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After completing this article, readers should be able to: Rapid age-related physiologic changes in the pediatric age group, especially during the first postnatal year, affect the absorption, distribution, metabolism, and elimination of drugs. This article reviews pharmacokinetic principles in neonates, infants, and children to help pediatricians understand the rationale for drug therapy and toxicity in these patients.Drugs are administered through a wide range of routes (Table 1). General pharmacokinetic and pharmacodynamic principles can be defined by grouping them in two major routes: intravascular and extravascular. Extravascular administration entails absorption, distribution, metabolism, and excretion. Bioavailability is the fraction of drug reaching the systemic circulation following its administration by any route. Because drugs administrated intravenously do not require an absorption process, their bioavailability is 100%.Among the extravascular routes, oral administration commonly is used not only because it is painless, but also because technology involved in oral formulations is relatively less costly and requires fewer pharmaceutical processes. However, in some cases, the choice of administration route depends on the site of action, the desired plasma drug concentrations, and the time at which a certain drug concentration must be achieved. Bioavailability after oral administration naturally is less than after intravenous administration. The primary factors affecting oral bioavailability are listed in Table 2.Gastric emptying is slow (6 to 8 h) in neonates and infants. Consequently, the rate at which most orally administrated drugs are absorbed is slower in neonates and young infants, and the time to achieve the maximal plasma concentrations (Tmax) and, therefore, the therapeutic effect may be prolonged.Gastric pH is neutral at birth and decreases to 1 to 3 within 24 hours. Hence, acid-labile drugs such as penicillin G, amoxicillin, nafcillin, and erythromycin are absorbed more efficiently in neonates and infants than in adults when administrated orally. Oral absorption of drugs that are weak acids, such as phenobarbital, has been shown to be lower in infants than in older children and adults.Food intake stimulates gastrointestinal secretions, hormones, and bile salts (which lower gastric pH), delays stomach emptying, and increases gastrointestinal transit time. Fluid volume and dietary fat in the meal appear to be the primary food-related factors affecting drug absorption. Meals can alter the absorption rate of sustained-release drugs such as theophylline, making it unpredictable. Iron absorption is facilitated by meat ingestion. Multivitamins containing iron and calcium interfere with the absorption of various medications, such as levothyroxine, tetracycline, fluoroquinolones, captopril, and folic acid.The activity of gastrointestinal enzymes (eg, pancreatic enzymes) is low in infants younger than 4 months of age. Absorption of lipid-soluble drugs is decreased in neonates due to low production of lipase and bile acids. Peristalsis also may affect drug absorption. Prokinetic agents, such as cisapride, have been shown to increase the absorption of morphine, diazepam, and cyclosporin. In the neonate, peristalsis is irregular, making the absorption of drugs in the small intestine highly variable. Diarrhea shortens intestinal transit time and may decrease the absorption of sustained-release formulations.Rectal administration of drugs that have a large first-pass effect, such as diazepam, have been used effectively in children. Diazepam bioavailability is higher following rectal than oral administration by circumventing the portal system. Midazolam also is more effective when administrated rectally compared with intramuscular injection. The absorption time of rectal acetaminophen suppositories is greater among infants younger than 3 months of age versus older infants.Absorption following intramuscular administration depends on various factors inherent to the drug (eg, lipophilicity versus water solubility), the site of administration, and blood supply to and from the injected site. The latter may be compromised in newborns whose peripheral perfusion is poor. Muscular mass and activity also are decreased in neonates compared with older children.For certain dermatologic conditions, the topical route of administration is easier, faster, and safer, minimizing systemic adverse effects. Transdermal absorption and systemic exposure to drugs, such as corticosteroids, antihistamines, and antiseptics, may be increased in children, particularly in neonates and infants, due to increased body surface area and thinner epidermis and stratum corneum.Administration of drugs via inhalation is used commonly in children. The primary goal is to achieve a localized pulmonary effect, although systemic exposure occurs (eg, inhaled corticosteroid therapy for asthma).Independent of the route of administration, once the drug enters the bloodstream, it is distributed into various compartments of the body. Drug distribution varies significantly with age due to developmental changes in body composition, protein binding, hemodynamic factors (cardiac output, tissue perfusion), and membrane permeability.The preterm neonate has more total body water (80% of total body weight) compared with a term neonate (70% to 75%) and the adult (50% to 60%). The extracellular water compartment is about 40% of total body weight in the neonate compared with 20% in