Absorption

Absorption is a complex phenomenon controlled by the physicochemical properties of the drug, the formulation, and the physiologic conditions at the sites of absorption: stomach, small intestine, colon, rectum, buccal and nasal mucosa, and muscle. Most drugs are given orally as solid formulations, which must first disintegrate into small particles that are then dissolved in the gastrointestinal fluid. Only after a drug is dissolved is it available for absorption. Most drugs are absorbed by passive diffusion of the unionized form but some drugs use active transport mechanisms. Gastrointestinal absorption is influenced by age-dependent changes in physiologic variables, such as gastric emptying time, stomach and intestinal pH, absorptive area, and gastrointestinal transit time. Food intake may affect antiepileptic drug pharmacokinetics, especially absorption. Although there is concern that the ketogenic diet may alter dosing requirements, a recent study indicated that there are no significant changes in the concentrations of several antiepileptic drugs (valproate – free or total, topiramate, phenobarbital, lamotrigine, clonazepam) during the ketogenic diet [Dahlin et al., 2006].

Absorption is described in terms of rate and extent. The term absorption half-life describes the rate at which drug reaches the systemic circulation. An indirect measure of absorption rate is the T_max. This measure is useful in comparing the rates of absorption of different brands or formulations of the same drug. A lower (i.e., earlier) T_max usually is an indication of a faster rate of absorption. When all other pharmacokinetic parameters are constant, a faster rate of absorption will result in a lower T_max and higher maximum concentration (C_max).

The extent of absorption describes the amount of a drug that reaches the blood relative to the dose. It is termed oral bioavailability (F) and is the fraction of the dose that reaches the systemic circulation. Absolute bioavailability of a drug is determined by comparing the area under the concentration vs. time curve after an oral (or rectal, intramuscular, and so on) dose with the area under the concentration vs. time curve after intravenous (IV) administration of the same drug. However, because many antiepileptic drugs do not have IV formulations, an absolute biovailability cannot be determined. Rather it can be estimated by comparing available oral formulations, termed relative bioavailability. Relative bioavailability is determined by comparing the area under the concentration vs. time curve for a specific formulation to that of a reference product. For example, the relative bioavailability of a generic brand of phenytoin sodium 100-mg capsule is measured by comparing its area under the concentration vs. time curve with that for brand phenytoin (Dilantin 100-mg capsule).

Because the hepatic portal system drains the entire gastrointestinal system (except for the distal rectum and buccal and nasal mucosa) all drugs swallowed are first delivered to the liver after crossing the gastrointestinal mucosa. Thus, a fraction of these drugs may be metabolized before entering the systemic circulation. The average plasma concentration is determined by the bioavailability and the rate of elimination (clearance) by the following relationship:

Therefore, changes in bioavailability of a drug from alterations in drug formulation, alterations in gastrointestinal physiology, or interactions with inhibitors or inducers can result in clinically significant increases or decreases in drug concentrations in plasma or at the receptor site.

Descriptors of absorption, such as C_max and T_max, and the bioavailability, may vary considerably among different formulations of the same drug. The relative rates of absorption, and thus T_max and C_max, adhere to the following order of most rapid to slowest, and highest peak concentration to lowest: solutions > suspensions > capsules > tablets > extended-release formulations [Garnett and Cloyd, 1993]. Formulation-related differences in absorption characteristics are greatly influenced by the composition of the inactive ingredients (e.g., filler, particle size of drug) and nature of the capsule or tablet coating).

Volume of Distribution

Volume of distribution (V_d) is a measurement of how the drug is distributed throughout the body (tissues and blood), and is expressed in terms of liters or liters per kilogram. Mathematically, it is expressed as the following:

where V_d is the volume of distribution and C_max corresponds to the concentation immediately after IV administration, if this was the route of administration. Because many antiepileptic drugs do not have an IV formulation, the V_d of these is estimated from the concentration at T_max. V_d values may differ markedly among antiepileptic drugs because drugs distribute to tissues with different binding characteristics. For example, drugs that concentrate in fat tissue have relatively low plasma concentrations, but may have a V_d value measured in the hundreds of liters because the C_max is low. Changes in body composition, such as increases or decreases in fat, muscle, or water, may thus alter V_d values.

V_d is very useful for calculating loading doses. The purpose of a loading dose is to fill body compartments rapidly to reach a targeted plasma concentration and thus a targeted concentration at the site of action. The equation for calculating a loading dose is the following:

The change in plasma concentration term denotes the desired increase after administration of the loading dose. For example, if a patient has a plasma concentration of 5 mg/L and the target concentration is 20 mg/L, the desired change in concentration is 15 mg/L. For phenytoin, the V_d is approximately 0.75 L/kg, so an IV dose of 11.25 mg/kg is required. When loading doses are administered intramuscularly, orally, or rectally, resultant maximum plasma concentrations are usually less than after IV loading, owing to slower and incomplete absorption and the elimination of some drug during the absorption phase. Table 59-4 presents loading dose information for six major antiepileptic drugs.

