© 2014 Direct One Communications, Inc. All rights reserved. 1 One Size Does Not Fit All: Personalized Treatment of Patients with Epilepsy Vikram R. Rao,

© 2014 Direct One Communications, Inc. All rights reserved. 1

One Size Does Not Fit All:Personalized Treatment of Patients with Epilepsy

Vikram R. Rao, MD, PhD

University of California, San Francisco, Epilepsy Center, San Francisco, California

A REPORT FROM THE 67TH ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY (AES 2013)


Personalized Treatment in Epilepsy

Epilepsy: enduring tendency for recurrent seizures

4th most common neurological disorder; lifetime prevalence is 1 in 26 individuals.

Evidence for superiority of one antiepileptic drug (AED) over another is often lacking.

AEDs are chosen based on patient-specific factors:» Genetic information» Physical characteristics and comorbid conditions» Concurrent medications

Individualizing treatment may maximize tolerability, adherence, and efficacy

Chang BS, Lowenstein DH. N Engl J Med. 2003;349:1257; Fisher RS et al. Epilepsia. 2005;46:470; Institute of Medicine, 2012; Glauser T et al. Epilepsia. 2013;54:551; French JA, Gazzola DM. Continuum. 2013;19:643


Pharmacogenomics in Epilepsy


Pharmacogenomics:Overview

Pharmacogenomics: use of biomarkers related to a patient’s genome to guide drug therapy

Chan A et al. Ann Neurol. 2011;70:684


Pharmacogenomics:To Avoid Adverse Drug Reactions

HLA-B*1502 allele predicts carbamazepine (CBZ)-induced Stevens-Johnson syndrome in patients of Han Chinese and South Asian ancestry; pre-treatment testing recommended in these patients.

HLA-A*3101 allele may be a marker of CBZ-induced drug reactions in other patient populations.

Avoid sodium channel blockers, such as lamotrigine (LTG), in syndromes with SCN1A mutation (eg, Dravet syndrome).

Research is ongoing for markers of valproate (VPA)-induced weight gain and vigabatrin retinopathy.

Chung WH et al. Nature. 2004;428:486; McCormack M et al. N Engl J Med. 2011;364:1134; Ozeki T et al. Hum Mol Genet. 2011;20:1034; Belcastro V et al. Epilepsy Res. 2013;107:1; Kinirons P et al. Epilepsy Res. 2006;70:144


Pharmacogenomics:To Predict Favorable Treatment Responses

Some previously medically refractory patients can achieve seizure freedom with levetiracetam (LEV).» Genetic basis of these “dramatic responders” is

elusive.

Functional variants of cytochrome P-450 enzymes affect phenytoin (PHT) metabolism.

SCN1A polymorphisms may influence maximum dose and serum levels of CBZ and PHT.

A patient’s genetic profile may eventually be used to determine optimal medical therapy, but ethical, financial, and legal issues abound.

Nicolson A et al. Neurology. 2004;63:568; Lynch JM et al. Epilepsy Res. 2009;83:44; Dibbens et al. Epilepsy Res. 2012;101:277; Aynacioglu AS et al. Br J Clin Pharmacol. 1999;48:409; Chaudhry AS et al. J Pharmacol Exp Ther. 2010;332:599; Tate SK et al. Proc Natl Acad Sci U S A. 2005;102:5507; Tate SK et al. Pharmacogenet Genomics. 2006;16:721; Zimprich F et al. Epilepsia. 2008;49:1108


Personalizing Drug Delivery


Personalizing Drug Delivery:Formulation Extended-release (ER) AED formulations allow

more gradual systemic absorption vs immediate-release

ER formulations offer several advantages:» Less variability in serum drug levels» Lower incidence of peak-dose toxicity» Increased patient convenience (may favor

compliance)

Benefit directly demonstrated for LTG vs ER CBZ

Potential disadvantages of ER formulations:» Higher cost» High peak serum levels may be desired when

treating seizures with predictable diurnal variation» Shorter “forgiveness period”

Bialer M. CNS Drugs. 2007;21:765; Canger R et al. Acta Neurol Scand. 1990;82:9; Brodie MJ et al. Epilepsy Res. 1999;37:81; Saetre E et al. Epilepsia. 2007;48:1292; Guilhoto LM et al. Epilepsy Behav. 2011;20:334


Rectal diazepam in solution leads to a more rapid increase in serum drug levels than rectal suppositories (basis for Diastat®)

RAMPART study: Intramuscular midazolam is superior to intravenous (IV) lorazepam for pre-hospital treatment of status epilepticus

Higher rate of seizure freedom on arrival to hospital:» Lower rates of hospital/ICU admission

» Issues: difficulty obtaining IV access; shorter half-life of lorazepam out of refrigeration

