adjunctive drug therapy for advanced parkinson’s disease combination strategies and sequencing...

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


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


Goals of Current Therapeutic StrategiesGoals of Current Therapeutic Strategies


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


DADA GABAGABA

AChACh

StriatumStriatum

LevodopaLevodopa

AmantadineAmantadine

SelegilineSelegiline

Dopamine agonistsDopamine agonists BromocriptineBromocriptine PergolidePergolide


BBBBBB CarbidopaCarbidopa BenserazideBenserazide

MAO-BMAO-B

Sites of Action of PD Drugs: 1990’sSites of Action of PD Drugs: 1990’s


DADA GABAGABA

AChACh

StriatumStriatum

Substantia NigraSubstantia Nigra

LevodopaLevodopa


SelegilineSelegiline Dopamine agonistsDopamine agonists BromocriptineBromocriptine PergolidePergolide PramipexolePramipexole PopinirolePopinirole

BaclofenBaclofen


BBBBBB CarbidopaCarbidopa BenserazideBenserazide TolcaponeTolcapone EntacaponeEntacapone

MAO-BMAO-B

Sites of Action of PD Drugs: 2000Sites of Action of PD Drugs: 2000


DADA GABAGABA

AChACh

StriatumStriatum


LevodopaLevodopaAmantadineAmantadine

SelegilineSelegilineZydis selegilineZydis selegilineRasagilineRasagiline

Dopamine agonistsDopamine agonists ApomorphineApomorphine BromocriptineBromocriptine PergolidePergolide PramipexolePramipexole RopiniroleRopinirole RotigotineRotigotine

BaclofenBaclofen


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


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


DAGABA

ACh

StriatumStriatum


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


Plasma Levels – Rotigitine CDSPlasma Levels – Rotigitine CDS


Adjunctive Transdermal SystemAdjunctive Transdermal System


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

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ent

Mot

or s

core

impr

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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


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


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


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

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Bas

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( Ho

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-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

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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


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

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FF

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)M

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OF

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(Dia

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******

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


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


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

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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


PlaceboPlacebo

All patients on LD/DDIAll patients on LD/DDI

Cha

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Tot

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Tot

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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.

adjunctive drug therapy for advanced parkinson’s disease combination strategies and sequencing...

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