Protein Binding

Several antiepileptic drugs are highly bound to one or more plasma proteins, most commonly albumin or α₁-acid glycoprotein. Drug assays usually measure the total concentration of drug, which is the sum of the bound and unbound concentrations. The free fraction is the ratio of unbound to total plasma drug concentration:

In general, only the unbound drug is able to cross the blood–brain barrier and is in equilibrium with brain and spinal fluid (Figure 59-1; see also Table 59-3). Consequently, clinical response and toxicity correlate better with the unbound drug concentration than with the total drug concentration. For drugs that have limited protein binding (less than 50 percent) or a constant ratio of unbound to total concentration, measurement of total plasma concentrations is a reliable indicator of response. However, if a drug is highly protein-bound (greater than 85 percent), measurements of total concentrations may be an unreliable guide to clinical outcomes. The fraction bound may change because of illness, age, or other drugs that compete for binding sites. In these circumstances, it may be necessary to measure the free concentration to understand the clinical effect better. Low-extraction drugs are those that have only a small portion of the drug metabolized by each pass through the liver. Most of the antiepileptic drugs are low-extraction drugs and alterations in protein binding do not affect the steady-state concentration of the unbound drug. Thus, adjustments in dose generally are not necessary when protein binding is altered because the unbound concentrations remain unchanged. Erroneously increasing the dose when total levels are low, but unbound levels have not changed, will likely result in toxicity.

Fig. 59-1 Relationship of unbound drug in vascular and nonvascular compartments.

Metabolism and Elimination

Antiepileptic drugs are eliminated from the body through metabolism and renal excretion. Clearance (Cl) and elimination half-life (t_½) are the pharmacokinetic terms that quantitatively describe drug elimination. Clearance describes the rate of elimination and defines dosage requirements, whereas t_½ is useful in determining time to steady state and dosing intervals.

Clearance is the volume of blood from which drug is removed (cleared) per unit of time. It is identical conceptually and mathematically to the more familiar physiologic parameter of creatinine clearance. For antiepileptic drugs that are eliminated by the liver, clearance is determined by the free concentration of the drug and the intrinsic ability of hepatic enzymes to metabolize the unbound drug. Although, for most drugs, clearance is proportional to dose, some drugs exhibit nonlinear pharmacokinetics in which clearance changes with concentration (Figure 59-2).

Fig. 59-2 Effect of dose on elimination kinetics.

Curve A plots nonlinear pharmacokinetics (of the Michaelis–Menten type) in which clearance decreases with increasing dose, as with phenytoin. Curve B plots linear pharmacokinetics, in which clearance remains the same with increasing dose, as with phenobarbital, felbamate, vigabatrin, tiagabine, topiramate, and valproic acid (unbound drug). Curve C plots nonlinear pharmacokinetics in which clearance increases with dose, as with valproic acid (total), carbamazepine, and lamotrigine.

The following points are important to remember:

Clearance and absorption determine the amount of drug a patient requires to maintain a targeted steady-state plasma concentration.

Changes in clearance lead to changes in concentration and in the resultant pharmacologic response.

Changes in protein binding can affect total drug concentration without affecting unbound drug concentration.

Changes in total drug concentration without a corresponding change in unbound concentration do not require a dosage adjustment.

Addition or removal of other drugs can induce or inhibit metabolism and alter hepatic clearance.

The t_½ is the time required for the plasma concentration to decline by 50 percent. Half-life is determined by both distribution volume and clearance:

Thus, t_½ is not a direct measure of Cl, but is useful in calculating the time to reach steady state or the time required for drug elimination. After initiation or modification of therapy or after any change in clearance, 5 half-lives must elapse for a new steady-state plasma concentration to be reached (see Figure 59-2). The time required to attain steady state can be explained by using the definition of t_½. The plasma concentration in the body declines 50 percent in 1 t_½; therefore, the percentage of drug remaining in the body, as indicated by the plasma concentration after 2, 3, 4, and 5 half-lives, is 75 percent, 87.5 percent, 93.75 percent, and 96.875 percent, respectively. The actual amount of drug remaining in the body and the additional amount of drug removed in subsequent half-lives are so small (after 5 half-lives) that, for practical purposes, it can be ignored. However, the rate of decline is most rapid in the first two half-lives, and the risk of seizures is greatest during this period.

