The clinical relevance                                                                             adherence to therapy is...
Pharmacokinetics (PK) briefly is what            These parameters can then be inputted       skin, or from the site of an ...
distribution is a virtual volume that gives           Among the AEDs, the potential for           Metabolisman indication ...
with increased neurotoxicity. In addition       complicate the management of other co-           drugs such as pravastatin...
reduced in patients receiving enzyme inducers.16     less likely to interact with the CYP isozyme          half-lives rela...
are increased whereas protein binding isdecreased. For most AEDs, the optimal doseincreases as pregnancy progresses.19    ...
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Clinical relivance of pk interaction with anti epleptic drugs

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Clinical relivance of pk interaction with anti epleptic drugs

  1. 1. The clinical relevance adherence to therapy issues, substance abuse history, and prior history of AED use. Many of the new drugs are approved only forof pharmacokinetics adjunctive use; thus, polypharmacy and drug interactions should also be considered.3 Pharmacokinetics has an important role to play in the clinical use of AEDand drug interactions therapy.4 The term pharmacokinetics includes the quantitative assessment of changes of drug concentrations over time as awith anti epileptic drugs function of the absorption, distribution, metabolism and elimination processes. These processes determine drug plasma concentrations and in turn the drug plasma therapeutic ranges.5 PharmacokineticsJanet Mifsud BPharm(Hons), PhD(QUB) is thus important in estimating the drug dosage regimens necessary to achieve drug plasma concentrations and predictingDepartment of Clinical Pharmacology and Therapeutics, University of Malta the time to steady-state concentrationEmail: janet.mifsud@um.edu.mt that will control seizures without causing unacceptable toxicity.6 In this paper anKeywords: pharmacokinetics, drug interactions, antiepileptic drugs, epilepsy overview will be given of how a knowledge of pharmacokinetic mechanisms will determine the ideal pharmacokinetic characteristics ofNo single antiepileptic drug (AED) is appropriate in all clinical an AED, and an appreciation of the relevance of parameters such as bioavailability,situations and therapeutic decisions on the selection of the steady-state concentrations, protein-binding,appropriate AED should be made on a variety of specific factors. metabolism and clearance in AED therapy.4,7Pharmacokinetics has an important role to play in the clinical Various clinical factors such as age, underlying physiological conditions and drugpractice of antiepileptic drug therapy, as it is important in estimating interactions will also affect efficacy of AEDindividualised drug dosage regimens necessary to achieve drug plasma medication.2 Interaction among AEDs, andconcentrations without causing unacceptable toxicity. between AEDs and other classes of drugs, can result in undesirable drug levels and thus difficulty in achieving seizure control.5 In this paper an overview will be given Introduction By anticipating possible drug interactionsof how knowledge of pharmacokinetic Data from the World Health Organization or alterations in metabolism, adversemechanisms determines which indicate that as many as 1 in 20 people may effects and breakthrough seizures maypharmacokinetic characteristics an AED have an epileptic seizure during their lives be averted. An awareness of AED clinicalshould have. Various clinical factors such and that at least 1 in 200 people will have pharmacokinetics will thus aid the choice ofas age, underlying physiological conditions epilepsy.1 No single antiepileptic drug (AED) an appropriate drug and permits the designand drug interactions will also affect the is appropriate in all clinical situations and of an optimal dosage schedule for eachpharmacokinetics and efficacy of AED epileptologists agree that proper seizure patient.8medication. It will be shown how by diagnosis and classification is importantanticipating changes in pharmacokinetics in individualizing pharmacotherapy.2 What is Pharmacokinetics?due to possible drug interactions, or Therapeutic decisions should be made on Pharmacokinetics is the quantitativealterations in one