View
216
Download
1
Category
Preview:
Citation preview
Adjunctive Drug TherapyAdjunctive Drug Therapy for Advanced Parkinson’s Disease for Advanced Parkinson’s Disease
Combination Strategies andCombination Strategies and
Sequencing PharmacotherapySequencing Pharmacotherapy
Adjunctive Drug TherapyAdjunctive Drug Therapy for Advanced Parkinson’s Disease for Advanced Parkinson’s Disease
Combination Strategies andCombination Strategies and
Sequencing PharmacotherapySequencing Pharmacotherapy
Lawrence Elmer, MD, PhDProgram Chairman
Associate ProfessorDepartment of Neurology
University of ToledoCollege of Medicine
Lawrence Elmer, MD, PhDProgram Chairman
Associate ProfessorDepartment of Neurology
University of ToledoCollege of Medicine
The Science and Medicine The Science and Medicine of Parkinson’s Diseaseof Parkinson’s Disease
Stages of Parkinson’s DiseaseStages of Parkinson’s Disease
► Mild symptoms, no disabilityMild symptoms, no disability► Non-pharmacological approachesNon-pharmacological approaches
► Moderate symptoms with some disabilityModerate symptoms with some disability► Multiple treatments available including l-dopaMultiple treatments available including l-dopa
► Progression of symptomsProgression of symptoms► Levodopa required +/- other medsLevodopa required +/- other meds
EarlyEarly ModerateModerate AdvancedAdvanced
► Disease progressesDisease progresses► Non-motor complications mayNon-motor complications may outweigh motor disturbances outweigh motor disturbances
Adjunctive Drug Therapy for Advanced PD
Report of the Quality Standards Subcommittee of theAmerican Academy of Neurology 2006
Early or Moderate Stage Management of PDEarly or Moderate Stage Management of PD
► Level A – MAO-B inhibitors – selegiline, Level A – MAO-B inhibitors – selegiline, rasagilinerasagiline► Level A – Dopamine agonists – pramipexole, ropinirole, Level A – Dopamine agonists – pramipexole, ropinirole,
rotigotinerotigotine – – caution in elderly, cognitive impairment, young caution in elderly, cognitive impairment, young males (?)males (?)
► Level A - Carbidopa/levodopa – immediate releaseLevel A - Carbidopa/levodopa – immediate release► Level B - Carbidopa/levodopa – controlled releaseLevel B - Carbidopa/levodopa – controlled release
RecommendedRecommended
Years 1-5 (possibly more?)Years 1-5 (possibly more?)
QuestionableQuestionable ► Co-enzyme Q10Co-enzyme Q10► AmantadineAmantadine
Therapeutic Agents
Adjunctive Drug Therapy for Advanced PD
Miyasaki, JM, et al., Neurology 2002;58:11–17O. Suchowersky, et al., Neurology 2006; 66: 976-982
Long-term Treatment of Parkinson’s Disease Long-term Treatment of Parkinson’s Disease Associated with Motor ComplicationsAssociated with Motor Complications
Adjunctive Drug Therapy for Advanced PD
Goals of Current Therapeutic StrategiesGoals of Current Therapeutic Strategies
Adjunctive Drug Therapy for Advanced PD
DADA GABAGABA
AChACh
StriatumStriatum
Substantia NigraSubstantia NigraSubstantia NigraSubstantia Nigra
LevodopaLevodopaLevodopaLevodopa
AnticholinergicsAnticholinergics
