pregabalin in epilepsy

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    Pregabalin (Lyrica) In the

    Treatment of Epilepsy

    Department of Neurology

    & Biomedical Engineering

    UAB ED Staff Lunch */**/06

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    Current Therapies for Epilepsy

    Anticonvulsants

    Ketogenic Diet

    Investigational Drugs

    Resective surgery

    Disconnection procedures

    Vagal Nerve Stimulation

    Intracranial Electrical StimulationReactive Neurostimulation System (RNS)

    + Pregabalin

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    AED

    IntroductionHistory

    ANTICONVULSANT INTRODUCED

    Phenobarbital 1904

    Phenytoin 1938

    Primidone 1954

    Ethosuximide 1960

    Carbamazepine 1974

    Valproate 1978

    Felbamate 1993

    Gabapentin 1993

    Lamotrigine 1994

    Fosphenytoin 1996

    Topiramate 1996

    Tiagabine 1997

    Levetiracetam 1999

    Oxcarbazepine 2000

    Zonisamide 2000

    Pregabalin(Lyrica)

    September 2005

    Pfizer

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    Pregabalin Structure

    Structural analogue of gamma aminobutyric acid (GABA)

    S-isomer has efficacy in animal models &clinically, R-isomer has virtually none

    S-(+)-3-isobutylgaba

    http://www.biomedcentral.com/1471-2210/4/14/figure/F1?highres=yhttp://www.biomedcentral.com/1471-2210/4/14/figure/F1?highres=y
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    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

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    Pregabalin Distribution & Elimination

    L-transporter substrate Negligible human metabolism (

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    Pregabalin Absorption Linearity

    Ben-Menachem, Pregabalin Pharmacology and Its Relevance to Clinical Practice,

    Epilepsia, 45 (Suppl. 6):13-18, 2004

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    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 oralcontraceptives

    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

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    Carbamazepine

    CBZ-Epoxide

    Phenytoin

    Lamotrigine Valproate

    Pregabalin-AED Interaction Data

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

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    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

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    Mechanism of Action

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

    2 is an auxiliary protein associated withvoltage-gated calcium channels

    Pregabalin reduces (not block) depolarization-induced 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 ananticonvulsant, analgesic, and anxiolytic

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    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)

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    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 forpartial 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

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    n=453 n=287 n=312

    Clinical Trial Results

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

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    Clinical Trial Results

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

    n=453 n=287 n=312

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    Clinical Trial Results

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

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    Pregabalin Adverse Side Effects

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

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    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