the adult. These changes result in a relatively higher volume of distribution and lower concentration of water-soluble drugs at receptor sites in neonates and infants compared with adults. For example, the volume of distribution of gentamicin is 0.5 to 1.2 L/kg in neonates and infants and 0.2 to 0.3 L/kg in adults. This effect translates to a need for larger doses in younger infants.Total body fat in preterm neonates may be as low as 1% of total body weight compared with about 15% in term neonates, about 25% in 4-months-old babies, and about 20% in adults. Therefore, the volume of distribution of lipid-soluble drugs, such as diazepam and flunitrazepam, is less in preterm neonates compared with those in other age groups.Drug distribution may be limited by certain permanent natural barriers (eg, blood brain barrier [BBB] and placenta). The BBB, however, may be altered by infectious diseases, traumatic lesions, or surgical procedures. Certain drugs (eg, morphine) evidence higher permeability through the BBB in neonates.Plasma protein binding indicates how much of the total amount of a drug in plasma is bound to plasma proteins. Because only the unbound fraction of the drug reaches the receptors to exert the therapeutic or toxic effects, the extent of protein binding is important. Albumin and alpha1-acid glycoprotein are the two major drug-binding proteins in plasma. Albumin has higher binding affinity for acidic compounds and alpha1-acid glycoprotein for basic compounds. Lipoproteins are other plasma proteins whose primary physiologic role is to synthesize and transport endogenous fatty acids such as triglycerides, phospholipids, and cholesterol. These proteins also are important in the binding of very lipophilic or basic compounds. Other specific proteins contribute to plasma binding and transport of certain endogenous compounds, including hormones. The red and white blood cells and platelets also can bind drugs, especially basic compounds.Protein binding usually is reversible, although covalent binding may occur occasionally (eg, with alkylating compounds). The fraction of the total drug in plasma that is bound to proteins is determined by the drug concentration, its affinity for the binding sites, and the number of available binding sites. Protein binding is a saturable and nonlinear process. However, for most drugs, the therapeutic range of plasma concentrations is limited, and the ratio between bound and unbound fraction of the drug is relatively constant. Hypoalbuminemia due to severe liver or kidney disease, malnutrition, or cystic fibrosis may result in reduced drug binding, increasing the unbound fraction of plasma drug concentration. Burns, surgery, trauma, inflammatory processes, and malignancy may increase alpha1-acid glycoprotein serum concentrations, enhancing the binding of basic drugs. Plasma protein levels are decreased in neonates and during the course of nephrotic syndrome.Several endogenous substances may compete for plasma protein binding sites, reducing the bound fraction of a compound in neonates. Hyperbilirubinemia, for example, reduces the protein binding for ampicillin, penicillin, phenobarbital, and phenytoin, whereas some drugs such as sulfonamides can displace bilirubin from albumin binding sites, leading to more profound neonatal jaundice.Drugs may be eliminated unchanged from the plasma by renal and bile excretion or following hepatic metabolism. After liver biotransformation, metabolites, which may be pharmacologically active or inactive, can be eliminated by either renal or biliary excretion or both. Some drugs exhibit enterohepatic recirculation, which involves drug excretion in bile into the small bowel and subsequent reabsorption by the portal system into the liver. Certain drugs are metabolized by enzymatic systems that may be saturated at certain serum concentrations. This form of elimination is known as Michaelis-Menten elimination kinetics. However, most plasma drug concentrations typically decay at a constant rate. The half-life of any drug is the time at which a certain plasma concentration decays by 50%. This elimination process is known as first-order elimination kinetics, and the half-life of each drug is constant until the drug is completely eliminated from the systemic circulation.Clearance rate is the measure of the body’s ability to eliminate a drug from plasma and is defined as the unit of blood volume (mL) cleared of the drug per unit of time (hour). Changes in clearance rate affect half-life inversely. If a drug undergoes hepatic clearance, a patient who has liver disease exhibits a lower clearance rate and longer half-life of certain drugs. Drug accumulation may become a problem in certain cases. Similar conclusions can be derived for a drug that is cleared renally in a patient who has renal failure. However, pharmacokinetics in a patient who has hepatic failure and receives a drug that is primarily cleared renally are not significantly affected unless other systemic changes affect the renal function directly or indirectly. Similar conclusions apply to a patient who has renal failure and is receiving a drug cleared mainly by the liver. Biotransformation and renal elimination of drugs often exhibit differences between newborns and older children due to immature systems, and differences may be more evident when immaturity is combined with disease.In general, metabolism transforms lipophilic parent drugs to more hydrophilic metabolites, which can be excreted readily into bile or urine. Drug metabolism can be divided into two