38 • DOSAGE FORM CONSIDERATIONS IN THE TREATMENT OF PEDIATRIC EPILEPSY 529 10% to 20%, which makes it difficult to administer an effective dose (82). Oxcarbazepine Clemens et al performed a study in 10 healthy volunteers to characterize the bioavailability of rectally administered oxcarbazepine suspension (300 mg/5 mL) diluted 50% with water. Mean relative bioavailability calculated from plasma AUCs was 8.3% (SD 5.5%) for monohydroxy derivative (MHD) and 10.8% (SD 7.3%) for OXC. The C max and AUC differed significantly between routes for both MHD and OXC (P Ͻ 0.01). The total amount of MHD excreted in the urine following rectal administra- tion was 10 Ϯ 5% of the amount excreted following oral administration. Oral absorption was consistent with pre- vious studies. The most common side effects were head- ache and fatigue with no discernable difference between routes. MHD bioavailability following rectal administra- tion of OXC suspension is significantly less than after oral administration, most likely because of OXC’s poor water solubility. It is unlikely that adequate MHD concentra- tions can be reached by rectal administration of diluted OXC suspension (83). Paraldehyde Rectally administered paraldehyde has been widely used to control severe seizures, particularly in children (84, 85). However, information on the efficacy, toxicity, and pharmacokinetics is limited. Rectal bioavailability is 75% to 90% versus 90% to 100% for the oral route. Time to peak concentrations after rectal administration is 2.5 hours versus 0.5 hours for oral administration. Paralde- hyde should be diluted with an equal volume of olive oil or vegetable oil to reduce mucosal irritation. Phenobarbital There is no commercially available rectal dosage form for phenobarbital. Graves and coworkers gave seven volunteers phenobarbital sodium parenteral solution rectally and intramuscularly (86). After rectal administra- tion absorption was 90% complete, with a time to peak concentration of 4.4 hours versus 2.1 hours for the IM injection. Suppositories containing phenobarbital sodium are more rapidly absorbed than phenobarbital acid given either orally or intramuscularly (87, 88). Phenytoin Occasionally, there arises a need to administer phenytoin rectally, although no commercial rectal dosage form is available. Several studies of investigational suppository formulations have failed to demonstrate absorption. Rectal administration of phenytoin sodium parenteral solution in dogs produced low but measurable serum concentrations, but absorption was slow (89). Rectal administration of phenytoin is not recommended. Valproic Acid Valproic acid absorption has been studied after rectal administration of diluted syrup and suppositories. Rectal absorption of the commercially available syrup is complete, with peak concentrations occurring approximately 2 hours after a dose (90–92). High osmolality necessitates 1:1 dilu- tion of the syrup to minimize catharsis. The syrup has been used to treat status epilepticus when other therapy is ineffective. Various suppository formulations are absorbed well, albeit more slowly than the syrup, with time to peak concentration occurring in 2 to 4 hours (93, 94). Topiramate Topiramate is also readily absorbed following rectal administration. In a study of twelve healthy subjects who received either 100 or 200 mg of topiramate orally and a 200 mg dose of topiramate given rectally, the relative bioavailability (F rel ), which was determined by calculat- ing the dose-normalized areas under the concentration time curves, was 0.72 Ϯ 0.18 h/L for the rectal dose and 0.76 Ϯ 0.20 h/L for the oral dose.The relative bio- availability for topiramate administered rectally was 0.95 Ϯ 0.17 with a range of 0.68 Ϯ 1.2 (95). Zonisamide Nagatomi et al investigated two zonisamide supposito- ries compared with IV and oral dosing in rats (96). The bioavailability of the hydrophilic base was 96%, and that from the lipophilic base was 108%. The C max following both rectal suppositories was significantly greater than an equal oral dose, and T max occurred faster after the hydrophilic-based suppository (2 hrs) than after either the lipophilic-based or the oral dose (4 hrs). STUDIES OF OTHER ADMINISTRATION ROUTES Buccal/Sublingual Buccal/sublingal administration of diazepam and loraz- epam has been recommend by some clinicians as a part of routine clinical practice. However, there are no studies documenting their efficacy. Limited data exist for pharma- cokinetic and efficacy for this route of administration. Buccal administration of midazolam was studied in 10 healthy adults in a study in which 2 mL of the IV • GENERAL PRINCIPLES OF THERAPY 530 intravenous preparation of midazolam 5 mg/mL fla- vored with peppermint