Biotransformation (metabolism) of medications is accomplished through biochemical reactions. These reactions create compounds that are more polar (more water-soluble) and are eliminated from the body, usually through the kidneys. Phase I reactions (e.g., using the cytochrome P-450 system) involve oxidation and reduction. Phase II reactions (non-cytochrome P-450-mediated) couple the drug or its metabolite with endogenous substrates by conjugation or synthesis. The endogenous substrate may be glucuronic acid, glutathione, glucose, sulfate, or acetate, making the drug more polar and hence water-soluble [Capparelli, 1994]. Antiepileptic drugs may undergo metabolism by phase I or II reactions, or a combination of both. As persons mature, the pathways may change and the metabolite profile will be altered.

In the neonate, phase I reactions, such as hydroxylation and, to a lesser extent, dealkylation, are significantly depressed [Anderson and Lynn, 2009]. In older children, however, phase I activity generally exceeds that in adolescents or adults. As a general rule, the rate of drug metabolism reaches a peak at 0.5–2 years of age and then declines in an exponential manner, reaching adult values in early adolescence. As an example, the clearance of valproic acid, in which metabolism includes both phase I and phase II reactions, is fastest in young children and then declines to reach adult values at the age of approximately 12–15 years. Also, its metabolism shifts from phase II to phase I reactions.

For most drugs, the evaluation of maturation-related (as contrasted with chronologic age-related) enzymatic clearance has not been studied systematically. It is likely that some of the variance in drug clearance noted in children of the same age is due to differences in maturational development. As children grow, the dose may need to be increased to compensate for the increased body (and liver) mass, but later re-adjusted for the decline in phase I and II reactions.

Active metabolites formed after biotransformation of the parent compound can contribute significantly to desired and toxic effects of the parent drug. Metabolites exist in both bound and unbound states. Only the unbound metabolite is available for elimination or biotransformation to an inactive metabolite. As with unbound parent drug, the unbound metabolite concentration in the plasma most closely correlates with the concentration of metabolite at the site of action. The presence of active metabolites complicates interpretation of plasma drug concentrations and clinical response. As with the parent drug, the relationship between unbound and total metabolite concentrations can be disrupted by displacement from serum proteins or changes in metabolism. In fact, parent or metabolite concentrations may be altered independently by drug interaction or physiologic change in metabolism. Table 59-5 displays the cytochrome P-450 isoform families involved in antiepileptic drug metabolism, along with known inducers and inhibitors.

Renal elimination is accomplished by glomerular filtration and/or renal tubular secretion. Glomerular filtration rate and renal tubular function in newborns are less efficient than in adults [Linday, 1994]. After 1 year of age, glomerular filtration rate, corrected for body surface area, is the same as for older children and young adults. Renal tubular function reaches adult values, normalized to body surface areas, within several months. Decreases in clearance can be better correlated with sexual maturity than with chronologic age. Making correlations with physiologic or sexual maturation and developmental age, rather than chronologic age, may be helpful in accounting for the variability observed in clearance of drugs that are renally eliminated [Finkelstein, 1994].

Barbiturates

Phenobarbital, primidone, and methobarbital were the mainstay of the treatment of epilepsy for many years. Primidone itself is active and is metabolized to the active metabolites PEMA and phenobarbital. Because phenobarbital has a half-life measured in days and the other metbolites have relatively short half-lives, phenobarbital is considered to be the primary active agent during primidone use. Methobarbital is also metabolized to phenobarbital. Side effects of this group, including paradoxical hyperactivity in children, have markedly reduced the use of these medications.

Benzodiazepines

As a group, the benzodiazepines are rapidly (T_max of 30–180 minutes) and completely absorbed when given orally. The exception to this is midazolam, which is subject to a high first-pass effect when administered orally. Intramuscular administration of diazepam or lorazepam is not recommended because of slow or erratic absorption, but midazolam is more consistently and rapidly absorbed by this route. Diazepam is also absorbed rectally.

The benzodiazepines rapidly cross the blood–brain barrier. Brain concentrations reach equilibrium with plasma concentrations within seconds after IV administration. But the highly lipid-soluble nature of diazepam and lorazepam causes them to redistribute to other body tissues, resulting in a rapid decrease in brain concentrations and a very high V_d. This redistribution is responsible for the short duration of action after a single dose [Greenblatt et al., 1989; Leppik et al., 1983]. The benzodiazepines are metabolized by the liver and have linear elimination kinetics. Some of the metabolites exhibit antiepileptic activity and also may contribute to toxicity. Because the active metabolites have very long half-lives, repeated administration of these drugs, culminating in large total doses, may lead to long periods of sedation, usually most problematic for diazepam and chlorazepate.

Carbamates

The carbamates are organic compounds derived from carbamic acid, NH₂COOH. Some have been found effective for the treatment of epilepsy. Carbamazepine is the oldest of this class; oxcarbazepine and, more recently, eslicarbazepine acetate, have been added to this category.

