr. In young children, who can have a GFR >130 mL/min/1.73 m², a gentamicin dosing interval of every 6 hr may be necessary in selected patients who have serious infections that require maintaining steady-state peak and trough plasma concentrations near the upper boundary of the recommended therapeutic range. In contrast, to maintain “therapeutic” gentamicin plasma concentrations in neonates during the first few weeks of life, a dosing interval of 18-24 hr is required.

The impact of developmental differences in GFR on the elimination characteristics of a given drug can be assessed by estimating the apparent elimination rate constant (Kel) for a drug by using the following equation:

where the Fel represents the fraction of the drug excreted unchanged in an adult with normal renal function, GFR_observed is the value calculated (from creatinine clearance or an age-appropriate estimation equation) for the patient (in mL/min/1.73 m²), GFR_normal is the average value considered for a healthy adult (120 mL/min/1.73 m²), and Kel_normal is estimated from the average elimination T_1/2 for a drug taken from the medical literature using the following equation:

Likewise, the elimination T_1/2 for a drug in patients with reduced renal function can be estimated using the equation as follows:

An estimate of the drug elimination T_1/2 in patients with reduced renal function with knowledge of the desired interdose excursion in steady-state plasma concentrations can provide an ability to determine the desired drug-dosing interval.

Surrogate Endpoints

The assessment of pharmacodynamics in human infants and children has been hampered historically by a relative inability to use invasive methods for the direct assessment of physiologic changes produced by drug effect. As a result, surrogate endpoints and biomarkers have been explored and, in some cases, used to evaluate the impact of ontogeny on pharmacodynamics.

Biomarkers and surrogate endpoints (markers) are ideally simple, reliable, inexpensive, and easily obtainable measures of a biologic response or disease phenotype that may be used to facilitate clinical research or patient care. A biomarker has been defined by the National Institutes of Health as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.” A surrogate endpoint is defined as “a biomarker that is intended to substitute for a specific clinical endpoint. A surrogate endpoint is expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence.” Surrogate endpoint and surrogate marker are often used interchangeably in the literature, although the use of the term “surrogate marker” is discouraged because it suggests that a substitution is being made for the biologic marker instead of the clinical endpoint.

Reliable surrogate endpoints predict a specific physiologic event (e.g., gastroesophageal reflux), which may be used in diagnosis, in prognosis, or in predicting a specific drug response (therapeutic, subtherapeutic, or adverse). They may be used instead of true clinical effect or efficacy measures when the endpoint is difficult to measure consequent to considerations implicit in performing invasive procedures in pediatric patients, and they may be used in studies of reasonable cost, size, and duration. Surrogate endpoints may also be used to evaluate drug safety and, potentially, to evaluate the impact of ontogeny on pharmacodynamics.

Specific examples of surrogate endpoints used in pediatric pharmacology include (but are not limited to) measurement of esophageal pH to assess the action of prokinetic or acid-modifying drugs, gastric scintigraphy and stable isotope-labeled compounds (e.g., ¹³C-acetate, ¹³C-octanoic acid) to assess gastric emptying rate, and pulmonary function tests (e.g., forced expiratory volume in 1 sec [FEV₁]) to evaluate the effects of drugs on pulmonary function in patients with conditions such as asthma and cystic fibrosis. Biomarkers that have been used in pediatric studies to assess drug disposition or effect include (but are not necessarily limited to) urinary excretion of 6-β hydroxycortisol (to assess induction of CYP3A4), hemoglobin A_1c plasma concentration (to assess efficacy of peroral hypoglycemic agents), urinary leukotriene concentrations (to assess effects of nonsteroidal anti-inflammatory drugs), minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) of drugs to selected anti-infective agents, hybrid pharmacokinetic-pharmacodynamic parameters (e.g., MIC/AUC and % time above MIC) to comparatively assess antibiotic and antimycobacterial drug regimens, and genotypes of drug receptors and metabolizing enzymes that have a predictive association with either pharmacokinetics (e.g., CYP2C19 and proton pump inhibitors) or pharmacodynamics (e.g., leukotriene synthase and drugs that inhibit the enzyme).

Pediatric Dosage and Regimen

Historically, the pediatric dosage was determined from the child’s weight relative to an adult’s; if the dosage of a drug for a 100-kg adult was 500 mg, the pediatric dosage for a child weighing 20 kg would be 100 mg. When known developmental differences in drug disposition are considered, this old approach was, in most cases, not effective in producing a degree of systemic drug exposure in a pediatric patient approximating that in an adult.

