Epilepsy Pharmacotherapy: Treatment Considerations with Older AEDs BARRY E. GIDAL, PHARMD PROFESSOR SCHOOL OF PHARMACY & DEPT. OF NEUROLOGY Disclosures Speaking honoraria: UCB, Eisai, Sunovion Consultant: UCB, Eisai, Sunovion, Upsher-Smith, Acorda, Epilepsy Consortium AED Options Focal Generalized Tonic Tonicclonic Myoclonic Atonic Infantile Spasms Absence Phenytoin, Carbamazepine eslicarbazepine, Phenobarbital, Gabapentin, Tiagabine, Oxcarbazepine Perampanel Pregabalin Lacosamide i b t i Vigabatrin ACTH Ethosuximide Valproate, Lamotrigine, Topiramate, Felbamate Zonisamide, Levetiracetam, lamotrigine, preampanel, rufinamide
Challenges in AED Treatment Co-morbidities Pharmacokinetic issues Pharmacodynamic issues Noncompliance Limited data on efficacy and side effects of AEDs in the elderly Pharmacokinetic Interactions Absorption Adsorption Intestinal Metabolism Transporters Distribution Protein Binding Transporters BBB distribution of drug? Elimination Renal Excretion Hepatic Metabolism polymorphic metabolism? AEDs & Solubility Low Solubility: Phenytoin Carbamazepine Lamotrigine Zonisamide oxcarbazepine
Hepatic Drug Metabolism CYP450 UGT 1A 2 2E 1 2C 9 2C1 9 2D 6 3A 4 1A 3 1A 4 1A 9 2B 7 AED effects on Drug Metabolizing Isozymes Older Enzyme inducers (CYP1A2, 2C, 3A, UGTs) carbamazepine phenytoin phenobarbital Inhibitor VPA (CYP2C19, UGT, EH) Newer No effects on CYP: levetiracetam lamotrigine zonisamide vigabatrin Gabapentin/pregabalin Lacosamide rufinamide Modest inducer Oxcarbazepine, Eslicarbazepine, topiramate (CYP3A) Inhibitors Topiramate, oxcarbazepine, Eslicarbazepine (CYP2C19) Anderson GD. Pharmacokinetics and Drug Interactions. In: : Treatment of Epilepsy. Principles and Practice. Wyllie eds. 6 th. Ed. 2015, 530-538 Traditional AEDs Carbamazepine Phenytoin Sodium Valproate Phenobarbital
Carbamazepine: Absorption/Distribution Tablet 80% absorbed compared to solution Slow, erratic absorption Peak = 6-12 hours Suspension: more rapidly absorbed Sustained/controlled release tablet & sprinkle Give BID IV form finally on the way with cyclodextrin vehicle 80-85% protein bound - albumin and alpha 1 acid glycoprotein Guerreiro C, Guerreio M, Mintzer S. Carbamazepie, Oxcarbazepine, Eslicarbazepine. In: Treatment of Epilepsy. Principles and Practice. Wyllie eds. 6 th. Ed. 2015, 615-625 Metabolism 100% metabolized by the liver Carbamazepine epoxide--major metabolite CBZ CBZ-epoxide CBZ dihydrodiol epoxide CYP 3A4 hydrolase Active metabolite Equal anticonvulsant activity to CBZ May be responsible for many CNS adverse effects Autoinduction of CYP 3A4 Adult single dose t ½ = 33 hours (18-55 hrs) vs approximately 15 hours in chronic dosing: Takes 4-6 weeks to get maximum auto induction. Adverse Effects CNS side effects common (35-50%), more common during initiation therapy, and may dissipate with chronic therapy diplopia ataxia drowsiness headache dizziness anticholinergic side effects blurred vision urinary retention, dry mouth, etc. paresthesias hyponatremia nystagmus
Adverse Effects Hematologic Leukopenia Transient leukopenia (2000-4000) and low platelet count is common Thrombocytopenia Aplastic anemia 1/50,000 incidence, fatal in 50%. Most patients on other drugs concurrently Hepatitis Rash Teratogenicity Osteoporosis CBZ RASH - Genetics Increased risk of serious rash (toxic epidermal necrolysis, Stevens-Johnson syndrome) in patients with HLA-B*1502 & HLA-A 3101 Found almost exclusively in patients with Asian ancestry -10-15% of patients from China, Thailand, Philippines, Malaysia and Indonesia may test positive. Far less common (1%) in patients from Japan or Korea HLA-A 3101 2-5% prevalence in N. European Gidal BE. Carbamazepine Hypersensitivity: Progress toward predicting the unpredictable. Epilepsy Curr. 2011 Nov;11(6):189-91. doi: 10.5698/1535-7511-11.6.189. Powell G, Holmes EA, et al. Pharmacogenetic testing prior to carbamazepine treatment of epilepsy: patients' and physicians' preferences for testing and service delivery. Br J Clin Pharmacol 2015;80:1149-59 Phenytoin Absorption/Distribution Good overall bioavailability, but may display marked day-to-day variability in absorption. Decreased & delayed absorption with larger doses (>400 mg) Extensively protein bound 90% to serum albumin Renal failure, hypoalbuminemia, pregnancy, liver disease - alter protein binding Conway J, Morita DA, Glauser TA.Phenytoin and Fosphenytoin. In: Treatment of Epilepsy. Principles and Practice. Wyllie eds. 6 th. Ed. 2015, 691-704