Sites of Action of PD Drugs: 1960’sSites of Action of PD Drugs: 1960’s
Adjunctive Drug Therapy for Advanced PD
DADA GABAGABA
AChACh
StriatumStriatum
LevodopaLevodopa
AmantadineAmantadine
SelegilineSelegiline
Dopamine agonistsDopamine agonists BromocriptineBromocriptine PergolidePergolide
AnticholinergicsAnticholinergics
BBBBBB CarbidopaCarbidopa BenserazideBenserazide
MAO-BMAO-B
Sites of Action of PD Drugs: 1990’sSites of Action of PD Drugs: 1990’s
Adjunctive Drug Therapy for Advanced PD
DADA GABAGABA
AChACh
StriatumStriatum
Substantia NigraSubstantia Nigra
LevodopaLevodopa
AmantadineAmantadine
SelegilineSelegiline Dopamine agonistsDopamine agonists BromocriptineBromocriptine PergolidePergolide PramipexolePramipexole PopinirolePopinirole
BaclofenBaclofen
AnticholinergicsAnticholinergics
BBBBBB CarbidopaCarbidopa BenserazideBenserazide TolcaponeTolcapone EntacaponeEntacapone
MAO-BMAO-B
Sites of Action of PD Drugs: 2000Sites of Action of PD Drugs: 2000
Adjunctive Drug Therapy for Advanced PD
DADA GABAGABA
AChACh
StriatumStriatum
Substantia NigraSubstantia Nigra
LevodopaLevodopaAmantadineAmantadine
SelegilineSelegilineZydis selegilineZydis selegilineRasagilineRasagiline
Dopamine agonistsDopamine agonists ApomorphineApomorphine BromocriptineBromocriptine PergolidePergolide PramipexolePramipexole RopiniroleRopinirole RotigotineRotigotine
BaclofenBaclofen
AnticholinergicsAnticholinergics
BBBBBB CarbidopaCarbidopa BenserazideBenserazide TolcaponeTolcapone EntacaponeEntacapone
MAO-BMAO-BStalevo®Stalevo®(carbidopa/levodopa/entacapone)(carbidopa/levodopa/entacapone)
Parcopa®Parcopa®
Sites of Action of PD Drugs: 2008Sites of Action of PD Drugs: 2008
Adjunctive Drug Therapy for Advanced PD
Singh, et al, Progress in Neurobiology, 81:29-44 (2007).
Sites of Action of Pharmacological Sites of Action of Pharmacological Therapies Currently Prescribed for PDTherapies Currently Prescribed for PD
Sites of Action of PD Drug Treatment: EmergingSites of Action of PD Drug Treatment: Emerging
Adjunctive Drug Therapy for Advanced PD
DAGABA
ACh
StriatumStriatum
Substantia NigraSubstantia Nigra
Other Receptor TargetsOther Receptor TargetsSerotonergic AntagonistsSerotonergic AntagonistsAdenosine AntagonistsAdenosine Antagonists
AMPA AntagonistsAMPA AntagonistsAdrenergic AntagonistsAdrenergic Antagonists
Dopamine agonistsDopamine agonistsControlled-releaseControlled-releaseNovel DA’sNovel DA’sNasal spraysNasal spraysOther transdermalOther transdermal
MAO-B
Extended levodopaExtended levodopadelivery systemsdelivery systems
Advanced Management of PDAdvanced Management of PDTreating Motor FluctuationsTreating Motor Fluctuations
► Level A – entacapone, rasagilineLevel A – entacapone, rasagiline► Level B – pramipexole, ropinirole, tolcapone - Level B – pramipexole, ropinirole, tolcapone - caution caution
hepatotoxicityhepatotoxicity► Level C – apomorphine, cabergoline, and selegilineLevel C – apomorphine, cabergoline, and selegiline► Level C (surgical) – STN deep brain stimulationLevel C (surgical) – STN deep brain stimulation► Level C (dyskinesias) - amantadineLevel C (dyskinesias) - amantadine► Disregarded – bromocriptine, sustained release Disregarded – bromocriptine, sustained release