Developmental profiles for hepatic and extrahepatic drug-metabolizing enzymes and drug transporters that can influence drug clearance and/or bioavailability are incomplete. The lacunae in this information prevent us from using simple formulas and/or allometric scaling to predict the effective pediatric dosage. These approaches may have some potential clinical utility in children >8 years of age and adolescents, whose organ function and body composition approximates that of young adults, but their utility is severely limited in neonates, infants, and young children where ontogeny produces dramatic differences in drug disposition. This is especially problematic for therapeutic drugs whose dosages cannot be easily individualized using patient-specific pharmacokinetic data obtained from therapeutic drug monitoring. In the absence of such pharmacokinetic data and/or established pediatric dosing guidelines, alternative methods often must be employed.

More than 20 different approaches have been described for selecting an initial dosage for pediatric patients. The majority of these use either total body weight (BW) or body surface area (BSA) as surrogates reflecting the developmental changes of either body composition or organ function, which collectively are major determinants of drug disposition. Selecting a dosage based on BW or BSA generally produces similar relationships between drug dosage and resultant plasma concentration, except for drugs whose apparent Vd corresponds to the extracellular fluid pool (i.e., Vd <0.3 L/kg), in which a BSA-based approach is preferable. In contrast, for drugs whose apparent Vd exceeds the extracellular fluid space (i.e., Vd >0.3 L/kg), a BW-based approach for dosage selection is preferable and is the most commonly used method in pediatrics. When the pediatric dosage for a given drug is not known, these principles can be used to best approximate a proper dosage for initiating treatment, as is illustrated by the following equations:

This approach assumes that the child’s weight, height, and body composition are age appropriate and normal and that the “reference” normal adult has a BW of 70 kg and BSA of 1.73 m². It is useful only for selecting dosage size and does not offer information regarding dosing interval because the equations contain no specific variable that describes potential age-associated differences in drug clearance.

In neonates and young infants with developmental immaturity in either glomerular filtration or active tubular secretion, it is often necessary to adjust the dosing interval (i.e., that used for older infants and children who have attained developmental competence of renal function) for drugs with >50% renal elimination so as to prevent excessive accumulation of drug (and possible associated toxicity) with administration of multiple doses. To accomplish this therapeutic goal, it is necessary to estimate the apparent elimination T_1/2 of the drug.

Monitoring Drug Levels

Drug response (either therapeutic or toxic) occurs only as a consequence of drug exposure. Clinically, systemic drug exposure is most commonly evaluated through assessing the plasma drug concentration, a surrogate measurement for a drug reaching its pharmacologic receptor(s).

In the patient, drug level monitoring can be used to facilitate two approaches for evaluating the dose-concentration-effect relationship: therapeutic drug monitoring and pharmacokinetic-based individualization of dosage (clinical pharmacokinetics). Therapeutic drug monitoring largely entails a retrospective, reactive approach whereby drug concentrations in plasma (primarily) or other biologic fluids are measured at some point during a constant-rate intravenous infusion or during a dosing interval for drugs given by intermittent dosing schedules. These levels are then compared with desired levels for a given drug based on published information and are used to adjust the dosage or dosing regimen in a quasi-empirical fashion. For many drugs that are therapeutically monitored in the clinical setting (e.g., aminoglycoside antibiotics, vancomycin, phenytoin, phenobarbital, cyclosporine, tacrolimus, mycophenolate mofetil, selected antiretroviral drugs, acyclovir), desired plasma concentrations are generally determined from studies in adult patients, and their drug disposition and disease states may be quite different from those in infants and children.

In contrast to therapeutic drug monitoring, clinical pharmacokinetics represents a prospective, proactive approach where plasma drug concentrations are used to estimate pharmacokinetic parameters (e.g., apparent elimination rate constant, elimination T_1/2, apparent volume of distribution, total plasma clearance, area under the plasma concentration vs. time curve), which are then used to calculate a dosing regimen to attain a desired level of systemic exposure (e.g., AUC, steady-state peak and/or trough plasma drug concentrations) that would portend a desired pharmacologic response. Of these 2 approaches, the use of drug level data for performing clinical pharmacokinetics provides the optimal approach for individualizing the dosage and dosing regimen and maintaining some adaptive control over the dose-concentration-effect relationship. This approach is particularly useful for patients who by virtue of their age and/or disease states have “abnormal” pharmacokinetics. Approaches include the using established formulas for manually calculating pharmacokinetic parameters (generally using a simple 1-compartment open model consequent to the few plasma drug level observations obtained in the context of clinical care) or using computer-based algorithms (e.g., Bayesian estimation, population-based pharmacokinetic approaches).