Individual Total Phenytoin Serum Concentrations in Elderly Nursing Home Residents 35 Total PHT Concentrations (ug/ml) 30 25 20 15 10 5 Aged 65-74 (n=18) Aged 75-84 (n=21) Aged 85+ (n=17) 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 Individual Elderly Residents Categorized by Age Group at Enrollment Birnbaum et al, Neurology, 60:555-559 (2003) PHENYTOIN: Metabolism Pharmacokinetics Long t ½ : mean = 18.5-24 hrs range = 7-42 hrs Michaelis-Menten metabolism, 90-95% liver metabolized by saturable kinetics CYP 2C9 & 2C19 isozymes involved Genetic slow and fast metabolizers Liver disease - decreased metabolism Phenytoin-Simulated Dosing Requirements in Elderly vs Younger Adults Phenytoin Concentration (mg/l) 60 50 40 30 20 10 0 0 2 4 6 8 Daily Dose (mg/kg) as PHT Acid Elderly (aged 65-79 years) 1 Vmax=5.5 mg/kg/day Km=5.8 mg/l Nonelderly (aged 19-64 years) 2 Vmax=8.45 mg/kg/day Km=6.25 mg/l Differences in PHT content Capsules 92% Infatabs 100% Suspension 100% 1. Bauer LA, Blouin RA. Clin Pharmacol Ther. 1982;31:301-304. 2. Cloyd J, et al. Presented at: 10th Epilepsy International Symposium; 1978; Vancouver, British Columbia.
Phenytoin: Adverse Effects Concentration related Nystagmus (> 20 ug/ml) Ataxia (> 30 ug/ml) Confusion (> 40 ug/ml) Encephalopathy Phenytoin: Adverse effects Rash 5-10% (no genetic link confirmed yet) Gingival hyperplasia (30%-50%) Hirsutism and coarse facial features Osteopenia/osteoporosis- possibly related to increased Vit.D metabolism Vitamin D Metabolism 7-DehydroCholesterol Degradation P450C24 25-HydroxyVitamin D 3 Kidney 1α hydroxylase P450C1 Skin, UVB Liver 25 Hydroxylase P450C25/27 Degradation P450C24 Vitamin D 3 1, 25-HydroxyVitamin D 3
Sodium Valproate (VPA): Absorption 90-100% absorption for syrup and capsules Time to peak: 0.5-1.0 hr syrup 1.0-2.0 hr regular capsules 3.0-8.0 hr enteric coated tablets Birnbaum AK, Marino S. Valproate. In: Treatment of Epilepsy. Principles and Practice. Wyllie eds. 6 th. Ed. 2015, 726-733 VPA: Distribution Saturable protein binding within therapeutic range [VPA] < 50 ug/ml FF = 7-11% [VPA] 50-100 ug/ml FF = 11-15% [VPA] 100-150 ug/ml FF = 15-25% [VPA] 150-200 ug/ml FF = 25-30% VPA Metabolism 97% metabolized by the liver Glucuronidation, beta-oxidation - major routes CYP mediated oxidation - minor T ½ = 14 hrs (5-22 hr) adults 11 hrs (5-15 hr) children Polytherapy with inducers can double clearance
VPA: Adverse Effects Concentration related side effects - Drowsiness Tremor Confusion - encephalopathy Hyperammonemia Inhibition of platelet aggregation, lowering of platelet count? Drug induced Parkinsonism VPA: Adverse Effects Alopecia Weight gain Hepatotoxicity Transient elevated LFTs is common (15-30%) Fatal hepatotoxicity rare, highest incidence age 0-2 years only few cases in adults > 2 years Usually poorly controlled seizures, mental retardation, polytherapy Prodrome: loss of seizure control, malaise lethargy, drowsiness, weakness, vomiting anorexia, jaundice Incidence increases with polytherapy with inducers Usually occurs 0-3 months (mean 60 days) Pancreatitis--rare, primarily seen in children Teratogenicity Menstrual cycle abnormalities PCO & VPA Treatment Unifying Hypothesis Valproate related weight gain Obesity Insulin resistance Increased insulin secretion SHBG Hyperinsulinemia IGFBP-1 Bioactive androgens Ovarian androgen 1 synthesis Bioactive IGF- Structural changes in the ovaries