carbidopa/levodopacarbidopa/levodopa
EvidenceEvidence
Years 1-3 and followingYears 1-3 and following
Adjunctive Drug Therapy for Advanced PD Pahwa, R., et al., Neurology 2006;66:983–995
Published Reductions in “OFF” Time:Published Reductions in “OFF” Time:Moderate to Advanced PDModerate to Advanced PD
Pahwa, R., et al., Neurology 2006;66:983–995 Appendix E-1
DrugDrug DurationDuration ActiveActive PlaceboPlacebo Treatment EffectTreatment Effect
pramipexolepramipexole 32 week32 week 31%* (1.8 h)31%* (1.8 h) 7% (0.2 h)7% (0.2 h) 24% (1.6 h)24% (1.6 h)
pramipexolepramipexole 40 week40 week 15%*15%* 3%3% 12%12%
ropiniroleropinirole 12 week12 week 23%*23%* 4%4% 19%19%
ropiniroleropinirole 26 week26 week 11.7%*11.7%* 5%5% 6.7%6.7%
ODT selegilineODT selegiline 12 week12 week 32% (2.2 h)*32% (2.2 h)* 9% (0.6 h)9% (0.6 h) 23% (1.6 h)23% (1.6 h)
rasagiline (0.5mg)rasagiline (0.5mg) 26 week26 week 23% (1.4h)*23% (1.4h)* 15% (0.9 h)15% (0.9 h) 8% (0.5 h)8% (0.5 h)
rasagiline (1.0mg)rasagiline (1.0mg) 26 week26 week 29% (1.8h)*29% (1.8h)* 15% (0.9 h)15% (0.9 h) 14% (0.9 h)14% (0.9 h)
rasagilinerasagiline 18 week18 week 21% (1.2 hr)*21% (1.2 hr)* 7% (0.4 h)7% (0.4 h) 14% (0.8 h)14% (0.8 h)
tolcapone (100mg tid)tolcapone (100mg tid) 12 week12 week 32% (2.3 h)32% (2.3 h) 20% (1.4 h)20% (1.4 h) 12% (0.9 h)12% (0.9 h)
tolcapone (200mg tid)tolcapone (200mg tid) 12 week12 week 48% (3.2 h)*48% (3.2 h)* 20% (1.4 h)20% (1.4 h) 28% (1.8 h)28% (1.8 h)
tolcapone (100mg tid)tolcapone (100mg tid) 12 week12 week 31.5%*31.5%* 11%11% 20.5%20.5%
entacaponeentacapone 18 week18 week 21% (1.2 h)*21% (1.2 h)* 7% (0.4 h)7% (0.4 h) 14% (0.8 h)14% (0.8 h)
entacaponeentacapone 24 week24 week 25.8% (1.6 h)*25.8% (1.6 h)* 13.4% (0.9 h)13.4% (0.9 h) 12.4% (0.7 h)12.4% (0.7 h)
entacaponeentacapone 24 week24 week 23.6% (1.3 h)*23.6% (1.3 h)* 1.9% (0.1 h)1.9% (0.1 h) 21.7% (1.2 h)21.7% (1.2 h)
Goals of Current Therapeutic StrategiesGoals of Current Therapeutic Strategies
Adjunctive Drug Therapy for Advanced PD
Plasma Levels – Rotigitine CDSPlasma Levels – Rotigitine CDS
Adjunctive Drug Therapy for Advanced PD
Adjunctive Transdermal SystemAdjunctive Transdermal System
Adjunctive Drug Therapy for Advanced PD
UPDRS Motor Scores Following UPDRS Motor Scores Following Intermittent SC ApomorphineIntermittent SC Apomorphine
R. Pfeiffer, L. Gutmann, K. Hull, Jr., P. Bottini, J. Sherry; Parkinsonism & Related Disorders, 13:93-100 (2007).
Effect Of Tolcapone On Levodopa- Effect Of Tolcapone On Levodopa- Induced Improvement In PDInduced Improvement In PD
Mot
or s
core
impr
ovem
ent
Mot
or s
core
impr
ovem
ent
MinutesMinutes
Roberts et al, 1994.
LD doseLD dose
0
2
4
6
8
10
12
14
16
0 60 120 180 240
TolcaponePlacebo
Percentage Reduction in Off-time and Percentage Reduction in Off-time and Levodopa with COMT InhibitionLevodopa with COMT Inhibition
Rajput, A. H. et al. Neurology. 1997 Oct;49(4):1066-71.