Common to both of these approaches is the need to accurately assess plasma drug concentrations in a given patient. Figure 57-5 represents a hypothetical general steady-state plasma concentration vs. time profile for a drug given by an extravascular route. It is provided to illustrate the following general principles to be recognized and followed when plasma drug level monitoring is used in patients as a tool to individualize drug treatment:

Figure 57-5 Plasma concentration vs. time profile for a hypothetical drug at steady state. When dose size, route of administration, time of administration, and dosing interval remain constant, the resultant true peak (C_max) and trough (C_min) plasma concentrations and area under the plasma level–time curve (AUC) from dose to dose are identical. Apparent values for C_max and C_min are denoted to illustrate the potential difference from true values that can result when the actual times for obtaining samples for either therapeutic drug monitoring or clinical pharmacokinetic applications are not realized.

To reliably interpret any drug plasma concentration, it is imperative that the clinician know and consider the following:

This last point is illustrated by Figure 57-5, which denotes the “true” peak (C_max) and trough (C_min) plasma concentrations in relation to apparent values, a situation that often occurs when “peak” and “trough” blood levels are ordered and nursing or phlebotomy procedures allow some period of leeway as to when they can be obtained. When such a discrepancy is noted and the exact timing of the samples relative to dose administration is known, corrections can be made to ensure that pharmacokinetic parameters estimated from the data are accurate. If a discrepancy is not noted, the parameters can be incorrectly estimated and the dosing regimen can be incorrectly calculated, thereby compromising the safety and/or efficacy of drug treatment.

Drug Formulation and Administration

One of the more unusual challenges in pediatric therapeutics is the drug formulation itself. Although researchers are more sensitive to the need to study drugs in children before they are used in children and to have “pediatric-friendly” formulations, many drug products that are formulated only for use in adults are routinely given to pediatric patients. Their use can result in inaccurate dosing (e.g., administration of a fixed dose to children with widely varying body weights), loss of desired performance characteristics of the formulation (e.g., crushing a sustained-release tablet or cutting a transdermal patch), and exposure of infants and children to excipients (e.g., binding agents, preservatives) in amounts capable of producing adverse effects.

Adherence and Compliance

In addition to the previously discussed considerations, the success of drug treatment in a pediatric patient depends upon successfully administering the drug. Physical and cognitive immaturity make the infant and the child a dependent creature in almost all respects, including those related to administration of a therapeutic drug. Until children reach an age at which they can self-administer a drug in an accurate, proficient fashion and can mentally assume responsibility for it (generally 7-14 yr of age, depending on the child), compliance with a drug regimen becomes the responsibility of an adult. In a hospital environment, compliance is ensured through the actions of physicians, nurses, and pharmacists who, collectively through an integrated system of medical care, assume this responsibility. Upon discharge, the responsibility is transferred to an adult caregiver in a nonmedical environment. At this juncture, therapeutic compliance becomes a function of adherence as defined by the conflicting demands (e.g., multiple adult caregivers; different external environments such as home, daycare, school; parents tending to the needs of multiple children) that can introduce variability (anticipated and unpredictable) in drug administration. Whether treatment is for a self-limiting condition (e.g., antibiotic administration) or a chronic one (e.g., asthma, diabetes), challenges to therapeutic adherence have the potential to serve as rate-limiting events in determining drug safety and efficacy in infants and young children.

In contrast to the period encompassing infancy and childhood, adolescence poses its own unique challenges to therapeutic adherence. During this period, psychosocial maturation almost always lags behind physical maturation. Development of cognitive and physical skills in most adolescents enables them to properly self-administer a prescribed medication with little or no supervision. However, many adolescents experience psychodynamic issues that can precipitate therapeutic failure, through either undertreatment or overtreatment, the latter occasionally leading to drug toxicity. Some of these issues include incomplete understanding of the ramifications of undertreatment, disease progression, roles of disease prevention, roles of health maintenance; perceptions of immortality and the lack of need for treatment; disorganized patterns of thinking that can confounding treatment schedules; and defiant or oppositional behavior toward authority figures. Unfortunately, only the combination of vigilance by all caregivers and repetitive education coupled with positive reinforcement can facilitate therapeutic compliance and adherence in the pediatric patient. When children reach the age of assent (generally by 7 yr of age), they have elementary understanding about their medical condition(s) and how effective treatment can be used to improve their life. Through diligent educating and reeducating, older children and adolescents can assume a level of responsibility for active partnership in their overall medical management, which will mature as educational efforts are regularly made.

