Pharmacokinetics of Antiepileptic Drugs in Infants and Children

Gail D. Anderson

Jong M. Rho

Over the past 20 years, the greater susceptibility to seizures of the immature brain, compared with the adult brain, as well as the effects of antiepileptic drugs (AEDs) on the developing brain, has prompted numerous scientific investigations and educational efforts. During the same period, however, far less attention has been paid to developmental pharmacokinetics, that is, factors that ultimately influence drug disposition through age-related differences in absorption, distribution, metabolism, and excretion. Clinicians have long appreciated the need for individualized pharmacotherapy because of intrinsic variations in how each patient handles drug disposition, the pharmacologic trek that begins with drug formulation, liberation, and absorption and proceeds through multiple pathways and steps to its molecular targets and clinical effects. Moreover, simplified dosing strategies are unreliable, because the growth and maturation (and, hence, presumed function) of organ systems are not linear.

Drug use in the pediatric population has been fraught with uncertainties over efficacy and tolerability. The recent increased focus on pediatric drug development has tightened regulatory requirements for conducting clinical studies in the younger patient. General principles of treatment with AEDs have been established, although detailed knowledge of developmental pharmacology remains far from complete. This chapter summarizes the features of developmental pharmacokinetics and reviews the clinical literature for traditional and newer AEDs.

DEVELOPMENTAL PHARMACOKINETICS

Many age-related differences between neonates and infants, compared with older children and adults, can affect pharmacokinetic properties of drugs (1). For example, gastric pH is increased in neonates, infants, and young children (i.e., relative achlorhydria), decreasing to adult levels after 2 years of age, whereas gastric and intestinal motility is reduced in neonates and infants but increased in older infants and children to adult levels.

The belief that drugs are absorbed more slowly in neonates and young infants than in older children is based on the very few studies that have evaluated how the rate and extent of absorption evolve with age. In addition, little or nothing is known about the maturation of active transporters or drug-metabolizing enzymes in the gastrointestinal tract that significantly affect the bioavailability of some drugs.

Once a drug is liberated and absorbed, its distributing to various body compartments depends on its molecular size, ionization constant, and relative aqueous and lipid solubility. The increased ratio of total body water to body fat in neonates and infants helps to raise the volume of distribution (V_d) of drugs. Whether V_d increases or decreases also depends on the drug’s physiochemical characteristics. Because the plasma concentration that results from a loading dose is inversely proportional to the V_d, determination of loading doses for a given drug should account for age-related changes in V_d. For example, neonates and young infants require larger loading doses of phenobarbital to attain plasma concentrations similar to those in adults.

Protein binding also affects V_d. Albumin and α₁-acid glycoprotein concentrations are decreased in the neonate and infant, and reach adult levels only by age 1 year; this alters the ratio of unbound to total plasma concentrations of AEDs. For highly protein-bound AEDs, such as phenytoin, valproate, and tiagabine, total concentrations are unreliable
for therapeutic drug monitoring and underestimate the unbound, or active, concentration in neonates. Assessments of unbound plasma concentrations are required to avoid dose-dependent adverse events.

AEDs are eliminated through either renal excretion of unchanged parent drug or hepatic biotransformation to active and inactive metabolites, or to a combination of these pathways. The cytochrome P (CYP) 450 and uridine diphosphate (UDP) glucuronosyltransferase (UGT) enzymes catalyze the biotransformation of most AEDs, although some recently approved AEDs are eliminated by renal, mixed, and non-CYP or non-UGT pathways.

The CYP system represents families of multiple enzymes; each family is composed of distinct isozymes. CYP1, CYP2, and CYP3, the major CYP families, and eight primary isozymes are involved in the hepatic metabolism of most drugs: CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 (2). The UGT family of enzymes, UGT1 and UGT2, catalyze the transfer of a glucuronic acid moiety from a donor cosubstrate, UDP-glucuronic acid, to an aglycone. UGT1 isozymes are capable of glucuronidating a variety of drugs and endobiotics; UGT2 is more involved in the glucuronidation of steroids and bile acids in addition to some drugs.

The effect of age on hepatic metabolism depends on the types of enzymes involved (Fig. 46.1) (3). CYP-dependent metabolism is low at birth, approximately 50% to 70% of adult levels; by age 3 years, however, enzymatic activity actually exceeds that of adults. Therefore, young children have an increased ability (relative to adults) to metabolize drugs eliminated by a CYP450-dependent pathway. By puberty, CYP activity decreases to adult levels. Clinical studies suggest that the increased activity occurs with CYP1A2, CYP2C, and CYP3A4. UGT activity is deficient at birth and reaches adult levels by 4 years of age. Unfortunately, little is known about age-related pharmacokinetics of drugs metabolized predominantly by glucuronidation. Maturational difference in specific isozymes has not yet been determined.