was held in the mouth for 5 min- utes, then spat out. The researchers found that changes on electroencephalography were observed within 5 to 10 minutes of administration of the drug, suggesting rapid absorption and onset of effect (97). In a random- ized controlled trial conducted in a hospital emergency department, the safety and efficacy of buccal midazolam were compared with those of rectal diazepam (98). The dose used for each drug was determined by the age of the child, with a target dose of about 0.5 mg/kg (from 2.5 mg for children aged 6 to 12 months; 4 mg for those 1 to 4 years; 7.5 mg for those 5 to 9 years; and 10 mg for those 10 years or older). A total of 219 episodes of acute seizures in 177 children were treated.Therapeutic success was defined as cessation of seizure within 10 minutes of drug administration without respiratory depression and without seizure recurrence within 1 hour. A postivie out- come was achieved in 56% of patients treated with buc- cal midazolam, compared with 27% of patients treated with rectal diazepam (P Ͻ0.001; odds ratio [OR] 4.1, 95% CI 2.2–7.6). Median time to seizure termination was 8 minutes (range: 5–20 minutes) for buccal midazolam and 15 minutes (range: 5–31 minutes) for rectal diazepam (P ϭ 0.01; hazard ratio [HR] 0.7; 95% CI 0.5–0.9). Greenblatt et al compared the pharmacokinetics of sublingual lorazepam with IV, IM, and oral LZP (99). Ten healthy volunteers randomly received 2 mg of LZP in the following five formulations: IV injection, IM injection, oral tablet, sublingual administration of the oral tablet, and sublingual administration of a specially formulated tablet. Peak plasma concentrations, time to peak concen- trations, elimination half life, and relative bioavailability were not significantly different among the formulations. Peak concentrations were highest for the IM route, fol- lowed by oral and sublingual; time to peak concentrations was most rapid for the IM route, followed by sublingual and oral. Mean relative bioavailabilities were high for all routes: IM (95.9%), oral (99.8%), sublingual of oral tab- let (94.1%) and sublingual of special tablet (98.2%). It should be noted, however, that the efficacy, safety, duration of effect, and ease of buccal/sublingal adminis- tration by nonmedical caregivers have not been evaluated in settings outside of hospitals. INTRANASAL Several benzodiazepines possess the physical, chemical, and pharmacokinetic properties required of effective nasal therapies. Among the benzodiazepines considered for intranasal administration, midazolam has been most extensively studied. In one randomized, open-label trial involving 47 children with prolonged (Ͼ10 minutes) febrile seizures, the safety and efficacy of intranasal midazolam (0.2 mg/kg) were compared with those of intravenous diazepam (0.3 mg/kg) administered over 5 minutes (100). Intranasal midazolam was as safe and effective as intravenous diazepam and resulted in earlier cessation of seizures as a result of rapid administration. However, the role of intranasal midazolam in treat- ing seizure emergencies remains to be established. There are no adequately controlled trials demonstrating the safety and efficacy of intranasal midazolam for out-of- hospital treatment. Moreover, the short elimination half- life of midazolam—especially in patients taking enzyme- inducing drugs—raises concern as to whether its duration of effect is satisfactory in out-of-hospital settings. Intranasal lorazepam has also been studied (101). Intranasal LZP was absorbed with a mean percent bioavail- ability of 77.7 Ϯ 11.1%. A double-peak concentration- time curve was observed, indicating possible secondary oral absorption. The time to peak concentration was vari- able, ranging from 0.25–2 hours. Lorazepam’s relatively limited lipid solubility as compared with that of mid- azolam or diazepam results in a slower rate of absorption and onset of action. Diazepam has a lipid solubility and potency com- parable with those of midazolam and a much longer elimination half-life, properties that make it a good can- didate for intranasal administration. The bioavailability of a novel intranasal diazepam formulation has been compared with that of intranasal midazolam in healthy volunteers (n ϭ 4) (102). Both midazolam and diazepam were rapidly absorbed, but diazepam’s absorption was more extensive and its half-life longer than that of mid- azolam. Compared with rectally administered diazepam, the nasal diazepam formulation is absorbed to the same extent, but appears to be more rapidly absorbed, resulting in attainment of maximum concentrations as much as 30 minutes earlier (103). Nasogastric Tubes A nasogastric (NG) tube offers an alternative route of drug delivery. However, drug