Pregabalin (Lyrica) In the Treatment of Epilepsy

Department of Neurology & Biomedical Engineering

UAB ED Staff Lunch */**/06

Current Therapies for Epilepsy

Anticonvulsants + Pregabalin Ketogenic Diet Investigational Drugs Resective surgery Disconnection procedures Vagal Nerve Stimulation Intracranial Electrical Stimulation

Reactive Neurostimulation System (RNS)

ANTICONVULSANT Phenobarbital Phenytoin Primidone Ethosuximide Carbamazepine Valproate Felbamate Gabapentin Lamotrigine Fosphenytoin Topiramate Tiagabine Levetiracetam Oxcarbazepine Zonisamide

INTRODUCED 1904 1938 1954 1960 1974 1978 1993 1993 1994 1996 1996 1997 1999 2000 2000

AED Introduction History

Pregabalin (Lyrica)
September 2005

Pfizer

Pregabalin Structure

Structural analogue of gamma amino butyric acid (GABA) S-isomer has efficacy in animal models & clinically, R-isomer has virtually none
S-(+)-3-isobutylgaba

Pregabalin Pharmacokinetics
28 clinical pharmacology studies

Absorption: max [plasma] ~1hour

Oral bioavailability: >90%

Dosing with food has no effect Elimination t1/2 = 6.3 hours

Pregabalin Distribution & Elimination

L-transporter substrate Negligible human metabolism (<2%) No hepatic induction or inhibition Does not bind to plasma proteins Elimination 90% renal unchanged Elimination proportional to renal fxn Dose correction for Cr-CL <60mL/min No differences in sex, race, age, or

menopausal status (adjust for renal fxn)

Pregabalin Absorption Linearity

Ben-Menachem, Pregabalin Pharmacology and Its Relevance to Clinical Practice, Epilepsia, 45 (Suppl. 6):13-18, 2004

Pregabalin - Drug interactions

Low interaction predicted by low metabolism, low protein binding, and lack of hepatic effects No drug interactions have been reported Studies confirm no interactions with: VPA (2), PHT, LTG, CBZ, other CNS drugs, or oral contraceptives No effect on PGB pharmacokinetics by AEDs, hypoglycemics, diuretics, or insulin Co-administration w/GBP reduces Cmax18%

M. Bodie, et al. Epilepsia, 46(9):14071413, 2005

Pregabalin-AED Interaction Data

Carbamazepine Phenytoin

CBZ-Epoxide

Lamotrigine

Valproate

M. Bodie, et al. Epilepsia, 46(9):14071413, 2005

Mechanism of Action - Not

Pregabalin:

Does not act at the GABAA, GABAB, or BZD receptor sites Is not converted into GABA Is not a GABA agonist Does not affect GABA reuptake Does not affect GABA degredation

Does not elevate GABA brain levels

Mechanism of Action

Pregabalin binds potently to the alpha-2-delta (2) protein, widely distributed in CNS & PNS

2 is an auxiliary protein associated with

voltage-gated calcium channels Pregabalin reduces (not block) depolarizationinduced Ca++ influx at nerve terminals

Reduces vesicular release of excitatory (glut, NE, Subst.-P) & likely inhibitory substances
This modulation of neurotransmitter release CONTRIBUTES to the drugs efficacy as an anticonvulsant, analgesic, and anxiolytic

Efficacy in Animal Models

EFFECTIVE

Maximal Electroshock Sound induced GTC (DBA/2 rats) Pentylenetrazol (PTZ) induced Sz Hippocampal kindled rats Profile is similar to GBP, with x2-18 the efficacy In Li-pilocarpine rat model of TLE, pregabalin delayed onset of spontaneous Sz (N-protective?)

INEFFECTIVE spontaneous absence seizure (GAERS rats)

Clinical Efficacy

3 pivotal trials involving 1052 pts

Highly refractory patients (>18 y/o)

73% on two AEDs, 23% on three AEDs

Highly effective as adjunctive Rx for partial Sz with/without 2o GTC All doses studied were effective and well tolerated (150mg-300mg-600mg/day) Statistically sig. dose-response effect Seizure reduction as early as 1 week

Clinical Trial Results

n=453 n=287 n=312

M. Bodie, Epilepsia, 45(Suppl 6):1927, 2004

Clinical Trial Results

n=453 n=287 n=312

M. Bodie, Epilepsia, 45(Suppl 6):1927, 2004

Clinical Trial Results

M. Bodie, Epilepsia, 45(Suppl 6):1927, 2004

Pregabalin Adverse Side Effects

A. Beydoun, et al., Neurology, 64:475480, 2005

Summary

Pregabalin - Effective new AED

Novel mechanism of action

Linear pharmacokinetics Low interaction with drugs & proteins No effect on liver function Renal excretion (unchanged)

Rapidly effective
Additional efficacy=angesic-anxiolytic Good tolerability