different types of reactions: phase I and phase II metabolism. Phase I metabolism generally results in either the introduction of a functional group into the parent compound (eg, by oxidation, reduction, or methylation) or the exposure of new functional groups of the parent drug. Phase I metabolism reaches maximal maturity by 1 year of age. Phase II metabolism involves conjugation of functional groups of molecules with hydrophilic endogenous substrates (eg, glutathione conjugation, glucuronidation, sulfation, acetylation). In neonates, these processes progress at a substantially lower rate than in adults (50% to 70%).Glucuronidation reaches its full maturity by 3 to 4 years of age. Cytochrome P450 (CYP) mono-oxygenases play a role in the metabolism of various endogenous compounds, such as steroid hormones, bile acids, fat-soluble vitamins, and fatty acids, and are responsible for the metabolism of more than 85% of the drugs available for clinical use. The CYP mono-oxygenases are classified according to the extent of amino acid sequence identity of different enzymes rather than catalytic activities or substrate specificity. CYP3A4 is responsible for the metabolism of about 50% of drugs on the market, followed by CYP2D6 (25%), CYP2C9 (15%), and CYP1A2 (5%). Other classes are involved in the metabolism of about 5% of drugs. These processes mature at different ages. CYP1A2 is not available in fetal or in early neonatal microsomes. It is the last hepatic CYP to develop, and its concentrations rise progressively and reach 50% of the adult value at 1 year of age or older.Other enzymatic systems also are relevant in newborns, especially among preterm infants. About 85% of theophylline is metabolized in adults, and its plasma elimination half-life is approximately 9 hours. Approximately 95% of caffeine is metabolized, and its plasma half-life ranges from 3 to 7 hours. By comparison, the half-lives for these two compounds in the preterm infant are 50 hours and 20 to 36 hours, respectively. In neonates, only 10% of theophylline is methylated to caffeine, with 50% of the drug excreted unchanged in urine.As the hydroxylation and acetylation activities of hepatic enzymes mature in infants and young children, the clearance rate of theophylline increases, and the half-life decreases to 3 to 5 hours (compared with 9 h in adults).Some drugs may increase hepatic metabolism by inducing CYP subfamilies or other enzymatic systems, decreasing the half-life of many drugs. This effect is evident among the older antiepileptic drugs. Phenobarbital competitively interferes with the biotransformation of other drugs as well as endogenous substrates, such as steroid hormones, cholesterol, bile salts, and vitamins K and D. Carbamazepine induces hepatic metabolism and may lower concentrations of phenytoin, valproic acid, lamotrigine, and topiramate administered concurrently and induces the conversion of primidone to phenobarbital. Inversely, phenobarbital, phenytoin, and valproate may increase the metabolism of carbamazepine.Among neonates born to mothers who received phenobarbital during pregnancy, the ability of the neonate to metabolize certain drugs is greater than expected due to enzyme induction, leading to subtherapeutic plasma drug concentrations because of early maturation of fetal hepatic enzymes.Two major pathways of renal elimination of drugs and their metabolites are apparent: glomerular filtration and tubular secretion. As blood passes through the glomerular capillaries, the plasma is filtered through the glomerular capillary walls. Although glomerular filtration begins around the ninth week of fetal life, this function is not necessary for normal intrauterine homeostasis because the placenta serves as the major excretory organ. After birth, the glomerular filtration rate (GFR) increases. The GFR is approximately 2 to 4 mL/min per 1.73 m2 in term newborns and only 0.6 to 0.8 mL/min per 1.73 m2 in preterm newborns. It increases rapidly during the first postnatal week to reach 40 mL/min per 1.73 m2 in term neonates and 15 mL/min per 1.73 m2 in preterm neonates. By the end of the third postnatal week, the GFR is 50% to 60% of the adult value. At 3 to 6 years of age, the GFR exceeds adult values (per kg).In general, filtration of molecules that have a molecular weight of up to 5,000 is not restricted. As molecular size increases, filtration decreases and approaches almost zero for compounds that have a molecular weight of 68,000, such as albumin. Another important mechanism that limits protein filtration is ionic charge. Endothelial cells, basement membrane cells, and epithelial cells of the glomerular capillary wall have strong negative ionic charges. Proteins have a net negative charge and, consequently, are repelled, thereby restricting their filtration.Aminoglycosides are excreted almost entirely by glomerular filtration, and although excretion of these antimicrobials is similar in adults and children older than 6 months of age, elimination half-lives of the drugs may be prolonged significantly in the newborn. Tubular function capacities also are decreased in neonates due to a reduced GFR, tubular cell immaturity, reduced nephron length, reduced medullary solute gradient, and diminished tubular responsiveness to antidiuretic hormone.The ability to concentrate urine in infants is reduced compared with older children and adults—600 to 700 mOsm/kg H2O versus 1,000 mOsm/kg H2O, respectively. Tubular drug secretion in children and adolescents, however, can be greater than in adults. Drugs may