may adhere to the tubing, clog the tubing, or not be absorbed. Occlusion of the tube by the drug is also a concern. Tube occlusions may require replacement of the tube, which is both costly and incon- venient for the patient. Recently, it has been demonstrated that sustained-release carbamazepine (Carbatrol ® ) can be opened, mixed with 0.9% sodium chloride or apple juice as diluents, and reliably delivered through an NG tube or feeding tube 12 French or greater in size (104, 105). Topiramate has also been reported to be effective in patients with status epilepticus when given through an NG tube (106). However, absorption from nasogastric tubes is not always comparable to orally administered formula- tions. When patients who are receiving tube feedings are 38 • DOSAGE FORM CONSIDERATIONS IN THE TREATMENT OF PEDIATRIC EPILEPSY 531 switched from IV phenytoin (fosphenytoin) to oral phe- nytoin administered via a nasogastric tube, there appears to be decreased absorption of the oral formulation. This seems to occur regardless of whether the suspension or the oral capsule dosage form is used. Although the mechanism has not been clearly documented, it has been postulated that phenytoin may bind to proteins in the enteral feeding. Also, the enteral feeding may increase the GI motility, which may decrease the absorption (107). Sometimes very large oral doses may need to be given to maintain the desired serum concentrations in patients receiving phenytoin and enteral feedings via a nasogastric tube. Some practitioners try to stop the enteral feedings for two hours before and two hours after the dose of phe- nytoin. IM fosphenytoin would be an alternative (3). SUMMARY The selection of AED dosage forms is very important in pediatric epilepsy. Patients may be unwilling or unable to take oral solid dosage forms. Therefore, the avail- ability of alternative oral dosage forms such as suspen- sions, solutions, and sprinkles is important. Patients who experience concentration-dependent side effects or breakthrough seizures may realize improved control by switching to an alternative dosage form. For example, a controlled-release formulation will provide lower peaks and higher troughs, facilitating better seizure control with less toxicity. Although it has been the practice to crush oral solids and mix the contents with food, this is not always desir- able. Some products, such as Phenytek ® , Depakote-ER, Depakote ® , and Tegretol-XR ® , lose the properties they were designed to provide if the structure of the prepa- ration is disrupted. In some cases, the rate or extent of absorption may be altered when the drug is given with food. It also has been a custom to compound pediatric dosage forms extemporaneously. This is an important way to provide drug in a form that young children can take. However, clinicians should be cautious about extempora- neous compounding of pediatric formulations unless they can determine the amount of drug in the formulation, the stability of the product, and the bioavailability. This requires an assay for the compounded product and an assay of the drug in blood. In addition, with compounded drugs, someone should taste the preparation before it is given to the patient. For example, gabapentin has a very bitter taste when it is put into solution. Therefore, when a drug is compounded for pediatric delivery, the new formulation should be tested to ensure that it is being delivered properly. Specialized dosage forms generally are more expensive. Caregivers should be thoroughly educated in drug administration techniques for children. When carefully instructed, caregivers can properly administer medications (108). Drug administration techniques are summarized in Tables 38-4, 38-5, and 38-6. When doses are given as “teaspoonfuls,” caregivers should have a calibrated device for measuring the dose rather than using a com- mon utensil. The volume of “standard” teaspoons varies up to fourfold. Drugs given rectally, such as diazepam, require special caregiver education. Clinical assessment, selection of a drug, and deter- mination of the dose require special attention in the TABLE 38-4 Medication Administration Guidelines for Infants Use a calibrated dropper or oral syringe. Support the infant’s head while holding the infant in lap. Give small amounts of medication to prevent choking. If desired, crush non–enteric-coated tablets to a powder and sprinkle on small amounts of food. Provide physical comforting to calm the infant while administering medications. TABLE 38-5 Medication Administration Guidelines for Toddlers Allow child to choose a position in which to take medications. Disguise the taste with a small volume of flavored drink or food. Rinse mouth with flavored drink to