Carbamazepine

Carbamazepine is a very water-insoluble, neutral compound with a slow dissolution rate in gastrointestinal fluid. The relative bioavailability is similar for all four formulations (i.e., suspension, chewable tablet, extended-release, and regular tablet), ranging from 75 to 90 percent, although marked intrapatient and interpatient variability has been observed [Faigle and Feldmann, 1975; Maas et al., 1987]. In children on maintenance therapy, the rate of absorption is much faster for the suspension than for tablet formulations, resulting in a significantly earlier T_max and higher C_max (Figure 59-3). This property occasionally produces transient concentration-dependent central nervous system side effects. Administering the same daily dose in smaller amounts and giving it more frequently may correct this problem. Sustained-release preparations may permit twice-a-day dosing, eliminating the need for administration of medications during school hours. This improves medication compliance and decreases central nervous system side effects because peak concentrations will be lower. Studies conducted by the U.S. Food and Drug Administration have demonstrated that carbamazepine tablets are significantly less well absorbed after being exposed to high humidity [Meyer et al., 1992; Wang et al., 1993]. These findings emphasize the importance of storing all antiepileptic drugs at room temperature in a dry location.

Fig. 59-3 Comparison of serum concentration–time curves after administration of carbamazepine (CBZ) tablets and suspension.

Data are from a crossover study in a child with epilepsy on steady-state, maintenance therapy.

The V_d in children for carbamazepine based on oral preparations ranges from 0.8 to 2.0 L/kg. Both carbamazepine and its active metabolite, carbamazepine-10,11-epoxide, are bound to several plasma proteins [Eichelbaum et al., 1975; Rawlins et al., 1975]. Approximately 65–85 percent of carbamazepine and 30–60 percent of carbamazepine-10,11-epoxide are bound to albumin. Both also bind to the reactant protein α₁-acid glycoprotein. Binding to α₁-acid glycoprotein increases after physiologic stress, such as from burn injuries or inflammatory diseases (e.g., juvenile rheumatoid arthritis). Increased binding to α₁-acid glycoprotein can increase total carbamazepine and carbamazepine-10,11-epoxide concentrations without necessarily increasing the unbound drug concentrations. In such situations, patients may have total concentrations above the desired range but have no side effects. Adjusting dosage is not necessary; plasma concentrations return to baseline as α₁-acid glycoprotein declines.

Carbamazepine is eliminated primarily by phase I cytochrome P-450-mediated metabolism (see Table 59-5), forming an active metabolite (10,11-epoxide). Carbamazepine displays dose-dependent elimination pharmacokinetics, in which dosage increases produce a less than proportionate increase in steady-state total concentration (see Figure 59-2). Carbamazepine metabolism undergoes autoinduction, in which clearance increases over time after exposure to the drug. Within 30 days after beginning therapy, carbamazepine clearance may increase by as much as 300 percent. Further increases in maintenance doses may result in further induction [Kudriakova et al., 1992]. In some children, induction causes plasma carbamazepine concentrations to remain unchanged or even decline, despite increasing doses up to 40–50 mg/kg per day [Curatolo et al., 1988]. Carbamazepine and carbamazepine-10,11-epoxide metabolism also can be induced by phenytoin or phenobarbital, resulting in as much as a 100 percent increase in clearance [Kerr and Levy, 1989]. Initial carbamazepine t_½ ranges from 10 to 20 hours, but the t_½ decreases because of autoinduction to 4–12 hours. Consequently, many children require three or four doses a day to maintain targeted plasma concentrations. Sustained-release preparations help overcome this problem.

Felbamate

Approximately 95 percent of a dose of felbamate is absorbed in adults after oral administration. Absorption of the drug is fairly rapid, with T_max values ranging from 1 to 4 hours [Wilensky et al., 1985]. The V_d of felbamate is approximately 0.8 L/kg [Devinsky et al., 1994; Wilensky et al., 1985]. Distribution of felbamate is fairly uniform throughout the entire body. It binds mainly to albumin (22–25 percent), and the amount of binding is dependent on albumin concentration [Perhach and Shumaker, 1995].

About 90 percent of felbamate is eliminated in the urine. Approximately 40–50 percent of the absorbed dose is eliminated as the unconjugated parent compound, and up to 58 percent is found as metabolites and conjugates [Shumaker et al., 1990]. Felbamate is cleared at a faster rate in children. Population pharmacokinetic analysis of data from 139 pediatric patients gives clearance values approximately 40 percent higher in younger children (2–12 years of age) than those in older children and adults (13–65 years).