of the pharmacokinetic a variety of specific factors such as seizure description of what happens to a drugparameters, adverse effects and breakthrough type(s), onset of drug effect, the presence of when it enters the body, and includes theseizures may be averted and aid in the renal or hepatic disease, possibility of drug processes of drug absorption, distribution,choice of optimal AED therapy for each or disease state interactions, the possibility metabolism and elimination / excretion -patient. of pregnancy, the age of the patient, ADME and how these processes affect the drug plasma concentrations obtained.9Figure 1. The relationship between pharmacokinetics and pharmacodynamics6 Pharmacokinetic Phase Dose Absorption Interaction with Biological Distribution Target Tissues Effect Metabolism Excretion Pharmacodynamic PhaseIssue 15 Summer 2009 Journal of the Malta College of Pharmacy Practice 23
  2. 2. Pharmacokinetics (PK) briefly is what These parameters can then be inputted skin, or from the site of an injection. Mostthe body is doing to the drug; while into mathematical formulae that allow AEDs are administered orally since epilepsypharmacodynamics (PD) is what the drug is the estimation of the best dose of a drug is a chronic condition, and thus this willdoing to the body.9 in a specific patient depending on the enhance patient compliance.7 AEDs also Pharmacodynamic effects include both pharmacokinetic parameters in that patient.7 exist as formulations that are availablewanted and unwanted drug pharmacological If multiple doses have to be administered for intravenous, intramuscular or rectaleffects. The underlying assumption is that the graph would change as represented in administration.9 Thus rectal administrationmonitoring drug plasma concentrations is Figure 3. The plasma concentrations increase e.g. with rectal diazepam is useful as ituseful since they reflect drug concentration until, at the certain point, the minimum has been shown to terminate repetitiveat the receptor site, and thus being able and maximum plasma concentrations remain seizures in children with epilepsy andto predict drug plasma concentrations is constant i.e. steady state is achieved.6 other disabilities, and can be administeredimportant since it will have a bearing on This usually takes about five half-lives and by family members at home.2 Intravenousthe dose required to obtain therapeutic drug depends on the volume of distribution administration e.g. phenytoin, phenobar­concentrations. The individualisation of the and clearance of the drug. Ideally plasma bital, diazepam, lorazepam, levetiracetamdrug doses needed for specific patients as a concentrations at steady state should be and valproic acid are generally used forresult of varying pharmacokinetics is called within the therapeutic index for the drug i.e. emergencies such as status epilepticus sinceclinical pharmacokinetics. Pharmacokinetics the concentration that achieves therapeutic the lengthy absorption phase is avoided.11is useful because the basic principles are the effect, without going subtherapeutic or toxic With oral formulations, the rate ofsame for all drugs.7 Figure 1. levels, in order to ensure that the drug is absorption and bioavailability varies widely Plasma concentration time curves are a exerting its effect maximally.7 Figure 3. by drug, formulation, patient characteristics,snap shot of what happens to the drug in the The pharmacokinetics of a drug are concomitant drugs, and food. Absorptionbody. If we had to mathematically represent estimated in the first phases of drug can also be altered by drug interactions.12what is happening a plasma concentration discovery. Ideally the drug should: Absorption depends also on the excipentstime curve is obtained.5 • Be soluble in 250ml water that make up the formulation, and in Figure 2 represents what happens to a • Have a dose size < 500 mg fact differences between AEDs fromsingle dose of drug when given by any non- • Have complete passive absorption with different manufacturers may result iniv route.6 The graph may be divided into 3 no transporters such as p-glycoprotein differences in bioavailability of the activephases: involved in absorption/effusion drug. Thus changes in drug supply mayA: an initial absorption phase • Have bioavailability >80% result in breakthrough seizures.2 CalciumB: a distribution phase • Have Linear PK containing antacids