remove aftertaste. Use simple commands in the toddler’s jargon to obtain cooperation. Allow the toddler to choose which medi cations to take first. Allow toddler to become familiar with the oral dosing device. TABLE 38-6 Medication Administration Guidelines for Preschool Children Place tablet or capsule near back of tongue and provide water or a flavored liquid to aid in swallowing. Do not use chewable tablets if the child’s teeth are loose. Use a straw to administer medications that may stain teeth. Use a rinse with a flavored drink to minimize aftertaste. Allow child to help make decisions about dosage forms, place of administration, which medication to take first, and the type of flavored drink to use. IV • GENERAL PRINCIPLES OF THERAPY 532 pediatric patient, as does the selection of the appropri- ate formulation and dosage form. This last step in the therapeutic plan plays a pivotal role in the ultimate suc- cess of therapy. 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Administration of Carbatrol ® to children with feeding tubes. Pediatr Neurol 2002; 27(3):193–195. 106. Towne AR, Garnett LK, Waterhouse EJ, et al. The use of topiramate in refractory status epilepticus. Neurology 2003 Jan 28; 60(2):332–334. Review. 107. Au Yeung SC, Ensom MH. Phenytoin and enteral feedings: does evidence support an interaction? Ann Pharmacother 2000 Jul-Aug; 34(7–8):896–905. Review. 108. McMahon SR, Rimsza ME, Bay RC. Parents can dose medication accurately. Pediatrics 1997; 100:330–333. 535 Principles of Drug Interactions: Implications for Treatment with Antiepileptic Drugs harmacokinetic interactions, some- times leading to adverse clinical sit- uations, have long been recognized as an occasionally unavoidable facet of antiepileptic drug (AED) treatment (1, 2). Since the mid-1990s, a number of newer AEDs have entered the marketplace, both in the United States and globally. One general advantage of these newer medications is an improved pharmacokinetic profile, including a reduced potential for participating in drug-drug interactions, as compared to the older medications. The aim of this chapter is to summarize in-vitro and in-vivo data regarding drug interactions with both the newer as well as the older, traditional AEDs in terms of absorption, distribution, protein binding, and hepatic induction and inhibition. Clinical implications of these interactions will also be discussed. PATIENTS AT RISK Patients perhaps at the greatest risk for drug interac- tions are usually those who are the most severely ill. This includes patients in the intensive care unit, geriatric patients, premature neonates, and young children. Drug Barry E. Gidal interactions may be a significant contributor to both patient morbidity and mortality (3, 4). Clinicians should recognize that as a group, patients with epilepsy, including both children and adults, tend to receive more medications than does the general population. As the number of concomi- tant medications increases, so does the likelihood of drug interactions. The patients with the most refrac- tory epilepsy are consequently more likely to encounter problems with drug interactions related to concomi- tant AED therapy than their controlled counterparts. Although, historically, more attention has been paid to AED-to-AED interactions, there has been increasing attention to the potential for certain AEDs to interact (perhaps adversely) with other concomitant medica- tions that patients may be receiving. MECHANISMS FOR COMMON DRUG INTERACTIONS Oral Absorption of Drugs Most AEDs are well absorbed following oral administra- tion. However, absorption of some compounds can be altered by drug-drug or drug-food interactions. These P 39 IV • GENERAL PRINCIPLES OF THERAPY 536 interactions can affect maximum plasma concentration, time to reach maximum concentration, and even over- all extent of absorption. Among the older, traditional AEDs, oral absorption of phenytoin appears to be the most problematic. Of particular concern is the issue of concomitant administration of an AED with an enteral nutrition supplement. Concomitant administration of phenytoin with these nutritional formulations can result in marked reductions in oral bioavailablity (4–6). Because of this interaction, it is commonly suggested that the administration of phenytoin and enteral feed- ings be separated by at least 2 hours. Unfortunately, this may not be practical, particularly for patients requiring continuous feedings. Alternatively, clinicians can over- come this interaction by simply increasing the phenyt- oin dosage and using serum drug concentrations as a guide. This approach is also problematic. If for example, enteral feedings are discontinued, or interrupted for a significant period of