Gamma-Aminobutyric Acid Analogues

Gabapentin and pregabalin were initally conceived as drugs that may modulate gamma-aminobutyric acid (GABA) receptors. However, this is not their main mechanism of action.

Hydantoins

The hydantoins include ethytoin, mephenytoin, and phenytoin and its prodrug fosphenytoin. Although used in the past, ethytoin and mephenytoin are not widely used now.

Phenytoin

Phenytoin is a poorly water-soluble compound and is often formulated as a sodium salt. It is available as a suspension, chewable tablet, capsule, and a parenteral formulation. The nonlinear, saturation pharmacokinetics of phenytoin can make even small differences in dose clinically significant. The chewable tablet and the suspension contain phenytoin acid, whereas the capsules and the IV formulation contain phenytoin sodium, which is equivalent to only 92 percent of the acid (see Table 59-1). Thus, two 50-mg chewable tablets deliver 8 percent more phenytoin than a 100-mg phenytoin sodium capsule. The suspension is available in a 125-mg/5-mL strength. In the past, the reliability of the suspension has been questioned owing to its tendency to settle. It has been demonstrated that some agitation is sufficient to permit delivery of the specified amount of drug [Sarkar et al., 1989]. Unexpected fluctuations in plasma phenytoin concentrations associated with the use of suspensions likely have been the result of pharmacokinetics rather than formulation problems. Intramuscular injection of the parenteral solution (with a pH of 11) is contraindicated because it results in precipitation of drug that is then slowly and erratically absorbed [Kostenbauder et al., 1975]. It is also painful and causes tissue necrosis [Serrano and Wilder, 1974]. Phenytoin capsules are available in both prompt-release and extended-release formulations. Patient and family education about the differences in phenytoin dosage forms is important to maintain optimal therapy.

Bioavailability, T_max, and C_max are altered when large amounts of phenytoin are given as a single oral loading dose, presumably because of the formation of a multicapsule concretion. In a study involving six healthy adults, absorption was reduced by 10–15 percent and T_max increased from 18 to 32 hours, when phenytoin sodium capsules were given in single dose of 10 mg/kg or more [Jung et al., 1980]. Dividing the total loading dose into 5-mg/kg doses given every 2–3 hours overcomes this problem. The most rapid way to attain therapeutic plasma concentrations after oral loading is to use prompt-release phenytoin sodium capsules or suspension [Goff et al., 1984].

Some reports have suggested that phenytoin is poorly absorbed in newborns because of irregular gastric emptying time, relatively high gastric pH (greater than 4), or decreased absorptive surface [Morrow and Richens, 1989; Morselli, 1983; Painter et al., 1978]. Other evidence indicates that formulation-related differences in absorption, nonlinear pharmacokinetics, and age-dependent changes in elimination account for much of the variability in plasma concentrations [Dodson, 1984].

Phenytoin V_d in children and adolescents is approximately 0.7 ± 0.1 L/kg [Koren et al., 1984]. The relatively small variability in phenytoin V_d permits precise calculation of loading doses. For example, a 15-mg/kg loading dose given intravenously will result in a postinfusion mean concentration of 20 mg/L, with a range of 15–25 mg/L. Phenytoin is also highly protein-bound to albumin.

Phenytoin undergoes extensive hepatic metabolism. A small fraction, 5 percent or less, is excreted unchanged [Battino et al., 1995]. It is metabolized by a saturable cytochrome P-450 enzymatic pathway. Phenytoin follows Michaelis–Menten or saturable elimination kinetics (see Figure 59-2). As the plasma concentration rises, phenytoin clearance decreases, owing to saturation of enzymatic metabolism. Therefore, increases in dose result in disproportionately greater increases in steady-state plasma concentration.

Phenytoin half-life also varies with plasma concentration. As plasma concentration rises, the half-life increases. Half-life ranges from 8 to 12 hours at low concentrations to more than 60 hours at concentrations above 20 mg/L. At concentrations within or above the therapeutic range, 1–4 weeks may be required to reach steady state.

Phenytoin metabolism in neonates is reduced compared with that in older children. Within days to weeks after birth, the rate of metabolism accelerates, reaching a maximum in the 0.5- to 3-year age range. Children in this age group require the highest mg/kg daily doses (Figure 59-4). Thereafter, metabolism and dosage requirements decline gradually, reaching adult values during adolescence. Figure 59-5 illustrates that even minor alterations in dosage produce disproportionately large changes in plasma concentration. Therefore, small adjustments in daily dose are indicated as the plasma concentration approaches or exceeds K_m, which usually falls in the range of 5–10 mg/L. Use of the scored 50-mg chewable tablet, the 30-mg phenytoin sodium capsule, or the suspension facilitates making such adjustments in dose.