may interfere withC: an elimination phase, which is linear if • Have a half-life of 8-12 h i.e. permits a phenytoin, phenobarbital, carbamazepine, the plasma concentration axis is logged. twice daily dosing and gabapentin absorption by decreasing • Have balanced hepatic/renal clearance the acidity of the stomach and also by the This mathematical manipulation helps • Have low cytochrome (CYP450) formation of insoluble complexes that cannotus to estimate various pharmacokinetic interactions with no cytochrome-2D6 be absorbed absorption.11 Gabapentin (butparameters such as: metabolism not its chemical relative, pregabalin) is• Ka rate of absorption • Have no active metabolites and no absorbed by a saturable amino acid transport• Kel elimination rate constant genetic polymorphism in metabolic system and thus larger doses will cause• Vd volume of distribution pathways.9,10 saturation.13• T 1/2 half life of the drug Of particular concern is the issue of• Cl drug clearance – generally renal Absorption concomitant administration of an AED or hepatic Absorption is the entry of drug molecules with an enteral nutrition supplement.• F bioavailability of the drug into the systemic circulation via the mucous Concomitant administration of phenytoin membranes of the gut or lungs, via the with these nutritional formulations can result in marked reductions in oral bioavailablilty of this drug and it is commonly suggestedFigure 2. Plasma concentration time curve following a single dose not given by the IV route6 that the administration of phenytoin and enteral feedings be separated by at least 2 hours.11 Unfortunately, this may not be practical, particularly for patients requiring continuous feedings. Alternatively, clinicians can overcome this interaction by simply increasing the phenytoin dosage, and using serum drug concentrations as a guide.9 Co-administration of the newer AEDs such as valproate, levetiracetam, lamotrigine or gabapentin with enteral feeding supplements A- mostly absorption; depends on ka, F does not appear to result in significant B - mostly distribution; affected by %fu, Vd declines in AED serum concentrations.13 C- mostly elimination (renal/hepatic); Cl, t ½ Distribution Following absorption into the general circulation, the drug is distributed throughout the body. The volume of24 Journal of the Malta College of Pharmacy Practice Issue 15 Summer 2009
  3. 3. distribution is a virtual volume that gives Among the AEDs, the potential for Metabolisman indication of the extent of distribution of protein-binding interactions is greatest Enzymatic biotransformation andthe drug to the various tissues. It may vary for phenytoin and valproic acid. Both metabolism is the principal determinant ofif the patient has liver or cardiac problems or phenytoin, and valproic acid are extensively the pharmacokinetic properties of most AEDs,if the patient is pregnant.7 bound to plasma proteins (>90%). Valproic although some drugs are excreted by the Drugs are generally protein bound, to acid is also an inhibitor of cytochrome kidneys predominantly as unchanged drug.2a variable extent in the plasma, however P4502C19, one of the enzymes responsible Most AEDs exhibit linear enzyme kinetics, inthis process is reversible. It is the unbound for phenytoin metabolism.11 When these which clearance remains constant so changesdrug that crosses membranes and is thus two agents are co-adminis­ ered, unbound t in daily dose lead to proportional changesresponsible for the drug’s action (both phenytoin concentrations are higher than in serum concentration. It is to be notedtherapeutic and toxic), so changes in expected and total concen­ rations are t that some metabolites are themselves activeunbound, or free serum concentrations lower.9 In this setting, the clinician should (carbamazepine, oxcarbazepine, primidone).7have the potential to cause unanticipated consider monitoring both unbound and The metabolic pathways of AEDseffects.6 Drug-protein binding displacement total phenytoin concentrations.2 The most can vary, however, most metabolism isinteractions can occur when two highly important implication of this interaction achieved via oxidative metabolism and/protein bound agents (>90%) are is that in the presence of valproic acid or glucuronidation.9 Oxidative metabolismadministered together and compete for the “therapeutic” range of total plasma occurs via the cytochrome P450 (CYP)a limited number of binding sites.11 In phenytoin concentrations is shifted towards isoenzyme system. This system consistsmost cases, protein binding displacement lower values.12 With the exception of of three main families of enzymes: CYP1,interactions are transient clinical tiagabine (96% protein bound) an advantage CYP2, and CYP3. There are seven primaryevents, however if only total drug serum of the newer generation AEDs is that they are isoenzymes that are involved in theconcentrations are being monitored, this not extensively protein bound, and therefore metabolism of most drugs: CYP1A2, CYP2A6,may lead to misinterpretation of plasma drug in this group these types of pharmacokinetic CYP2C9, CYP2C19, CYP2D6, CYP2E1, andlevels.2 interactions are not likely.3 CYP3A4. Of these, those commonly involved with metabolism of AEDs include CYP2C9, Figure 3. Plasma concentration time curve following multiple doses given by the non IV route6 CYP2C19, and CYP3A4.14 Another important metabolic pathway for several AEDs including Cp valproic acid, lorazepam and lamotrigine is conjugation via the enzyme uridine diphosphate glucuronosyltransferase (UGT).13 By far the most important pharmacokinetic interactions with AEDs are those related to induction or inhibition of drug metabolism.6 Enzyme induction is due to increased synthesis of drug-metabolising isoenzymes in the liver and in other tissues and may be caused by carbamazepine, phenytoin, and barbiturates. If the affected drug has an active metabolite, enzyme induction can result in increased metabolite concentration and possible toxicity due to the metabolite.2 Enzyme inhibition is the phenomenon by which a drug or its metabolite blocks the Figure 4. Changes in phenytoin plasma concentration after increase in dose activity of one or more drug-metabolising due to non linear kinetics 6 enzymes, which results in a decrease in the rate of metabolism of the affected drug. This, in turn, will lead to high plasma concentrations of the drug and, possibly, clinical toxicity.14 In some cases, AED-AED interactions are bi-directional. In other words, both drugs impact the pharmacokinetics of the other. In general, enzyme inducers decrease the serum concentrations of other drugs metabolized by the same isoenzyme and enzyme inhibitors have the opposite affect.8 The bi-directional interaction between carbamazepine and valproate is one common example. In this setting, valproate can inhibit the enzyme epoxide hydrolase, which is responsible for the metabolism of the active metabolite of carbamazepine, carbamazepine- epoxide. Elevated carbamazepine -epoxide concentrations have been associatedIssue 15 Summer 2009 Journal of the Malta College of Pharmacy Practice 25
  4. 4. with increased neurotoxicity. In addition complicate the management of other co- drugs such as pravastatin and rosuvastatincarbamazepine can also significantly increase morbid disorders such as cardiovascular are not extensively metabolized, sothe metabolism of valproate, necessitating disease and affective disorders which more significant pharmacokinetic interactionslarger doses of this medication.2 commonly occur in the group of patients.12 with AEDs would not be anticipated.16 Other interactions may be of benefit The following sections provide an overview of Among the newer AEDs, only topiramatein certain cases e.g. the synergistic effect potentially clinically meaningful interactions and oxcarbazepine appear to display modestof valproic acid and lamotrigine which are that are likely to be encountered in practice. CYP3A4 inducing potential and thus themetabo­ized by (UDP)-glucuronyltranferase.14 l Tables 1-2. potential for interactions between these lipid-lowering drugs and AEDS is expectedRenal elimination Interactions of AEDs with drugs used in to be minimal. Unfortunately, at present no Elimination is the removal of drug the treatment of hypertension studies have been performed to documentmolecules from the body, usually by excretion The pharmacologic management this.11of the parent drug or metabolites through of hypertension may require multiplethe kidneys. Drug elimination rate is usually antihypertensive drugs of differing classes. Interactions of AEDs with anticoagulantsexpressed as the biological half-life and is Several commonly used antihypertensive Warfarin is administered as a racemicdefined as the time required for the serum medications