times, and phenytoin doses are not readjusted downward, there will likely be a marked rise in phenytoin concentrations, potentially leading to drug intoxication. If possible, therefore, this drug-nutrient interaction should be avoided. Concomitant ingestion of food may also delay the rate of absorption of older agents such as valproic acid but is unlikely to impact overall absorption (7). Generally speaking, oral absorption interactions with the newer-generation AEDs are unlikely to be of clinical significance in most patients. Unlike older, tradi- tional compounds such as phenytoin or carbamazepine, the newer-generation AEDs tend to be quite water soluble and are rapidly and completely absorbed. Indeed, in con- trast to the problems described for phenytoin, absorp- tion of newer-generation agents such as gabapentin, lamotrigine, and levetiracetam does not appear to be impaired when coadministered with enteral nutritional supplements (8–9). When topiramate is administered with food, the rate of absorption is decreased, delaying time to maximum concentration by approximately 2 hours and decreasing mean maximum concentration by approximately 10%, with no significant effect on overall extent of absorp- tion. Conversely, when oxcarbazepine is given with food, the mean maximum serum concentrations of the active monohydroxy metabolite is increased by 23% (10–11). Whether this is clinically meaningful is unclear. Coadministration of levetiracetam with food delays the time to peak concentration by approximately 1.5 hours and decreases the maximum concentration by 20%; however, the extent of absorption is not affected. Mixing with enteral feeding formulas does not appear to result in significant impairment of absorption, over and beyond that seen with concomitant administration with food (12). Role of Drug Transporter Proteins ATP-dependent drug transporters, including members of the multidrug resistance protein (MRP) family and P-glycoprotein (Pgp), have been implicated as a major limiting factor in drug pharmacokinetics (13). Pgp and MRP are located on the apical side of capillary endothe- lial cells and are thought to extrude drug molecules back into blood (or intestine) from cells. These efflux pumps appear to act in conjunction with drug-metabolizing enzymes such as CYP 3A4 to limit drug access to both the systemic circulation and various cellular compartments (14). This may be clinically important, in that several of the older AEDs, such as carbamazepine, display the abil- ity to induce the activity of CYP 3A4 and Pgp (15). At the intestinal level, induction of both CYP 3A4 and these efflux pumps would serve to significantly reduce the oral bioavailability of a number of medications. While most attention has been focused on the role of these trans- porters in modulating oral drug absorption, it has also become clear that these transporter proteins are localized in a variety of tissues including the liver, kidney, blood- brain barrier, and placenta. In addition to potentially limiting oral drug absorption or blood-brain barrier pen- etration, these drug efflux pumps may be important in protecting the fetus from drug/chemical exposure. Several studies have now demonstrated that PgP is expressed in the trophoblast layer of the placenta and may provide an important mechanism of protection to the fetus from maternal drug exposure (16). IS PROTEIN BINDING RELEVANT? In most cases, changes in protein binding are not clinically significant, but in some situations these alterations, as a result of either changes in protein concentration (e.g., hypo- albuminemia) or protein binding displacement, may lead to misinterpretation of serum drug concentrations (17). Protein binding displacement interactions can occur when two highly protein-bound (Ͼ90%) agents are administered together and compete for a limited num- ber of binding sites. Typically, the drug with the greater affinity for the binding site displaces the competing agent, increasing the unbound fraction of the displaced drug. It is the unbound drug concentration that is responsible for the drug’s pharmacologic activity. Unbound drug con- centrations are dependent on the drug dose and drug- metabolizing activity of enzymes (intrinsic clearance). Unbound drug concentrations may rise initially follow- ing the concomitant administration of two competing drugs but should return to preinteraction values fairly quickly. In other words, these interactions are transient. Total concentrations of drug, however, will be lower than 39 • PRINCIPLES OF DRUG INTERACTIONS: IMPLICATIONS FOR TREATMENT WITH ANTIEPILEPTIC DRUGS 537 expected. If serum concentrations are being monitored, this may lead to misinterpretation. Among the AEDs, the potential for