Fig. 59-4 Phenytoin dosing requirements in children.

Curves were derived from data of maximum capacity of the enzyme system to metabolize phenytoin (V_max) and the plasma concentration at which the rate of metabolism is 50 percent of maximum capacity for children (K_m) (see Table 59-2).

Fig. 59-5 Schematic of steady-state plasma concentrations of antiepileptic drugs when a particular antiepileptic drug is given alone or in combination with other medications.

(We wish to thank Nina Graves, Pharm.D., for her contribution to this figure.)

Lacosamide

Lacosamide (known as harkoside in earlier studies) was approved for use in the United States during 2009. It is completely and rapidly absorbed with a bioavailability of 100 percent [Hovinga, 2003]. Lacosamide appears to follow linear pharmacokinetics and its C_max is between 1 and 4 hours after an oral dose [Hovinga, 2003]. There does not seem to be a food effect on lacosamide pharmacokinetics [Kellinghaus, 2009]. Protein binding has been shown to be less than 15 percent. Lacosamide is metabolized to an inactive desmethyl metabolite, which is then cleared along with the parent drug via the kidney. Lacosamide is not approved for use in young children at this time; however, there is at least one clinical trial that is investigating the safety and pharmacokinetics in children with partial seizures between the ages of 2 and 17 years. Doses being studied are 8–12 mg/kg/day.

Lamotrigine

Lamotrigine has a bioavailability approaching 100 percent. Its T_max occurs 2–3 hours after administration of a single oral dose. With doses in the range of 15–240 mg, T_max and area under the concentration–time curve are directly proportional to dose [Yuen and Peck, 1987]. The V_d of lamotrigine is approximately 1.5 L/kg in children [Chen et al., 1999]. It is distributed uniformly throughout the body, and approximately 55 percent of lamotrigine is bound to plasma proteins [Garnett, 1997].

Lamotrigine is extensively metabolized to an inactive glucuronide by an inducible uridine diphosphate (UDP) glucuronyltransferase reaction [Lamictal, 2004]. Clearance is greater in younger children [Battino et al., 2001]. Infants (younger than 2 months of age) metabolize lamotrigine more slowly, and metabolic rates increase during the first year of life [Mikati et al., 2002]. Estrogen-containing oral contraceptives may cause dramatic cyclical fluctuations of blood levels (decreasing during the estrogen phase and rebounding in the placebo week), and levels decrease dramatically during pregnancy [Pennell et al., 2008]. There may be an impact of age on lamotrigine concentrations [Reimers et al., 2007]. However, data for weight were not available in a majority of the patients and the effect of age could be due to the fact that older children weigh more than younger children [Reimers et al., 2007].

Levetiracetam

Levetiracetam is extremely water-soluble and has an oral bioavailability of close to 100 percent. Its C_max is within 2 hours of dose administration. When the drug is administered with food, the rate of absorption is decreased, but the extent of absorption is unchanged. Therefore, levetiracetam can be administered without regard to timing of meals. Levetiracetam also exhibits linear pharmacokinetics after single doses ranging from 250 up to 5000 mg [Patsalos, 2000]. The V_d for levetiracetam is 0.5–0.7 L/kg, and protein binding is less than10 percent. Two-thirds of a dose is eliminated unchanged and the rest is eliminated as an inactive metabolite in the urine [Keppra package insert, 2004]. The clearance is 30–40 percent higher in children than in adults [Chhun et al., 2009; Glauser et al., 2007; May et al., 2003; Pellock et al., 2001]. Results are now available from studies in children as young as 2 months old and they confirm that the half-life of levetiracetam in younger children is approximately 5–6 hours, shorter than that seen in adults [Glauser et al., 2007]. An IV formulation and a sustained-release formulation are now on the market. It may be possible to give levetiracetam rapidly. Patients (4–32 years of age) who temporarily lost the ability to take medications by mouth were given an IV loading dose of levetiracetam via rapid infusion (given within 6 minutes). Levetiracetam concentrations ranged from 14 to 189 μg/mL and no significant changes in blood pressure or significant abnormalities in the electrocardiogram were experienced [Wheless et al., 2009]. There were also no local infusion site reactions noted; however, the formulation was diluted 1:1 with normal saline or dextrose 5 percent in water (D5W).

Drug–drug interaction information in children indicates that the concentrations of carbamazepine, valproic acid, topiramate, or lamotrigine are similar between study groups who receive levetiracetam or placebo [Otoul et al., 2007].