Figure 46.1 Effects of age on pharmacokinetic parameters affecting drug disposition. The shadows represent the relative rate of cytochrome P450 (CYP) activity. ^aUGT (uridine diphosphate glucuronosyltransferase) activity is initially decreased in the infant and reaches adult levels by 4 years of age. ^bUGT activity is decreased in the elderly only in some drugs but remains approximately the same with others. (From Morselli PL, Pippenger CE. Drug disposition during development: an overview. Am Assoc Clin Chem 1979;1-8, with permission.)

Renal function also varies with age (Fig. 46.1). At birth, renal blood flow, glomerular filtration rates, tubular secretion, and reabsorption are approximately 25% to 30% of adult values, increase steadily by 6 months to 50% to 75%, and reach full function by approximately 1 year of age. Transporter proteins participate in renal excretion of many drugs, but data about their maturation are scant. In general, weight-normalized doses of drugs excreted unchanged by the kidneys need to be reduced only for neonates and infants.

ANTIEPILEPTIC DRUGS

Benzodiazepines

Clobazam is available as a tablet. Absorption exceeds 85%, with peak concentrations occurring in 30 minutes to 2 hours (4,5). Clobazam is eliminated predominantly by hepatic metabolism to multiple metabolites. N-desmethylclobazam, the primary metabolite, accumulates to approximately eightfold higher serum concentrations than clobazam after
multiple doses. The polymorphically distributed CYP2C19 is primarily involved in the metabolism of N-desmethylclobazam. The poor-metabolizer phenotype of CYP2C19 occurs in 13% to 23% of Asians but in only 2% to 5% of whites and African Americans. Case reports have described children who had toxic reactions to normal doses of clobazam, with metabolite concentrations 10- to 27-fold higher than expected; these patients were heterozygous or homozygous for the mutant CYP2C19 alleles (6,7).

A population analysis of more than 400 epileptic patients receiving different comedications found significantly lower N-desmethylclobazam concentrations in children than in adults; the clobazam concentration-to-dose ratio did not differ with age (8). In another study of 74 children (9), clobazam and the metabolite concentrations increased with age from 1 to 18 years. Both studies showed large intersubject variability and poor correlation between plasma concentrations and efficacy. Therefore, it is unclear whether children require higher doses of clobazam than adults. Doses should be initiated with caution and titrated to effect in both populations.

Clonazepam is available as an oral or a disintegrating tablet, as drops, and in a parenteral formulation. After oral administration, bioavailability exceeds 80%, and peak concentrations occur in 1 to 4 hours (5). Clonazepam is well but variably absorbed after rectal administration; peak concentrations are reached within 10 to 30 minutes (10). After extensive metabolism to inactive metabolites, less than 1% of clonazepam is excreted unchanged in the urine. Neonates require lower weight-normalized doses than older children and adults. The elimination half-life is prolonged and clearance is significantly lower than in older children and adults (11). In small studies, the weight-normalized oral clearance was highly variable, though not significantly different from that in adults (12,13).

Diazepam is marketed as an oral solution, tablets, sustained-release capsules, and rectal suppository and gel; a parenteral formulation is also available (5). Absorption of the oral forms is complete, and peak concentrations occur within 30 to 90 minutes. Rectal administration of the solution or gel results in peak concentrations within 30 to 60 minutes (14); the suppositories exhibit slow and variable absorption and are not suitable for treatment of acute seizures (15). Diazepam is extensively metabolized to desmethyldiazepam, temazepam, and oxazepam; reactions are catalyzed by CYP2C19 and CYP3A4. The mean elimination half-life of diazepam and desmethyldiazepam is significantly prolonged in poor metabolizers of CYP2C19. Despite significant use in children, information on the age-related pharmacokinetics of diazepam is sparse. Neonates and young infants have decreased weight-normalized clearance owing to decreased formation of oxidative and conjugated metabolites (16). In a study of five children 4 to 8 years of age (16), oral clearance appeared to be twofold to threefold higher than that described in adults (17).

The recommended dosage of rectal gel for treatment of acute serial seizures in children reflects the expected increase in weight-normalized oral clearance for drugs metabolized by CYP3A4 and CYP2C19: ages 2 to 5 years, 0.5 mg/kg; 6 to 11 years, 0.3 mg/kg; children older than 11 years and adults, 0.2 mg/kg.

Lorazepam is available as oral and sublingual tablets and in a parenteral formulation. Bioavailability after oral administration is more than 90%, with peak concentrations achieved in 1 to 2 hours (5). Sublingual administration results in a bioavailability exceeding 98% and a latency before absorption of 23 minutes. Lorazepam is extensively metabolized to a glucuronide conjugate, with little renal excretion of unchanged drug. Neonates have significantly decreased oral clearance compared with children and adults (18,19). The pharmacokinetics of lorazepam are not known in children between the ages of 1 and 7 years. In children 7 to 19 years of age, the pharmacokinetics are not significantly different from values in adults. Because glucuronidation appears to reach adult levels by age 3 years, the weight-corrected dose in children after age 3 years should be the same as in adults. Infants and children younger than age 3 years should receive reduced doses.