protein-binding interactions is greatest for phenytoin and valproic acid. Both phenytoin and valproic acid are extensively bound to plasma proteins (Ͼ90%). Valproic acid is also an inhibitor of cytochrome P450 2C19, one of the enzymes responsible for phenytoin metabolism. When these two agents are coadministered, unbound phenytoin concentra- tions are higher than typically expected and total (bound ϩ unbound) concentrations are lower (16). When using this combination, it may be prudent to monitor unbound phenytoin concentrations as well as total. With the exception of tiagabine (96% protein bound), an advantage of the newer-generation AEDs is that they are not extensively protein bound, and therefore these types of pharmacokinetic interactions are not likely. Metabolism: Implications of Enzyme Induction and Inhibition Most clinically relevant drug interactions result from alterations in drug metabolism, either in the liver or in the gut. Drug-metabolizing enzyme induction can result in an increased rate of metabolism of the affected drug, leading to both decreased oral bioavailability and increased systemic clearance of extensively metabolized concomitant medica- tions. The clinical result therefore would be potentially sub- therapeutic serum concentrations of that drug. Conversely, a number of drugs (including several AEDs) have been shown to be inhibitors of various drug-metabolizing enzymes, and concomitant administration of these agents can slow the rate of metabolism of the affected drug and cause increased serum levels of drug, leading to toxicity. The metabolic pathways of AEDs can vary; however, most metabolism is achieved via oxidative metabolism and/or glucuronidation (18–20). Oxidative metabolism is accomplished via the cytochrome P450 (CYP) isoen- zyme system. This system consists of three main families of enzymes: CYP1, CYP2, and CYP3. There are seven primary isoenzymes that are involved in the metabolism of most drugs: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Of these, the ones com- monly involved with metabolism of AEDs include CYP2C9, CYP2C19, and CYP3A4 (21). Another important meta- bolic pathway for several AEDs, including valproic acid, lorazepam, and lamotrigine, is conjugation via the enzyme uridine diphosphate glucuronosyltransferase (UGT). Although they do not necessarily contraindicate AED therapy, these pharmacokinetic interactions can clearly complicate therapy in individuals receiving multi- ple AEDs. In some cases, it may be difficult to distinguish whether a change in a person’s clinical state (change in seizure frequency or appearance of toxicity) is due to an additive pharmacologic effect of the added drug or simply due to a change in serum concentration in the original AED. One approach to rational polytherapy would be to combine agents that do not interact with each other. In this way, the confounders of changes in drug disposi- tion can be excluded from the evaluation of therapeu- tic response to combined AED treatment. Interactions between AEDs and hepatic enzymes are summarized in Table 39-1 and discussed in the following paragraphs. Hepatic Enzyme Induction. Compounds that are hepatic inducers increase the synthesis of enzyme protein and thus increase the capacity for drug metabolism. Induction of hepatic enzymes occurs over a gradual period of days to TABLE 39-1 Effect of Antiepileptic Drugs on CYP Isoenzymes or Other Enzyme Systems DRUG EFFECT ON METABOLISM ENZYMES Phenobarbital, carbamazepine, Inducers Broad CYP, UGT phenytoin inducers Valproic acid Inhibitor CYP 2C19, UGT, Epoxide hydrolase Gabapentin, pregabalin No effect Lamotrigine Weak inducer UGT Levetiracetam No effect Oxcarbazepine Inducer (modest) CYP3A4 Tiagabine No effect — Topiramate Inhibitor (modest) CYP2C19 Inducer (modest) CYP 3A4 Vigabatrin None Zonisamide No effect IV • GENERAL PRINCIPLES OF THERAPY 538 weeks and is a reversible process. Addition of an inducer will cause a lowering of serum concentrations of the tar- get drug, conceivably resulting in inadequate therapeutic response. Conversely, removal of an enzyme inducer will cause a rise in the levels of the target drug, potentially causing toxicity. Among the older-generation AEDs, carbamazepine, phenytoin, and the barbiturates phenobarbital and primi- done are inducers of both the cytochrome P450 (CYP) and UGT enzyme systems (18). Combining these agents with other AEDs that are metabolized by either of these enzyme systems can result in markedly enhanced sys- temic clearance, and reduced serum concentrations of the affected drug, requiring higher doses in order to main- tain comparable (as compared to monotherapy) steady- state serum concentrations. An example of this sort of interaction would be the combination