Rufinamide

Rufinamide is slowly absorbed due to the fact that it is lipophilic and dissolves slowly in aqueous solutions. The bioavailability is nonlinear and decreases at higher doses, with doses of 1600 mg producing less than proportional concentrations. Steady-state doses of 200, 400, and 800 mg produced morning trough concentrations of 2.81, 5.23, and 11.0 μmol/L, whereas 1600-mg doses resulted in a mean trough concentration of 19.6 μmol/L (4.7 mg/L) [Elger et al., 2010; Limite, 2005; NoAuthors, 2005]. Dissolution is the rate-limiting step in absorption; therefore, changes in gastrointestinal environment, such as with the presence of food, could have an effect on the absorption of rufinamide. It is suggested that rufinamide be administered with food. Rufinamide exposure is increased by 31–34 percent and the C_max by 36–56 percent when the drug is given after high-fat meals [Perucca et al., 2008]. Rufinamide is metabolized to inactive metabolites via the carboxylesterase pathway. Although rufinamide does not appear to be metabolized via the cytochrome P-450, the carboxylesterase enzymes can be induced by inducers of the CYP450 enzymes. Rufinamide also appears to be a weak inhibitor of CYP2E1 and a weak inducer of CYP3A4.

Pharmacokinetic data in children are beginning to appear in the literature. The majority of the data concerning rufinamide is on file with the manufacturer; however, data on these trials have been summarized in Perucca et al. [2008]. A dosing regimen for children has been simulated from several phase II and III clinical studies involving patients with partial or generalized seizures and one study with Lennox–Gastaut syndrome patients. The simulation included 119 children (aged less than 12 years) and 99 adolescents (12–17 years) [Marchand et al., 2010], and was used in supporting material presented to the European Agency for the Evaluation of Medicinal Products. These studies involved patient populations and the presence of inducing and inhibiting polytherapy. Children who weigh less than 30 kg had greater variability in simulated rufinamide exposure measures than those children who were heavier than 30 kg. In addition, the co-administration of valproate resulted in higher rufinamide plasma concentrations. This study proposed a maximum daily dose of 600 mg for children who also receive valproic acid, and a maximum daily dose of 1000 mg for those children who do not also receive valproic acid. Indeed, valproic acid increased rufinamide steady-state plasma concentrations from 54.9 percent in male children and 70.1 percent in female children in a population pharmacokinetic study that is on file at Eisai [Perucca et al., 2008]. The increase in concentrations when valproic acid was a co-medication was approximately 3 times higher in children than in adults. (Adult concentrations were 15 percent higher.) Population studies involving children have also identified increases in rufinamide’s apparent clearance values due to the presence of inducing co-medications. Known antiepileptic drug inducers, such as carbamazepine, phenobarbital, phenytoin, or primidone, as well as vigabatrin, decreased rufinamide steady-state plasma concentrations in children from 23 to 46 percent [Perucca et al., 2008].

Tiagabine

Oral bioavailability of tiagabine is greater than 90 percent, and the bioavailability of tablets and that of the oral solution appear to be similar [Mengel et al., 1991a]. The absorption rate for tiagabine is reduced up to 65 percent when the drug is administered with food, although the extent of absorption is not affected [Mengel et al., 1991b]. Tiagabine has a V_d of 0.74–0.85 L/kg [Gustavson et al., 1997], and protein binding is approximately 96 percent [Gustavson et al., 1997; Ostergaard et al., 1995]. Tiagabine has a half-life of 5–9 hours [Gustavson and Mengel, 1995]. Tiagabine undergoes extensive metabolism by means of the cytochrome P-450 3A isoform, but no active metabolites have been identified. As observed with other drugs, clearances in children are faster than in adults; adjusting both V_d and clearance values according to body size gives values similar to those seen in adults [Gustavson et al., 1997].

Topiramate

Oral tablets of topiramate have a relative bioavailability of approximately 80 percent that of an oral solution. It is rapidly absorbed, with a T_max of approximately 2 hours [Easterling et al., 1988]. Overall absorption is not affected by co-administration with food [Doose et al., 1992]. The protein binding of topiramate is less than 15 percent [Ben-Menachem, 1995a], and its V_d is 0.6–0.8 L/kg [Johannessen, 1997]. Elimination is mainly through the kidney, although a portion of the dose is removed by the liver [Ben-Menachem, 1995a]. Preliminary observations in pediatric patients indicate that the mean oral topiramate clearance is 44–55 percent higher in children, and they may need a higher dose than adults to achieve a similar plasma concentration [Adin et al., 2004; Glauser, 1997].