Drug-Drug Interactions

Pharmacokinetic and/or pharmacodynamic properties of drugs may be altered when 2 or more drugs are administered. Although interactions largely occur at the level of drug metabolism, they can occur at the level of drug absorption (e.g., inhibition of intestinal CYP3A4 activity by grapefruit juice or St. John’s wort and consequent reduction in presystemic clearance of CYP3A4 substrates), distribution (e.g., displacement of warfarin plasma protein binding by ibuprofen with consequent increased hemorrhagic risk), or elimination (e.g., inhibition of active tubular secretion of β-lactam antibiotics by probenecid). Drug-drug interactions can occur at the level of the receptor (via competitive antagonism); many of these are intentional and produce therapeutic benefit in pediatric patients (e.g., antihistamine reversal of histamine effects, naloxone reversal of opiate adverse effects) (Tables 57-6 and 57-7).

Table 57-6 PARTIAL LISTING OF DRUG INTERACTIONS OF POTENTIAL IMPORTANCE IN PEDIATRIC PRACTICE

CNS, central nervous system; ?, possible effect.

* When possible, an alternative drug combination should be given. Otherwise, drug levels and signs of toxicity must be monitored.

Modified from Rizack M, Hillman C: The Medical Letter handbook of adverse drug interactions, New Rochelle, NY, 1989, The Medical Letter.

Table 57-7 PARTIAL LISTING OF ANTI-VIRALS USED TO TREAT HIV AND DRUG INTERACTIONS OF POTENTIAL IMPORTANCE IN PEDIATRIC PRACTICE*

* This table is not meant to be an all-inclusive list of drug-drug interactions. Care should be taken when prescribing all medications, and the potential of interactions should be considered. The practitioner is encouraged to assess the possibility of all interactions when prescribing medications.

† Considered to be drugs that are a contraindicated drug-drug interaction. An alternate drug combination should be given. If not possible, drug levels and signs of toxicity must be monitored.

Micromedex® 2.0. Thomson Reuters. Copyright 1974-2010.

Drug-drug interactions that occur at the level of drug metabolism can be somewhat predictable based on a priori knowledge of a given drug’s biotransformation profile. Information pertaining to drug-substrate interaction can be useful in ascertaining the direction (e.g., enzyme inhibition → reduced clearance → higher plasma concentration → enhanced effect vs. enzyme induction → increased clearance → reduced plasma concentration → diminished effect) of a drug-drug interaction. This information can be found in primary and secondary literature and drug labeling, but it might not be complete or updated. The data compilation from Indiana University (http://medicine.iupui.edu/clinpharm/ddis) appears to be the most complete and useful.

Drug interactions can also occur at a pharmaceutical level as a result of a physicochemical incompatibility of two medications when combined. Such interactions generally alter the chemical structure of one or both constituents, rendering them inactive and potentially dangerous (e.g., intravenous infusion of a crystalline precipitate or unstable suspension). For example, ceftriaxone should be avoided in infants <28 days of age if they are receiving or expected to receive intravenous calcium-containing products because neonates have died as a result of crystalline deposits in the lungs and kidneys. Alternatively, 2 drugs simultaneously administered perorally can form a complex that can inhibit drug absorption (e.g., co-administration of doxycycline with a food or drug containing divalent cations).

Over-the-counter (OTC) preparations, herbal supplements, and certain foods also have the potential to produce interactions with drugs. These are often challenging for the clinician, especially the alternative therapies, because composition (or potency) might not be discernable from the product labels and because many of these products have not been studied in children or adults. Many patients and their parents do not consider alternative therapies (including nutriceuticals) to be “medicines” but rather to be safe “nutritional supplements,” and they do not disclose their use during a routine medication history. An assessment, therefore, should begin with a thorough medication history that should include discussions of any OTC medications and herbal products that are used and how often. This allows the clinician to identify the primary ingredients contained in these products and query their potential for producing clinically significant drug-drug interactions.

One of the most daunting challenges for the clinician is to determine if a drug-drug or drug-food interaction will be clinically significant. Extensive databases of reported and/or potential (e.g., theoretical mechanism- or metabolism-based) drug interactions exist and are widely available on the Internet (e.g., http://www.medscape.com/druginfo/druginterchecker; http://www.drugs.com; http://www.umm.edu/adam/drug_checker.htm); some of these assess the potential significance of the interaction. Many computer-based information systems used by hospital and community pharmacies routinely screen a patient’s medication profile (generally restricted to prescribed drugs) against new prescriptions to evaluate the potential for drug-drug interactions.