22
-20-20-21-21
-32-32-24-24
-48-48-60-60
-50-50
-40-40
-30-30
-20-20
-10-10
00
1010
% Reduction in off time% Reduction in off time % Reduction in Ldopa dose% Reduction in Ldopa dose
PlaceboPlacebo Tolcapone 100 mg tidTolcapone 100 mg tid Tolcapone 200 m tidTolcapone 200 m tid
Adjunctive Drug Therapy for Advanced PD
Lew M, Kricorian G., World Congress of Neurology 2005
Long-term Surveillance of Long-term Surveillance of Tolcapone HepatotoxicityTolcapone Hepatotoxicity
► Entacapone prolongs the half-life of levodopa by Entacapone prolongs the half-life of levodopa by 85%,85%,with no change in Cwith no change in Cmaxmax or T or Tmaxmax
► Increases levodopa exposure by Increases levodopa exposure by 35%35%
Effect of Entacapone onEffect of Entacapone onLevodopa PharmacokineticsLevodopa Pharmacokinetics
Buottinen HM, et al. J Neurol Neurosurg Psychiatry. 1996. Diagnosis and Treatment of Parkinson’s Disease: Update 2004
Entacapone in Fluctuating PDEntacapone in Fluctuating PD
► Five (5) pivotal randomized, placebo-Five (5) pivotal randomized, placebo-controlled, double blind studiescontrolled, double blind studies● Increase in “on” time of approximatelyIncrease in “on” time of approximately
1 to 2 hours1 to 2 hours● Reduction in “off” time 1 to 1.5 hoursReduction in “off” time 1 to 1.5 hours● Reduction in daily levodopa dose ofReduction in daily levodopa dose of
33 to 140 mg33 to 140 mg● Improvement in UPDRS “on” scoreImprovement in UPDRS “on” score
► Five (5) pivotal randomized, placebo-Five (5) pivotal randomized, placebo-controlled, double blind studiescontrolled, double blind studies● Increase in “on” time of approximatelyIncrease in “on” time of approximately
1 to 2 hours1 to 2 hours● Reduction in “off” time 1 to 1.5 hoursReduction in “off” time 1 to 1.5 hours● Reduction in daily levodopa dose ofReduction in daily levodopa dose of
33 to 140 mg33 to 140 mg● Improvement in UPDRS “on” scoreImprovement in UPDRS “on” score
Ruottinen 1996; PSG 1997; Rinne 1998; Poewe 2002; Brooks 2003.
Zydis Selegiline: Zydis Selegiline: Reduction in “Off” Time at 12 WeeksReduction in “Off” Time at 12 Weeks
BaselineWeeks 10-12
Zel
apar
Pla
cebo0
5
10
15
20
25
30
35
40
45%
Wa
kin
g H
ou
rs "
OF
F"
Time
Reduction in % Waking Hours "OFF"
Zelapar
Placebo
32%*
*p<0.001 Observation Period
Adjunctive Drug Therapy for Advanced PD Waters CH, et al., Mov Disord 2004;19:426-32
Adjunctive Drug Therapy for Advanced PD
Lew M, Kricorian G. Long-term treatment of Parkinson's disease with a novel MAO-B inhibitor: analysis of safety and efficacy J Neurol Sci 2005;238 Suppl 1:S363
Zydis Selegiline: Zydis Selegiline: Long-term Follow-upLong-term Follow-up
Adjunctive Drug Therapy for Advanced PD
Lew M, Kricorian G. Long-term treatment of Parkinson's disease with a novel MAO-B inhibitor: analysis of safety and efficacy J Neurol Sci 2005;238 Suppl 1:S363
Zydis Selegiline: Zydis Selegiline: Long-term Follow-up – Concomitant MedsLong-term Follow-up – Concomitant Meds
Zydis SelegilineZydis Selegiline
CharacteristicCharacteristic Continuing Continuing (n=171),n (%)(n=171),n (%)
Prior PlaceboPrior Placebo(n=83),n (%)(n=83),n (%)
All PatientsAll Patients(n=254) ),n (%)(n=254) ),n (%)
Dopamine agonists Dopamine agonists AnticholinergicsAnticholinergics
4 (2.3)4 (2.3)3 (1.8)3 (1.8)
2 (2.4)2 (2.4)0 (0)0 (0)
6 (2.4)6 (2.4)3 (1.2)3 (1.2)
Rasagiline: Reduction in “OFF” Time Rasagiline: Reduction in “OFF” Time Similar to EntacaponeSimilar to Entacapone
Ch
ang
e fr
om
Bas
elin
e C
han
ge
fro
m B
asel
ine
( Ho
urs
)H
ou
rs)
-1.20-1.20-1.18-1.18
-0.40-0.40
Rasagiline 1 mgRasagiline 1 mgRasagiline 1 mgRasagiline 1 mg
Entacapone 200 mgEntacapone 200 mg Entacapone 200 mgEntacapone 200 mg
Placebo-LD/DDIPlacebo-LD/DDIPlacebo-LD/DDIPlacebo-LD/DDI
-0.2-0.2-0.2-0.2
-0.7-0.7-0.7-0.7
-2.2-2.2-2.2-2.2
-1.2-1.2-1.2-1.2
-1.0-1.0-1.0-1.0
P = 0.0001P = 0.0001P < 0.0001P < 0.0001
Adjusted Means ±SE
Rascol. Lancet. 2005; 365:947-54.Rascol. Lancet. 2005; 365:947-54.