may be susceptible to mixture of R- and S- enantiomers.concentration to decrease by 50% following interactions with enzyme-inducing S-warfarin is exclusively metabolized viaabsorption and distribution. The half- antiepileptic drugs.16 For example, lipophilic CYP2C9, while R-warfarin is metabolizedlife also determines the dosing frequency beta antagonists such as propranolol and by several CYP isozymes including CYP1A2required for a drug to be maintained at a metoprolol are extensively metabolized and CYP3A4.2 Since the S- enantiomer ofsteady state in the serum.6 by several isozymes of the CYP system. warfarin is considerably more active than Drugs that undergo extensive renal Therefore, larger doses of these medications the R- enantiomer, interactions involvingelimination in unchanged form may be might be required in patients receiving CYP2C9 are far more likely to have importantsusceptible to interactions affecting the AEDs, which would be expected to increase clinical consequences. Carbamazepineexcretion process, particularly when it their rate of clearance.2 Conversely, fewer and phenobarbital can in fact reduce theinvolves active transport mechanisms or potential interactions would be expected anticoagulant effect by increasing warfarinwhen the ionised state of the drug is highly with the hydrophilic beta antagonists, such metabolism.16sensitive to changes in urine pH, e.g. agents as atenolol and labetalol, which are primarily The interaction between warfarin andthat cause alkalisation of urine increase the renally excreted.15 phenytoin is far more complex. Initially,elimination of phenobarbital by reducing the Another commonly used class of the coadministration of phenytoin mayreabsorption of this acidic drug from renal antihypertensive medication are the result in an increase in anticoagulanttubuli.7 calcium channel antagonists. Drugs such effect, possibly due to the combined Particular mention should be made as felodipine, nifedipine, nicardipine, effect of protein-binding displacement andof phenytoin since it has unusual amlodipine, and nimodipine are members competitive inhibition of CYP2C92, causing apharmacokinetics which are saturable or of the dihydropyridine class of agents, and seemingly “paradoxical” anticoagulant effectnon-linear.6 In other words, unlike drugs these agents are extensively metabolized (i.e. increased prothrombin time, INR). Inthat display linear elimination kinetics by CYP3A4. Concomitant treatment with the long term however, enzyme induction(where changes in serum concentration enzyme inducers such as carbamazepine will probably lead to increased warfarinare proportional to dose), phenytoin and phenytoin can result in substantial metabolism, necessitating increased warfarinconcentrations will show disproportionate reductions in the oral bioavailability of doses.11changes in concentration following dose these medications.13 Other commonly used Clearly, in patients receiving warfarinadjustment. In clinical terms, this suggests antihypertensive drugs such as diuretics and AED treatment, careful monitoring ofthat dose adjustments with this medication and ACE inhibitors are not extensively international normalized ratios is crucial.be small since increasing the dose by 50% metabolized, and thus would not be expected Whenever possible, this drug combinationcould increase the plasma concentration four to interact with AEDs. should be avoided. Newer AEDS such asfold. 2 gabapentin, pregabalin, lamotrigine, Some AEDs eg gabapentin and pregabalin Interactions of AEDs with drugs used in levetiracetam and zonisamide do not appearare only eliminated renally and do not the treatment of lipid disorders to interact with warfarin, and may beundergo any metabolism.7 HMG-CoA reductase inhibitors safer (from a drug interaction viewpoint) (“statins”) are among the most commonly alternatives.15,16Drug interactions: impact of AED prescribed lipid-lowering medications.treatment on commonly used Lovastatin, simvastatin, and atorvastatin Interactions of AEDs with drugs used inmedical therapies are metabolized extensively via CYP3A4. the treatment of depression As has been explained, the occurrence Simvastatin and atorvastatin are also Most psychotropic drugs are metabolizedof pharmacokinetic interactions has the metabolized via glucuronidation (UGT by one or more of the CYP isozymes.14potential to substantially complicate the 1A3) in both