Sublingual lorazepam associated with higher rates of treatment failure compared with rectal diazepam

Personalizing Drug Delivery:Route of Administration

Knudsen FU. Acta Paediatr Scand. 1977;66:563; Kriel RL et al. Pediatr Neurol. 1999;20:282; Silbergleit R et al. N Engl J Med. 2012;366:591; Silbergleit R et al. Epilepsia. 2013;54(suppl 6):74; Malu CK et al. J Child Neurol. 2013


Setting (eg, pre-hospital vs hospital; household vs ambulance)

Clinical urgency (eg, status epilepticus vs self-limited seizure)

Ease of obtaining IV access Logistical considerations of particular

medications and formulations (eg, availability, storage requirements, cost)

Regulatory approval status and extent of data supporting clinical efficacy

Personalizing Drug Delivery:Dosing Considerations


Cutaneous Drug Reactions


Cutaneous Drug Reactions:Epidemiology

Among treatment-related side effects underlying AED intolerance, rash is one of the most common.

Adverse cutaneous drug reactions (ACDRs) affect 2% of hospitalized patients.» With AEDs, 15% of patients will develop a rash

within 4 weeks of drug initiation.

Risk factors for ACDRs:» Age» Number of comorbid conditions» Polypharmacy» Immunosuppression» Female gender (?)

Chung S et al. J Br Epilepsy Assoc. 2007;16:296; Arndt KA, Jick H. JAMA. 1976;235:918; Porter J, Jick H. JAMA. 1977;237:879; Blaszczyk B et al. Pharmacol Rep. 2013;65:399; Liao PJ et al. Int J Clin Pract. 2013;67:576; Todd G. Dermatol Clin. 2006;24:459


Broad spectrum of severity: » Mild, diffuse, morbiliform rash life-

threatening multisystem illness

Key factors for initial evaluation:» Need to determine chronicity, distribution, pattern,

organization, morphology, probable anatomic depth, and mucosal membrane involvement

Reactions that are likely immunologic:» Activated T lymphocytes and macrophages can be

found in areas of damaged skin.

Cutaneous Drug Reactions:Clinical Manifestations

Caproni M et al. Br J Dermatol. 2006;154:319


Drug reaction with eosinophilia and systemic symptoms (DRESS): » Morbiliform cutaneous eruption involving the face,

trunk, and limbs, along with fever, lymphadenopathy, hematologic abnormalities, and organ dysfunction (especially the liver)

» Mortality ~ 10%

Aromatic AEDs, particularly CBZ, and sulfonamides are the most common inciting agents.

Typically develops 2–6 weeks after treatment initiation

Several formal diagnostic criteria existHusain Z, et al. J Am Acad Dermatol. 2013;68:693; Kardaun SH et al. Br J Dermatol. 2013;169:1071; Bocquet H et al. Sem Cutan Med Surg. 1996;15:250; Kelly JP et al. J Clin Epidemiol. 1995;48:1099

Cutaneous Drug Reactions:DRESS


Stevens-Johnson syndrome (SJS): less than 10% body surface area (BSA) skin detachment

Toxic epidermal necrolysis (TEN): differs from SJS only in severity; greater than 30% of BSA involvement, higher mortality

Usually 1–3 weeks after drug initiation, prodromal phase of flu-like symptoms

PHT, PHB, CBZ, and LTG are most often associated with SJS/TEN; estimated incidence: 1–10/10,000 new users; case reports exist of other AEDs causing SJS/TEN

Tartarone A, Lerose R. Ther Drug Monit. 2010;32:669; Mockenhaupt M et al. Neurology. 2005;64:1134; Zou LP et al. Seizure. 2012;21:823; Duong TA et al. JAMA Dermatol. 2013;149:113; Naveen K et al. Int J Crit Illness Injury Sci. 2012;2:44

Cutaneous Drug Reactions:SJS/TEN


Prompt withdrawal of the offending agent and initiation of aggressive supportive care remain the mainstays of treatment

Topical corticosteroid therapy is common. Systemic corticosteroids and other

immunosuppressive agents are controversial. Intensive care or burn unit needed for

management of systemic complications and to optimize fluid status, nutrition, analgesia, and infection control

Cutaneous Drug Reactions:Treatment

Husain Z et al. J Am Acad Dermatol. 2013;68:709; Tas S, Simonart T. Dermatology. 2003;206:353


Epilepsy in Women


Epilepsy in Women:Catamenial Epilepsy

Estrogen: proconvulsant Progesterone: neuroinhibitory One-third of women with focal epilepsy

demonstrate a catamenial pattern.» Seizures occur at times during menstrual cycle

when estrogen level exceeds progesterone level or when levels of either hormone are changing rapidly.