Valproic Acid

Valproic acid appears to be completely absorbed from all the available products (except for the extended-release formulation), but the rate of absorption varies significantly with dosage form (see Table 59-1). Its T_max is 0.5–1 hour after ingestion for the syrup, 0.5–2 hours after the capsule, 1–6 hours for the enteric-coated tablet, and 3–6 hours for the sprinkle capsule [Cloyd et al., 1983, 1985, 1992]. Absorption after ingestion of the enteric-coated tablet is delayed for several hours; during this lag phase, plasma concentrations may continue to decline. Food further delays, but does not decrease, valproic acid absorption from the enteric-coated tablet [Fischer et al., 1988]. The extended-release tablet has an absolute bioavailability of 90 percent [Dutta et al., 2004]. The extended-release tablets and the enteric-coated tablets are not interchangeable. The extended-release tablets need to be prescribed at a dose that is 8–20 percent higher than the enteric-coated dose to attain similar plasma concentrations [Dutta and Zhang, 2004]. An IV formulation is also available and has been studied in children. The IV formulation should not be given intramuscularly due to toxic muscle necrosis [Gallo et al., 1997].

Valproic acid distribution volumes vary more than those of carbamazepine, phenobarbital, or phenytoin, and range from 0.12 to 0.49 L/kg. When loading doses are calculated, a volume of 0.2 L/kg is recommended. Valproic acid protein binding to albumin is saturable. At concentrations below 40–50 mg/L, the bound fraction averages 90–95 percent. As total concentration rises to the upper boundary of the therapeutic range, the percentage bound falls to 80–85 percent. Saturable protein binding results in a nonlinear relationship between total valproic acid concentration and dose. Unbound valproic acid concentrations, however, remain linear with dose [Cloyd et al., 1993; Riva et al., 1983]. The percentage of unbound valproic acid can be unpredictable and unusually high after rapid infusion in children who are critically ill [Birnbaum et al., 2003].

Valproic acid is extensively metabolized to both active and inactive metabolites. Principal pathways include glucuronidation, β-oxidation in the mitochondria, and oxidation through cytochrome P-450. The monounsaturated metabolites 2-ene-valproic acid and 4-ene-valproic acid possess anticonvulsant activity; the 2-ene-valproic acid achieves pharmacologically relevant concentrations in the brain. 2-Ene-valproic acid accumulates in the brain more slowly than does valproic acid, which may account for the slow onset and cessation of valproic acid anticonvulsant activity. Although the diunsaturated metabolite 2,4-diene-valproic acid, is a potent hepatotoxin, its role in valproic acid hepatotoxicity remains unclear.

The elimination half-life of valproic acid is short. In the first few weeks after birth, half-life ranges from 17 to 40 hours, but rapidly declines from 3 to 20 hours in infants and young children. The full antiepileptic effect of valproic acid is obtained days to weeks after steady state is reached, and this effect continues for some time after the drug is discontinued. The lingering effect may be partly the result of its inhibitory effect on the enzymes responsible for the degradation of GABA, or may be due to the accumulation of 2-ene- valproic acid. This prolonged duration has prompted some investigators to propose single daily dosing [Stefan et al., 1984]; however, with other proposed mechanisms of action, seizure control is related to plasma valproic acid concentrations. Under these circumstances, dosing at least every half-life is indicated to minimize fluctuations in plasma concentrations. When valproic acid is given as monotherapy, the half-life may be long enough to maintain therapeutic concentrations for up to 24 hours in some children. Such children may be able to take valproic acid once a day [Cloyd et al., 1985].

Vigabatrin

Vigabatrin is a 50:50 racemic mixture of R(−) and S(+) enantiomers, with the S(+) enantiomer responsible for the drug’s pharmacologic activities and toxic effects [Haegele et al., 1983; Rey et al., 1990]. Bioavailability is approximately 75 percent in adults when the drug is given orally and is similar for both the tablet and the solution [Hoke et al., 1991]. Administration of vigabatrin with food does not significantly affect vigabatrin pharmacokinetics [Frisk-Holmberg et al., 1989]. Vigabatrin has been studied in children [Rey et al., 1989, 1990], and bioavailability appears to be somewhat lower in children than in adults [Rey et al., 1992]. Vigabatrin does not bind to plasma proteins, and it has an apparent V_d of 0.8 L/kg [Ben-Menachem, 1995b]. Clearance or the dose to concentration ratio of vigabatrin appears to be greater in children than in adults, indicating that a higher dose is needed in children to achieve a particular concentration when compared to adults [Armijo et al., 1997].

Most of a vigabatrin dose appears unchanged in the urine. Studies in infants and children show that the half-life of the inactive R(–) enantiomer, but not the half-life of the active S(+) enantiomer, increases with linear age. Vigabatrin exerts its pharmacologic effect by irreversible inhibition of GABA transaminase, causing increases in synaptic GABA concentrations by inhibiting its breakdown. Because the half-life of GABA transaminase is much longer than that of vigabatrin itself, the pharmacologic effect is determined by the half-life of the enzyme [Ben-Menachem, 1995b; Jung et al., 1977].

Zonisamide