the gut and the liver. Therefore, co-medication with an inducingmanagement of the patient with epilepsy. Fluvastatin is metabolized by CYP2C9. drug would be expected to increase theThis may be particularly true when dealing All of these agents would therefore be metabolism, and therefore systemic clearancewith the elderly patient.8 In treating the expected to be susceptible to interaction of these medications. Serum concentrationsolder patient with epilepsy, it is important with enzyme inducing AEDs.15 Indeed, one of tricyclic antidepressants such asfor the clinician to recognize that treatment pharmacokinetic study suggested that amitriptyline, nortriptyline, imipramine, andwith AEDs, particularly the older enzyme systemic exposure to simvastatin may be desipramine, as well as nontricyclics such asinducing AEDs such as phenobarbital, reduced by nearly 80% in patients receiving sertraline, paroxetine, mianserin, citalopram,phenytoin and carbamazepine15, may carbamazepine. Alternatively, other related and nefazodone, would be expected to be26 Journal of the Malta College of Pharmacy Practice Issue 15 Summer 2009
  5. 5. reduced in patients receiving enzyme inducers.16 less likely to interact with the CYP isozyme half-lives relative to adults.2 Some children Conversely, treatment with some SSRI system the likelihood of meaningful require almost twice the adult mg/kg dosage,compounds has the potential to impact AED pharmacokinetic interactions is also reduced.11 particularly if combination therapy withpharmacokinetics. For example, fluoxetine enzyme-inducers is employed.17has been shown to inhibit several CYP Patient influences on drug Despite frequent drug administration,isozymes, and concomitant treatment pharmacokinetics large swings in peak-to-peak concentrationswith phenytoin or carbamazepine may Various physiological and pathological are possible, especially in young children,result in elevated serum concentrations of conditions can influence pharmacokinetic because of their fast elimination rates.18those agents.2 In contrast to the inducers, and pharmacodynamic parameters.9 Solid oral dosage forms overcome thisvalproate can inhibit certain CYP and UGT problem by providing a longer absorptionenzymes and may cause significant increases Children phase that reduces peak and increases(50%-60%) in serum concentrations of Drug metabolism and disposition in trough concentrations. Crushed tablets areantidepressants such as amitriptyline and children can differ significantly from that preferable to liquids in younger children fornortriptyline.14 In some patients, this in adults.17 Beyond the neonatal period, similar reasons. Rapid gastrointestinal transitincrease may be sufficient to result in the when protein binding and drug metabolic times in children may, however, impedeemergence of adverse effects. Given that rates are low, children usually have faster absorption.17 In children, drug metabolismmany of the newer AEDs are, in general, drug elimination rates and reduced serum and disposition can differ significantly from that in adults. Beyond the neonatal period,Table 1. Effect of older AEDs on newer AEDs3,8,16 when protein binding and drug metabolic rates are low, children usually have faster gabapentin/ lamo- levetir- zonisa- drug elimination rates and reduced serum pregabalin trigine topiramate tiagabine acetam mide Ox-carbazepine half-lives relative to adults.8 Some children require almost twice the adult mg/kg dosage, phenytoin none i i i none i mhd1 slt particularly if combination therapy with carbamazepine none i i i none i mhd slt enzyme-inducers is employed. Furthermore, valproic acid none i none none none none none because of shorter paediatric half-lives, phenobarbital none i i i none i mhd slt most AEDs require at least three times daily primidone none i i i none i mhd slt administration in children 1-10 years of age.13 Elderly 1: Monohydroxy-derivative In the elderly, AEDs should usually be started at a lower dose and increased at Table 2. Effect of newer AEDs on older AEDs3,8,16 a slower rate than in younger patients.18 Elimination of many drugs is slower in the phenytoin carbamazepine valproic acid phenobarbital primidone elderly, mainly because of reduced hepatic and renal blood flow, which lengthens drug Gabapentin none none none none none half-life above published values based on Pregabalin young adults. In addition, albumin levels