of phenytoin and lamotrigine. Lamotrigine is extensively (Ͼ90%) metabolized hepatically by N-glucuronidation via UGT 1A3 and UGT 1A4. Lamotrigine does not appear to significantly alter concentrations of carbamazepine or carbamazepine epox- ide (21, 22) nor any of the other AEDs. However, the half- life of lamotrigine is reduced from 24 hours to 15 hours when administered with enzyme-inducing drugs as just described. Following the withdrawal of the enzyme induc- ers carbamazepine and phenytoin, lamotrigine plasma concentrations have been observed to increase by 50% and 100 %, respectively (23). Levetiracetam shows limited metabolism in humans, with 66% of the dose renally excreted unchanged. Its major metabolic pathway is via hydrolysis of the acet- amide group to yield a carboxylic derivative, which is mainly recovered in the urine. Levetiracetam is not sig- nificantly metabolized by CYPs or UGTs and appears to be devoid of pharmacokinetic drug interactions (24, 25). Similarly, the drugs gabapentin and pregabalin appear to be devoid of enzyme-inducing (or inhibition) properties. Oxcarbazepine is converted to 10-hydroxycarbam- azepine (OHCZ), the metabolite primarily responsible for pharmacologic activity. This active metabolite is mostly excreted by direct conjugation to glucuronic acid. Oxcar- bazepine does not seem to be a broad-spectrum enzyme inducer, although it does posses modest, specific induc- tion potential toward the CYP3A subfamily, as evidenced by the increased metabolism of estrogens and dihydro- pyridine calcium channel antagonists (1, 2). Clinicians should be aware that this drug does indeed have modest potential for causing enzyme induction interactions, but that this potential may vary among different patients. Topiramate is approximately 60% excreted unchanged in the urine. It is also metabolized by hydrox- ylation and hydrolysis. Two of its metabolites are con- jugated as glucuronides. While not considered a potent enzyme inducer, topiramate can increase clearance of val- proate by approximately 13% and may lower oral con- traceptive serum concentrations (26, 27). Whether these changes in valproic serum concentration are clinically meaningful is unclear. Topiramate metabolic clearance can be increased when it is administered with enzyme- inducing AEDs, thereby reducing half-life and lowering serum concentrations by up to 40%. Zonisamide is a synthetic 1,2-benzisoaxole deriva- tive that is metabolized in large part by reduction and conjugation reactions. Oxidative reactions involving CYP3A4 and CYP2D6 are also involved. Zonisamide elimination can be altered by other drugs. Specifically, enzyme-inducing drugs such as carbamazepine and phe- nytoin can significantly increase the clearance of this drug, effectively reducing the half-life of zonisamide by about half. Hepatic Inhibition. Hepatic enzyme inhibition can occur when two drugs compete for the same enzyme site, reduc- ing the metabolism of the target drug. A resultant increase in the object drug can occur if a substantial portion of the target drug is prevented from occupying the enzyme site. Inhibition is usually a rapid process that is dose/ concentration dependent. Addition of an enzyme inhibitor may cause a very rapid rise in serum concentrations of the target drug, potentially leading to acute toxicity (18). In contrast to enzyme induction, inhibition of selected CYP and/or UGT enzymes can be caused by several AEDs of both the older and newer generations. These combinations may result in unexpectedly high serum concentrations of the affected AED. An exam- ple is the interaction of valproic acid and lamotrigine. Lamotrigine’s half-life is increased to approximately 59–70 hours when it is coadministered with valproate, resulting from valproate’s inhibition of glucuronidation. Inhibition of lamotrigine clearance can occur at val- proate doses as low as 125–250 mg/day and becomes maximal at dosages approaching 500 mg/day (28). The clinical implication is that lamotrigine dose and dose escalation will need to be substantially reduced in order to reduce the potential for adverse effects (including perhaps severe rash). Topiramate may decrease the clearance of phenyt- oin, suggesting inhibition of CYP2C19. Topiramate has been shown to increase phenytoin serum concentration in some patients. While this interaction is not clinically meaningful in most patients, given the non-linear phar- macokinetics of phenytoin, the potential does exist for this interaction to result in phenytoin intoxication. A significant advancement of oxcarbazepine over carbamazepine is its lack of susceptibility to inhibitory interactions. Consistent with its differing metabolism (as compared to carbamazepine), oxcarbazepine’s pharmaco- kinetics are not altered by erythromycin. Oxcarbazepine [...]