All patients on LD/DDI
Impr
ovem
ent
Adjunctive Drug Therapy for Advanced PD
22 44 66 88 1010 1212 1616 2020 24241414 1818 2222 2626
PRESTO: Change From Baseline in Total PRESTO: Change From Baseline in Total Daily “OFF” (Hours) by VisitDaily “OFF” (Hours) by Visit
0.50.5
0.00.0
-0.5-0.5
-1.0-1.0
-1.5-1.5
-2.0-2.0
-2.5-2.5
WeekWeek
Rasagiline 0.5 mgRasagiline 0.5 mgRasagiline 1 mgRasagiline 1 mg
PlaceboPlacebo
00
Ho
urs
Adjunctive Drug Therapy for Advanced PD
Heinz Reichmann, Wolfgang JostWorld Congress on Parkinson’s Disease and Related Disorders, 2007
Open Label Study of Rasagiline in Open Label Study of Rasagiline in Fluctuating Patients: Delayed Benefit?Fluctuating Patients: Delayed Benefit?
0
20
40
60
80
100
120
140
BaselineBaseline 4 weeks4 weeks 4 months4 months
Med
ian
tota
l dai
ly O
FF
tim
e (D
iary
)M
edia
n to
tal d
aily
OF
F ti
me
(Dia
ry)
******
N=545N=545
******##
*** p< 0.001 vs. baseline*** p< 0.001 vs. baseline
# p<0.001 vs. 4 weeks# p<0.001 vs. 4 weeks
Concomitant Medication Concomitant Medication Usage in PRESTOUsage in PRESTO
RasagilineRasagiline
CharacteristicCharacteristic PlaceboPlacebo(n=159)(n=159)
0.5 mg/day0.5 mg/day (n=164)(n=164)
1 mg/day 1 mg/day (n=149)(n=149)
Dopamine agonists Dopamine agonists
EntacaponeEntacapone
AmantadineAmantadine
111 (69.8)111 (69.8)
61 (38.4)61 (38.4)
38 (23.9)38 (23.9)
113 (68.9)113 (68.9)
55 (33.5)55 (33.5)
34 (20.7)34 (20.7)
106 (71.1)106 (71.1)
49 (32.9)49 (32.9)
26 (17.4)26 (17.4)
Data = N (%)Data = N (%)
Elmer, L and the Parkinson Study Group. MDS, 2005
-1.95-1.78
-1.67
-1.27-1.05
-0.83
-2.4
-2
-1.6
-1.2
-0.8
-0.4
0
Rasagiline 1.0 mg/dayRasagiline 1.0 mg/day
Rasagiline 0.5 mg/dayRasagiline 0.5 mg/day
PlaceboPlacebo
Without COMT-IWithout COMT-I(n=307)(n=307)
With COMT-IWith COMT-I(n=165)(n=165)
All patients on LD/CDAll patients on LD/CD*p<0.05; ***p<0.001 vs placebo*p<0.05; ***p<0.001 vs placebo
Cha
nge
from
bas
elin
e in
mea
nC
hang
e fr
om b
asel
ine
in m
ean
Tot
al d
aily
OF
F t
ime
(hou
rs)
Tot
al d
aily
OF
F t
ime
(hou
rs)
Rasagiline with and without Rasagiline with and without Concomitant COMT-IConcomitant COMT-I
Adjunctive Drug Therapy for Advanced PD Elmer, L and the Parkinson Study Group. MDS, 2005
******
**
-1.89-1.75
-0.85
-1.06
-2
-1.6
-1.2
-0.8
-0.4
0
Rasagiline 1.0 mg/dayRasagiline 1.0 mg/day
PlaceboPlacebo
All patients on LD/DDIAll patients on LD/DDI
Cha
nge
from
bas
elin
e in
mea
nC
hang
e fr
om b
asel
ine
in m
ean
Tot
al d
aily
OF
F t
ime
(hou
rs)
Tot
al d
aily
OF
F t
ime
(hou
rs)
Without DAsWithout DAs(n=91)(n=91)
With DAsWith DAs(n=217)(n=217)