be secreted at the proximal tubule by active transport through the tubular membranes. Organic anions and cations are secreted into proximal tubules by separate transport processes. Some drugs, such as quinidine and amiodarone, may inhibit tubular secretion of digoxin by the P-glycoprotein a increase in serum digoxin concentration, in are responsible for neonatal failure of the drug to be with acid due to activity of in the liver of the first postnatal and renal excretion of drug by the newborn. plasma concentrations of because its tubular secretion is decreased in the immature neonatal the administration of the pharmacokinetics of any drug from those after a Drug administration may be at to its elimination each drug concentration and However, after about drug elimination drug and the rate of in the amount of the drug in the body This is known as and the time to reach it depends only on the It is of the The concentrations at are to the and to the ratio between drug in plasma and clearance rate. The for different drugs (eg, such as phenobarbital and at reaching the therapeutic range not the The varies in of the age (Table Although volume of distribution also may affect differences are due primarily to the maturation of liver enzymatic of serum drug concentrations is when the between drug concentration and is a of is not the drug has a therapeutic range with the of therapy is to from the in drug is and a small is on and a drug concentration within a therapeutic within the therapeutic however, some do not achieve the expected effect, and toxic adverse effects. In general, should be at serum concentrations after to In specific cases, the time to first may of theophylline is due to its may appear after administration. are relatively at concentrations 40 but and have at plasma concentrations as low as Although in adults, the conversion of theophylline to caffeine is an important in infants, and of caffeine may be after doses of also is for For or a to a and a after intramuscular or intravenous administration are at The concentration is used to the therapeutic concentration for levels have been with a of and The concentration is to by drug levels are for administered once should be used when the desired therapeutic are not after administration of a of when an amount of digoxin has been administered or when renal function is drug are and when a toxic is of blood should be to a but at 4 hours after the last drugs can be by plasma concentrations. For example, diazepam metabolites a large of the desired effect but be effectively by the parent drug. Similar are with drugs that are of a of of which is significantly more For many other drugs (eg, certain is between serum concentrations and of of the or of of drug by or administration of drug. These can occur at pharmacokinetic limited are available the of immature enzyme systems on drug in infants and young children, due to and it is to drug from other such as disease processes and factors (eg, in the gastrointestinal may decrease the oral bioavailability of the drug. The rate and extent of oral absorption of many drugs such as and can be significantly by oral administration of or compounds. in the rate of gastric emptying by certain drugs the rate of absorption of the drug. Drug also may result from of plasma drugs by other drugs that have a higher affinity for the protein binding sites protein The most drug are those affecting hepatic Some of these differences have been to differences in the maturation of different enzymatic systems, primarily of the CYP in children, such as and have on hepatic enzymatic systems, reducing the metabolism of drugs such as theophylline, corticosteroids, and In such cases, toxicity may In phenobarbital, and are enzymatic that increase the metabolism of other drugs metabolized by the decreasing their plasma concentration and In this the of the drug may need to be is expected that as enzymatic systems mature specific drug that are in adults may For example, topiramate pharmacokinetics with age, and that drugs as phenytoin, phenobarbital, and significantly lower topiramate plasma enzymes also are involved in the metabolism of and may and especially in early However, the metabolism by CYP enzymes is more that fetal can metabolize different drugs and that exposure to those in may result in to metabolize drugs in elimination may be decreased by administration of medications, especially for drugs that are excreted by the For example, can inhibit tubular secretion of leading to adverse drug which are and are by of the are by more and with adults, children are at higher of changes in pharmacokinetics may play a role in some cases. and newborns may be for certain pathways but may a with their in the developmental process. For example, immature CYP2D6 may contribute to with toxicity in the first 4 postnatal among neonates in to or of due to valproic acid is in children younger than 2 years of age who are receiving This effect that increased to adverse drug may occur at certain developmental The mechanism of valproic acid to be to its and to of It that CYP2C9 may be responsible for most of the whereas CYP2D6 a greater role during with the neonatal metabolism is increased of toxic metabolites of different drugs (eg, valproic acid, may be responsible for such as from valproic acid and from and are most during the first years after birth, pharmacokinetic maturation may at a slower This process of and maturation may have an important on drug drug including toxicity and

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