Carbamazepine

Carbamazepine is available in oral and chewable tablets, as a suspension, and in extended-release formulations (20). The time to peak concentration is 4 to 8 hours with the tablets and extended-release formulations and 1 to 2 hours with the suspension. In six newborn and two older infants, the oral suspension was adequately absorbed from the gastrointestinal tract, with a time to peak of 7 to 15 hours (21). Rectal administration of the suspension results in equivalent blood concentration with a delayed peak concentration (22). The significantly shorter elimination half-life in children compared with adults may require three-times-daily or even four-times-daily dosing of the tablet and suspension. The controlled-release or sustained-release formulation provides significantly less fluctuation in plasma concentrations and fewer toxic reactions associated with high peak concentrations (23). Tegretol-XR loses its sustained-release properties if broken or chewed, whereas the Carbatrol capsule can be emptied onto food and maintain the sustained-release characteristics. Both can be substituted milligram for milligram for other carbamazepine products and administered twice a day.

After extensive metabolism, less than 1% of carbamazepine is excreted unchanged in the urine. Carbamazepine-epoxide accounts for approximately 25% of the dose in monotherapy and 50% in polytherapy with other inducing AEDs. Carbamazepine is a substrate for CYP3A4 (major), with minor metabolism by CYP1A2 and CYP2C8. The epoxide metabolite contributes to the drug’s therapeutic effects and neurotoxicity. The effects of age on carbamazepine also must consider the active
metabolite, which is rarely measured in the clinical setting. Studies have found a higher weight-adjusted total body clearance and higher carbamazepine-epoxide-to-carbamazepine ratio in children than in adults (24,25). Adult values are reached by ages 15 to 17 years with the greatest change in oral clearance occurring between 9 and 13 years of age (26). Children need weight-normalized maintenance doses approximately 50% to 100% higher than those in adults to achieve comparable serum levels.

Ethosuximide

Ethosuximide is available as capsules or syrup. Absorption is complete, with a time to peak concentration of 3 to 7 hours (27). Ethosuximide is eliminated primarily by CYP3A4-dependent metabolism, with approximately 20% excreted unchanged in the urine. The weight-adjusted oral clearance is higher in children than in adults, and the concentration-to-dose ratio is 50% higher in children 2.5 to 10 years of age than in those 15 years of age or older (28). Children need approximately 50% to 100% higher mg/kg maintenance doses than do adults to attain similar concentrations. As ethosuximide therapy is initiated primarily in young children, doses will need adjustment according to plasma concentrations to account for increased body weight and decreased clearance with age (29).

Felbamate

Felbamate is marketed as a tablet and a suspension. Absorption is nearly complete; peak concentrations occur 2 to 4 hours after administration (20). Felbamate is eliminated through renal excretion of unchanged drug (50%) and glucuronidation (20%) and is a substrate for CYP3A4 (20%) and CYP2E1. The weight-adjusted apparent clearance of felbamate is approximately 40% higher in children 2 to 12 years of age than in adults 13 to 65 years of age on monotherapy or polytherapy with other AEDs (30). A significant negative correlation in apparent clearance was noted in 17 children 2 to 12 years of age, with higher clearance in the very young decreasing to adult values by age 12 years (31). Children require weight-normalized maintenance doses approximately 40% higher than adults to attain similar concentrations.

Gabapentin

Gabapentin is available as a capsule, a tablet, and an oral solution. Absorption is less than 60% and varies significantly owing to saturation of active L-neutral amino acid transporters in the gastrointestinal tract (32). Peak concentrations occur in 2 to 3 hours. A study in two children found poor absorption of rectally administered solution (33). There is no information on the time course of maturation of the L-neutral amino acid transporter. Gabapentin is eliminated almost completely unchanged by the kidneys, with oral clearance proportional to creatinine clearance; active tubular secretion is also involved in the renal elimination. A population analysis in subjects 2 months to 13 years of age found that children younger than 5 years had a significantly higher and more variable oral clearance than did older children (34). Infants and children younger than age 5 years required 33% higher weight-normalized doses to attain similar concentrations. The weight-normalized oral clearance in children older than age 5 years was comparable to that in adults. As creatinine clearance did not differ significantly in younger and older children, the age-related variation might be the result of decreased oral bioavailability, possibly as a result of delayed maturation of the L-neutral amino acid transporter. A small study (35) found 33% higher oral clearance in children age 10 years or younger compared with young adults. Therefore, children younger than 5 years of age will need higher weight-normalized doses than will children older than that age. After 5 years of age, weight-normalized doses higher than those in adults may be needed.

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