lamotrigine none none i 25% none none fall with age; this increases the free fraction topiramate may h none none none none of drugs that are highly protein bound, thus tiagabine none none none none none increasing risk of toxicity, especially for zonisamide none none none none none highly protein-bound drugs.17 Regarding the levetiracetam none none none none none elderly, elimination of many drugs is slower, oxcarbazepine none none none none none mainly because of reduced hepatic and renal blood flow, which lengthens drug half-life Table 3. Summary of PK characteristics of AEDS3,4,8,16 above published values based on young adults.2 In addition, albumin levels fall with Drug Absorption Elimination Half life Protein Causes age and this increases the free fraction of (Hours) binding interactions drugs that are highly protein bound, thus increasing risk of toxicity, especially for Carbamazepine 80% 100% hepatic 6 -12 75-80% yes highly protein-bound drugs. Further, older Valproic Acid 100% 90% hepatic 12-20 85-95%; yes people are often more sensitive to drug Phenobarbitone 100% 75% hepatic 17-124 50% yes effects at a given free level. In the elderly, Phenytoin 95%, 100% hepatic 12-60 70-95% yes AEDs should usually be started at a lower Clobazebam 90%; 100% 10-50 83% yes dose and increased at a slower rate than in Gabapentin < 60% 100% renal 5-8 0% no younger patients.8 Flebamate well absorbed 40-49% renal 13-30 20-25% yes Lamotrigine 98% 100% hepatic 18-30 55% yes Pregnancy Pregnancy increases the volume of Levetiracetam 100% 66% renal 4-8 <10% no distribution and the rate of drug metabolism, Oxcarbazepine (MHD) 100% 100% hepatic 5-11 40% yes and decreases protein binding. For most Pregabilin 90% 90% renal no AEDs, the optimal dose increases as Tiagabine 96%. 97% hepatic 5-13 96% no pregnancy progresses.2 It is also noteworthy Topiramate >80%; 30-55% renal 18-30 15% yes that in cases of pregnancy, the volume of Zonisamide 80-100% 50-70% hepatic 50-80 40-60%. no distribution and the rate of drug metabolismIssue 15 Summer 2009 Journal of the Malta College of Pharmacy Practice 27
  6. 6. are increased whereas protein binding isdecreased. For most AEDs, the optimal doseincreases as pregnancy progresses.19 • Pharmacokinetics is the quantitative description of what happens to a drug when it enters the body, and is important in estimating the drug dosage regimens necessary toOthers Fever can increase the metabolic rate, achieve drug plasma concentrations without causing unacceptable toxicity.resulting in more rapid drug elimination and • Knowledge of pharmacokinetic mechanisms will determine the ideal pharmacokineticlower serum con­ entrations. Febrile illnesses c characteristics of an AED, and an appreciation of the relevance of parameters such asmay also elevate serum proteins that bind bioavailability, steady-state concentrations, protein-binding, metabolism and clearanceAEDs, resulting in decreased free levels.2 in AED therapy. Severe hepatic disease impairs • Various clinical factors such as age, underlying physiological conditions and drugmetabolism, increasing serum levels and risk interactions will also affect efficacy of AED medication.of toxicity of many drugs. However, complex • Interaction among AEDs, and between AEDs and other classes of drugs, can resultinteractions among hepatic blood flow, in undesirable drug levels and thus difficulty in achieving seizure control. Bybiliary excretion, and hepatocellular function anticipating possible drug interactions or alterations in metabolism, adverse effects andmake the net effect of hepatic disease on breakthrough seizures may be averted.drug levels difficult to predict.18 Renal disease reduces elimination of • An awareness of AED clinical pharmacokinetics will thus aid the choice of an appropriatesome drugs such as gabapentin. In chronic drug and permits the design of an optimal dosage schedule for each patient.renal disease where there is protein loss, onecan commonly see a higher free fraction of antiepileptic drugs for several reasons.9 that drug interactions may occur not onlyhighly protein bound AEDs which then are Patients with epilepsy generally require when an inducer or inhibitor is added tomore susceptible to elimination lower serum chronic therapy, and, therefore, a dosing a patient’s medication regimen, but alsoconcentration of the drug. More frequent Practice points strategy that enhances