Download - 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