To provide individualized, optimal drug therapy, the clinician must assess potential drug-drug interactions and their significance. This requires knowledge of the interaction, the patient’s condition, concomitant treatments (prescriptions, OTC drugs, alternative medicines), the impact of development on the dose-concentration-response relationship, and a consideration of the risk:benefit profile of the drug being prescribed. If the clinician considers a potential drug-drug interaction a contraindication to using a drug, an alternative drug choice could produce less benefit or greater risk. Although many drugs have the potential to cause drug interactions, not all cases are deemed clinically relevant. For patients with complex histories requiring multiple medications, consultation with a clinical pharmacologist or pharmacist can help provide guidance on drug-drug interactions and their potential to affect therapy.

Adverse Drug Reactions

Adverse drug reactions (ADRs) have been defined by the World Health Organization as “a response to a drug that is noxious and unintended, and occurs at doses normally used in man for the prophylaxis, diagnosis or therapy of disease or for the modification of physiological function.” In the pediatric population, ADRs are common and a major burden to patients and the health care system. Studies concerning ADRs in pediatric patients suggest that ∼9% of all pediatric patients admitted to the hospital experience an ADR during their treatment, the apparent incidence of ADRs in children in outpatient clinics is ∼1.5%, ADRs have been reported as being responsible for >2% of pediatric admissions to children’s hospitals, and ∼40% of ADRs occurring in hospitalized children are potentially life-threatening. In considering these “statistics” it should be recognized that the true incidence of ADRs in children is not known because they are under-reported by health care providers (physicians > nurses > pharmacists), parents and caregivers, and patients, who might not recognize signs and symptoms and/or might not be able to report them. Many countries, including the USA, lack a standardized surveillance and real-time reporting system. Thus, estimated incidence of ADRs relies on spontaneous reporting under volunteer reporting systems that lack uniformity and critical evaluation and that do not provide the numerator and denominator data necessary to determine true incidence.

Despite the limitations associated with determining the incidence of ADRs in children, it is estimated that their occurrence in patients 0 to 4 years of age (3.8%) is more than double that seen at any other time during childhood and adolescence. The reasons for this are not currently known but might involve developmental differences in pharmacokinetics, and/or pharmacodynamics (i.e., altered dose-concentration-effect relationship), age-associated differences in physiologic “systems” that modulate drug- and/or metabolite-mediated cellular injury (e.g., the immune system), and/or the therapeutic use of drugs known to have a relatively high incidence of producing ADRs (e.g., delayed hypersensitivity reactions associated with β-lactam antibiotics). Also, it is important to recognize that infants can experience ADRs from drugs that are not administered to them therapeutically but rather from drug exposure occurring as a result of transplacental drug passage and/or breast-feeding. Examples include neonatal abstinence syndrome associated with maternal opiate use, production of a hyperserotoninergic state in neonates born to mothers who received selective serotonin reuptake inhibitors during pregnancy, and opiate toxicity in breast-fed infants whose mothers were taking codeine for pain. In these instances, drug accumulation can result from reduced activity of drug-metabolizing enzymes associated with development and, potentially, pharmacogenetically determined phenotypic changes that, in concert, can produce a level of systemic drug exposure capable of producing exaggerated drug response or frank toxicity.

Some ADRs occur much more commonly in infants and children than in adults. Examples include aspirin-associated Reye syndrome, cefaclor-associated serum sickness–like reactions, lamotrigine-induced cutaneous toxicity, and valproic acid (VPA)-induced hepatotoxicity in infants <2 yr of age. It is not clear whether the age predilection for these specific ADRs are associated with developmental differences in drug biotransformation that relate to metabolite formation and detoxification or that have a pharmacogenetic basis. Children, like adults, do experience hypersensitivity reactions to drugs. Examples include hypersensitivity reactions to anticonvulsant drugs (e.g., phenytoin, carbamazepine, phenobarbital), sulfonamides (e.g., sulfamethoxazole, sulfasalazine), minocycline, cefaclor, and abacavir. These ADRs are not characteristic of type I (i.e., immediate) hypersensitivity reactions (e.g., true penicillin allergy) or anaphylactoid reactions but have been previously classified as idiopathic. A relatively common constellation of symptoms (fever, rash, lymphadenopathy) suggests that abnormal activation or regulation of the immune system is a predominant component of their pathogenesis. Data from in vitro studies of sulfamethoxazole hypersensitivity also support this assertion. A role for metabolic bioactivation (for anticonvulsants, sulfamethoxazole, cefaclor) and, possibly, genetic factors such as allelic variants in HLA-B (e.g., HLA-B*5701 and HLA-B*1502 associated with hypersensitivity reactions to abacavir and carbamazepine) appears also to be involved in their etiology.