compliance is when the inducing (e.g. carbamazepine) ordoses may need to be given. Effects of essential. Also, many patients will be inhibiting (e.g. valproate) agent is removed.dialysis differ among AEDs. Some, such as prescribed two or more antiepileptic drugs, Removal of an enzyme-inducing drugphenobarbital, are significantly removed.2 often times at the highest possible doses.8 will result in “deinduction,” and if dosesTable 3. Additionally, all patients with chronic are not adjusted, serum concentrations of epilepsy can be expected to develop during many metabolized concomitant drugs mayPK parameters and drug interactions of their lifetime concomitant nonepilepsy- increase.2 Loss of enzyme induction canAEDs: which way to go? related diseases that require additional drug occur with days to several weeks following Determining the pharmacokinetics and therapy, increasing the potential for drug discontinuation of the inducing drug. Giventhe avoidance of durg-drug interactions interactions and toxicity. Thus, it is desirable that it will take about five half-lives for theare useful selection criteria for AED that the drugs do not cause interactions that previously induced medication to reach aselection. Indeed, the characterization of can precipitate toxicity.13 new steady-state level, these de-inductionthe clinical pharmacokinetic profile of a new Finally, it is important to recognize that interactions may have an insidious onset.10antiepileptic drug is an integral and early drug interactions are not a “one-way street”. Thus good knowledge of thecomponent of drug development.9 Interactions can be bi-directional, meaning pharmacokinetic mechanisms of the various Consequently, pharmacokinetic that two drugs can influence each other.18 AEDs will significantly aid the decision ofconsiderations are especially relevant with In addition, another important concept is which dosing strategy is the most efficient and enhance clinical therapy of AEDs.References1. Shorvon SD. Drug treatment of epilepsy in the 8. Gidal BE. Pharmacokinetics of the new 14. Lynch T, Price A. The effect of cytochrome P450 century of the ILAE: the second 50 years, 1959- antiepileptic drugs. Am J Manag Care. 2001 metabolism on drug response, interactions, 2009. Epilepsia. 2009 Mar;50 Suppl 3:93-130. Jul;7(7 Suppl):S215-20. and adverse effects. Am Fam Physician. 20072. Sander JW The use of antiepileptic drugs-- 9. Perucca E, Johannessen SI. The ideal Aug 1;76(3):391-6. Review. principles and practice. Epilepsia. 2004;45 Suppl pharmacokinetic properties of an antiepileptic 15. Hachad H, Ragueneau-Majlessi I, Levy RH.New 6:28-34. drug: how close does levetiracetam come? Epileptic antiepileptic drugs: review on drug interactions.3. Tidwell A, Swims M. Review of the newer Disord. 2003 May;5 Suppl 1:S17-26. Ther Drug Monit. 2002 Feb;24(1):91-103 antiepileptic drugs. Am J Manag Care. 2003 10. Steinhoff BJ et al., The ideal characteristics of 16. Perucca E. Clinically relevant drug interactions Mar;9(3):253-76; quiz 277-9. AED therapy: an overview of old and new AEDs Act with antiepileptic drugs Br J Clin Pharmacol. 20064. Bourgeois BFD Pharmacokinetic properties of Neurol Scand Feb 2003; 107:87-95. Mar;61(3):246-55. current antiepileptic drugs. Neurology 2000; 55 : 11. Beyenburg S, Bauer J, Reuber M New drugs for 17. Gilman JT et al., PK consideration in the treatment D3 11-16. the treatment of epilepsy: a practical approach. of childhood epilepsy. Paediatric Drugs 2003;5. Eadie MJ. Therapeutic drug monitoring-- Postgrad Med J. 2004 Oct;80 (948):581-7. 5:267-277. antiepileptic drugs. Br J Clin Pharmacol. 2001;52 12. Berkovic SF. Treatment with anti-epileptic 18. Poza JJ. Management of epilepsy in the elderly. Suppl 1:11S-20S. drugs. Aust Fam Physician. 2005 Dec;34(12):1017- Neuropsychiatr Dis Treat. 2007 Dec;3(6):723-8.6. Rang HP, Dale MM, Ritter JM, Flower RJ. 20. 19. Penovich PE, Eck KE, Economou VV. Pharmacology 6th Edition. Chapter 7 and 13. Deckers CLP et al., Selection criteria for the clinical Recommendations for the care of women with8. Churchill Livingston. 2007. use of the newer antiepileptic drugs. CNS Drugs epilepsy. Cleve Clin J Med. 2004 Feb;71 Suppl7. Faught E. PK considerations in prescribing AEDs. 2003; 17:405-421 2:S49-57. Epilepsia 2002; 42:19-23.28 Journal of the Malta College of Pharmacy Practice Issue 15 Summer 2009

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