... Genton P, et al, eds Epileptic 40 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 • ACTH AND STEROIDS Syndromes in Infancy, Childhood, and Adolescence 3rd ed London/Paris: John Libbey, 2002:81–103 Oguni H, Tanaka T, Hayashi K, Funatsuka M, et al Treatment and long-term prognosis of myoclonic-astatic epilepsy of early childhood Neuropediatrics 2002; 33:122–132 Landau WM, Kleffner FR Syndrome... from randomized adjunctive therapy trials Epilepsy Res 2003; 53: 47 56 Rosenfeld WE, Liao S, Anderson G,et al Comparison of the steady-state pharmacokinetics of topiramate and valproate in patients with epilepsy during monotherapy and concomitant therapy Epilepsia 19 97; 38:329–333 Zupanc M Antiepileptic drugs and hormonal contraceptives in adolescent women with epilepsy Neurology 2006; 66Suppl 3): 37 45... JD Jr, Glaze DG High-dose, long-duration versus low-dose, shortduration corticotropin therapy for infantile spasms J Pediatr 1994; 124:803–806 Vigevano F, Cilio MR Vigabatrin versus ACTH as first-line treatment for infantile spasms: a randomized, prospective study Epilepsia 19 97; 38:1 270 –1 274 Yanagaki S, Oguni H, Hayashi K, et al A comparative study of high-dose and low-dose ACTH therapy for West syndrome... Neurology 19 57; 7: 523–530 Dulac O Epileptic encephalopathy Epilepsia 2001; 42 Suppl 3:23–26 McKinney W, McGreal DA An aphasic syndrome in children Can Med Assoc J 1 974 ; 110:6 37 639 Marescaux C, Hirsch E, Finck S, Maquet P, et al Landau-Kleffner syndrome: a pharmacologic study of five cases Epilepsia 1990; 31 :76 8 77 7 Lerman P, Lerman-Sagie T, Kivity S Effect of early corticosteroid therapy for LandauKleffner... shows 1- to 3-Hz high-amplitude spikes and slow waves; these may be unilateral, bilateral, unifocal, or multifocal, but often include the temporal region with or without parietal and occipital involvement, and are activated during sleep Valproate and benzodiazepines may control the clinical seizures but have only a partial and transient effect on the EEG abnormalities (72 ) In 1 974 , McKinney and McGreal... clobazam in the treatment of epilepsy was pioneered by Gastaut and Low, who reported its effectiveness in patients with partial seizures, idiopathic generalized epilepsy, reflex epilepsy, and Lennox-Gastaut syndrome (129) The antiepileptic effect of clobazam in partial and tonic-clonic seizures has been demonstrated in several placebo-controlled studies (121) In addition, clobazam monotherapy has been demonstrated... through the actions of progesterone on its receptor (100) The anticonvulsant effects of androgens may be mediated, in part, through actions of the testosterone metabolite and neuroactive steroid 5 alpha-androstane-3 alpha, 17 alpha-diol (3 alpha-diol) at GABAA receptors (91) Potential for Clinical Use Since progesterone and 3-reduced pregnane steroids have potent anticonvulsant effects, attempts to develop... by a 10-week taper (25) A multiple-daily-dose regimen is recommended to produce the sustained elevations of plasma cortisol demonstrated in high-dose ACTH therapy Adverse Effects of ACTH and Steroids ACTH and steroids, particularly at the high doses recommended for infantile spasms, can produce dangerous side effects These are more frequent and more pronounced with ACTH ( 37) Cushingoid features and extreme... JW, Myers GJ ACTH and prednisone in childhood seizure disorders Neurology 1983; 33:966– 970 Singer WD, Rabe EF, Haller JS The effect of ACTH therapy upon infantile spasms J Pediatr 1980; 96:485–489 Hrachovy RA, Frost JD Jr, Kellaway P, et al A controlled study of prednisone therapy in infantile spasms Epilepsia 1 979 ; 20:403– 477 Siemes H, Brandl U, Spohr H-L, et al Long-term follow-up study of vigabatrin... vigabatrin on developmental and epilepsy outcomes to age 14 months: a multicentre randomized trial Lancet Neurol 2005; 4 :71 2 71 7 Snead OC, Chiron C Medical treatment In: Dulac O, Chugani HT, Dalla Bernardina B, eds Infantile Spasms and West Syndrome London: WB Saunders, 1994:244–256 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 Heiskala H, Riikonen . out-of-hospital settings. Intranasal lorazepam has also been studied (101). Intranasal LZP was absorbed with a mean percent bioavail- ability of 77 .7 Ϯ 11.1%. A double-peak concentration- time. pharmacokinetic evaluation of twice-daily extended-release carbamazepine and four-times daily immediate-release carbamazepine in patients with epilepsy. Epilepsia 1998; 39: 274 – 279 . 41. Stevens RE, Limsakun. children. Acta Paediatr Scand 1981; 70 :369– 372 . 73 . Albano A, Reisdorff J, Wiegenstein JG. Rectal diazepam in pediatric status epilepticus. Am J Emerg Med 1989; 70 :168– 172 . 74 . Dreifuss FE, Rosman