***p<0.001 vs placebo***p<0.001 vs placebo
Rasagiline with and without Rasagiline with and without Concomitant DAConcomitant DA
Adjunctive Drug Therapy for Advanced PD Elmer, L and the Parkinson Study Group. MDS, 2005
******
Cognitive and Behavioral Adverse Events Cognitive and Behavioral Adverse Events Comparison of Rasagiline with Other AgentsComparison of Rasagiline with Other Agents
% Incidence of CBAE’s above placebo % Incidence of CBAE’s above placebo
(from package inserts)(from package inserts)
% Incidence of CBAE’s % Incidence of CBAE’s above placebo (from above placebo (from TEMPO and PRESTOTEMPO and PRESTO))
EntacaponeEntacapone PramipexolePramipexole RopiniroleRopinirole RasagilineRasagiline
As MonotherapyAs Monotherapy
Sleep disorderSleep disorder 55 N/AN/A N/AN/A
SomnolenceSomnolence 1313 3434 N/AN/A
DepressionDepression N/AN/A N/AN/A 33
Abnormal dreamsAbnormal dreams N/AN/A N/AN/A >1>1
HallucinationsHallucinations 66 44 N/AN/A
ConfusionConfusion 33 44 N/AN/A
As Adjunctive TherapyAs Adjunctive Therapy
Sleep disorderSleep disorder N/AN/A 11 N/AN/A 11
SomnolenceSomnolence 22 33 1212 1.61.6
DepressionDepression N/AN/A N/AN/A N/AN/A N/AN/A
Abnormal dreamsAbnormal dreams N/AN/A 11 11 2.72.7
HallucinationsHallucinations N/AN/A 1313 66 11
ConfusionConfusion N/AN/A 33 77 >1>1Elmer L, et al., J Neurol Sci 2006;248(1-2):78-83.
Deep Brain Stimulation: Deep Brain Stimulation: Reduction in “Off” TimeReduction in “Off” Time
The Deep-Brain Stimulation for Parkinson’s Disease Study Group. N Engl J Med 2001;345:956-963.
BaselineBaseline
Six MonthsSix Months27% ON 27% ON
50% OFF50% OFF
23%23%ON w/dyskON w/dysk
74% ON74% ON
19% OFF19% OFF
7% 7% ON w/dyskON w/dysk
All P values < 0.001
Conclusions: Advanced TreatmentConclusions: Advanced Treatment
► Combination therapy reasonable to consider Combination therapy reasonable to consider before before levodopa introducedlevodopa introduced
► Adjunctive therapy with multiple agents from different Adjunctive therapy with multiple agents from different classes has been demonstrated to be effective and well-classes has been demonstrated to be effective and well-toleratedtolerated
► Entacapone, zydis selegiline, and rasagiline have lower Entacapone, zydis selegiline, and rasagiline have lower incidence of cognitive and behavioral side effects incidence of cognitive and behavioral side effects compared to dopamine agonists as adjunctive agents. compared to dopamine agonists as adjunctive agents. Long-acting dopamine agonists are promising options for Long-acting dopamine agonists are promising options for advanced management of Parkinson’s disease.advanced management of Parkinson’s disease.
Recommended