Cyclic progesterone therapy may be beneficial for a subset of women with catamenial epilepsy.» Less robust evidence for acetazolamide and

clobazamPennell PB. Continuum. 2013;19:697; Herzog AG et al. Neurology. 2012;78:1959; Harden CL, Pennell PB. Lancet Neurol. 2013;12:72


Enzyme-inducing AEDs lead to increased clearance—and thus decreased contraceptive efficacy—of sex hormones.

Estrogen-containing contraceptives induce hepatic enzymes and may decrease the serum concentration of certain AEDs such as LTG.

Best options for women with epilepsy are long-acting reversible contraceptives:» Progestin implants

» Intrauterine devices (IUDs)

Epilepsy in Women:Contraception

Davis AR et al. Epilepsia. 2011;52:243; Reimers A et al. Epilepsia. 2005;46:1414.


Epilepsy in Women: Risk of Congenital Malformations

~3.5% of women in their reproductive years may be taking an AED for epilepsy or other indications (eg, headache, pain, or a mood disorder).

AED use increases the risk of major congenital malformations to 3%–9%, about two- to threefold higher than the risk in the general population.

Fetal exposure to valproate has been associated with dose-dependent impairment in cognitive abilities during childhood.

LTG is often considered the drug of choice during pregnancy.Pennell PB. Continuum. 2013;19:697; Meador KJ et al. Neurology. 2008;71:1109; Harden CL et al.

Neurology. 2009;73:133; Holmes LB et al. N Engl J Med. 2001;344:1132; Tomson T, Battino D. Lancet Neurol. 2012;11:803; Meador KJ et al. Lancet Neurol. 2013;12:244


Rates of major congenital malformations at one year after birth in relation to exposure to AED monotherapy

Epilepsy in Women: Risk of Congenital Malformations

Tomson T, Battino D. Lancet Neurol. 2012;11:803; Tomson T et al. Lancet Neurol. 2011;10:609


20%–33% of women with epilepsy experience an increase in seizure frequency during pregnancy.

Optimize seizure control before pregnancy; seizure freedom for at least 9 months prior to pregnancy is associated with an 84%–92% chance of remaining seizure-free during pregnancy.

Avoid polytherapy if possible Monitor therapeutic drug levels, especially of

LTG and LEV, monthly. Folic acid supplementation, 0.4–5.0 mg/d

Epilepsy in Women: Managing Epilepsy During Pregnancy

Anon. Neurology. 2006;66:354; Harden CL et al. Neurology. 2009;73:126; Pennell PB et al. Neurology. 2008;70:2130; Pennell PB, Hovinga CA. Int Rev Neurobiol. 2008;83:227; Harden CL et al. Neurology. 2009;73:142; Thomas SV. Neurol India. 2011;59:59


Epilepsy in Patients with HIV


Multiple considerations in the personalized treatment of epilepsy in patients infected with human immunodeficiency virusARV = antiretroviral therapyAED = antiepileptic drug

Epilepsy and HIV: Treatment Issues in Patients with HIV

From a presentation made by Gretchen L. Birbeck, MD, PhD, at AES 2013


Epilepsy and HIV: Drug Interactions

Concurrent use of AEDs with antiretroviral medications (ARVs) is common, and the potential interactions between these drug types are extensive, for example:» Avoid saquinavir in patients on potentially

arrhythmogenic AEDs, such as ezogabine or lacosamide

» Rilpivirine and etravirine are contraindicated with CBZ, oxcarbazepine, PHB, and PHT

» Avoid enzyme-inducing AEDs in patients taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors

» Most benzodiazepines are contraindicated with ARVs due to the risk of prolonged sedation.

AED/ARV interactions have clinical implications for disease progression and emergence of ARV resistance.

Birbeck GL et al. Neurology. 2012;78:139; Siddiqi O, Birbeck GL. Curr Treat Options Neurol. 2013;15:529


Treatment with ARVs is recommended for all HIV-positive patients, so potential drug-drug interactions should be anticipated before starting AEDs in an HIV-positive patient

The AED of choice in HIV-positive patients is LEV, due to its broad-spectrum activity, ease of use, minimal drug interactions, and favorable side-effect profile.» Alternatives: pregabalin, gabapentin, lacosamide

» Valproate is also favorable because it will not induce ARV metabolism, but its side-effect profile may be somewhat worse than that of other therapeutic options.

Siddiqi O, Birbeck GL. Curr Treat Options Neurol. 2013;15:529

Epilepsy and HIV: Management of Epilepsy

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© 2014 Direct One Communications, Inc. All rights reserved. 1 One Size Does Not Fit All: Personalized Treatment of Patients with Epilepsy Vikram R. Rao,