A Final Management of PD

8/2/2019 A Final Management of PD

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Risk Factor

Increasing age is the only definitive risk factor for Parkinsons disease. About 15% ofpeople are diagnosed before age 50, but the majority of new cases occur betweenthe ages of 50 and 70.

Some evidence suggests that Parkinsons disease is more common in males andwhites than in females and other races.

Risk factors for Parkinsons disease include exposure to environmental toxicants,genetic predisposition, and possibly, emotional stress.

Rarely occur on a familial basis.


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Parkinsonism andClassification of Symptoms

Parkinsonism is a collective term that is used to describe a number of conditions that

cause distinctive motor signs. Parkinsonism is typically classified into the following 3

categories:

Primary parkinsonism

Secondary parkinsonism

Parkinsonism-plus

Primary parkinsonism, or true Parkinsons disease, has an unknown or idiopathiccause.

Secondary parkinsonism has an identifiable cause, most commonly due to drug-related effects, but also due to stroke or encephalitis.

Parkinsonism-plus syndromes, also called atypical parkinsonism, involve multisystemdegeneration.


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Etiology of Parkinsons Disease


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Staging of Parkinsons Disease

Stages of disease progression are based on clinician ratings. Two of the most commonare:

Hoehn and Yahr Staging Scale and

Unified Parkinsons Disease Rating Scale.

Both scales provide numeric ratings that reflect the extent of a patients disability.

- Hoehn and Yahr have a 5-stage rating system. Severity of the disease ranges from verymild to very severe.

- Unified Parkinsons Disease Rating Scale is divided into 6 parts.

The accumulation of points determines severe signs and symptoms of Parkinsonsdisease.


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Diagnosis

When diagnosing Parkinsons disease, the physician evaluates the patient byperforming a comprehensive assessment of motor functioning.

Neuropsychological tests may pinpoint specific types of cognitive deficits.

Brain imaging techniques (computerized tomography and positron emissiontomography) are useful in cases of diagnostic uncertainty.


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Overview ofParkinsons Disease Therapies

In general, patients with Parkinsons disease are managed in 3 ways:

Nonpharmacologic treatments

Pharmacologic treatments

Surgical intervention

Along with medication, Parkinsons patients need additional therapy in order toeffectively manage the disease symptoms and maintain quality of life. Somecomplementary therapies include the following:

Patient education

Counseling Speech therapy

Physical therapy

Occupational therapy


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Pharmacological approaches to the treatment ofParkinsons Disease

The goal of therapy in treating Parkinsons disease is to maintain patient functioning for as long as

possible.

Nonpharmacologic treatments are important, but pharmacologic treatments are inevitably needed.

A variety of approaches are used to increase striatal dopamine levels and extend the availability oflevodopa to the brain:

Inhibit the action of acetylcholine (anticholinergics)

Prevent the degradation of dopamine in the CNS (MAO-B inhibitorsselegiline)

Provide a dopamine precursor to augment the production of dopamine (levodopa)

Further prevent the degradation of levodopa (COMT inhibitors) Enhance the release of or reduce dopamine reuptake (NMDA receptor antagonistamantadine)

Mimic the action of dopamine (dopamine agonists)

Prevent the degradation of levodopa in the periphery (DDC inhibitorcarbidopa)


9/42Stalevo Launch Training/21.04.10/FH

Surgical intervention

Surgery is used as last resort Treatment option. It is used in patients withincapacitating tremor who are unresponsive to medication or in those

who develop intolerable side effects from Levodopa


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Treatment Algorithm


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Levodopa: Timeline

Striatal dopamine

loss identified as

characteristic of PD

First

improvements

with intravenous

levodopa

Dopa decarboxylase

(DDC) inhibitors

introduced to prevent

peripheral conversion of

levodopa to dopamine

Success using

oral D-levodopa

Levodopa controlled release

formulations developed

Catechol-O-methyl transferase

(COMT) inhibitors introduced to

increase levodopa half-life and

extend clinical benefits

1960 1990s1980s1970s 2003

Stalevo

(Levodopa/carbidopa/entacapone)

introduced


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Levodopa benefits

Most potent oral antiparkinsonian drug

Virtually all PD patients respond

Virtually all PD patients will need it at some point

Improved disability with preserved capacity to maintain activities ofdaily living and employment

May improve mortality rate


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The challenges of Levodopa delivery


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BrainCirculation

DDC in intestine wall

DDC in periphery

COMT

Stomach

Blood and peripheral tissues

Bloodbrain barrier

90%

10%

9%


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Plasmale

vodopaconcen

trations

Time

Therapeuticwindow

Early disease

On Off

Moderate disease

On Off

Dyskinesiathreshold

Efficacythreshold

Dyskinesiathreshold

Efficacythreshold

Dyskinesiathreshold

Efficacy

threshold

Advanced disease

On Off

2. Levodopa Therapeutic WindowNarrows with Disease Progression


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Incidence of wearing-off and dyskinesiasafter 2 years of levodopa therapy

CALM-PD(n=150)

DATATOP(n=352)

Patients %

38%

0% 10% 20% 30% 40% 50% 60%

31%

50%

30%

2 years

Dyskinesia Wearing-off~ 40% of patientsaffected within 2years


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3.Levodopa: Limitations

Some PD symptoms are unresponsive to dopamine therapy

The development of complications are a source of disability

motor fluctuations (wearing-off, onoff fluctuations)

dyskinesia (peak dose, diphasic, off-period dystonia) mental status changes (confusion, hallucinations, psychosis)


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4.Motor complications in Parkinsons disease

Fluctuations, wearing-off, dyskinesias

Related to:

Levodopa use, duration, total dose Pulsatile stimulation of dopamine receptors

Severity of nigral degeneration

Age of patient


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Pulsatility

Pulsatile stimulation of brain dopamine receptors results from:

progressive PD pathology

the use of dopaminergic agents with short half-lives

Levodopa has a relatively short half-life (6090 min)

Obeso et al. 2000

Pulsatile or Intermittent Dopaminergic stimulation:

When dopamine receptors are exposed to high and low concentration oflevodopa. This pulsatile stimulation is thought to be key to the developmentof motor complication including dyskinesia


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Pulsatile dopaminergic stimulationin Traditional Levodopa therapy


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Identification of Wearing Off Symptoms

Wearing-Off

Non-Motor Symptoms(often precede/coincide with Motor Symptoms)

Motor Symptoms

AUTONOMIC

pallorBP changes

shortness of breath

tachycardia

sweating

facial flushing

laryngeal stridor

papillary dilationdrooling

dysphagia

belching

abdominal bloating

urinary frequency

micturition disturbances

Tremor

Rigidity

Akinesia/Bradykinesia

Postural Instability/Balance

SENSORY

PainParesthesias

Sensory loss

Akathisia

Fatigue

PSYCHIATRIC

AnxietyParanoia

Hallucinations

Depression

Panic

Cognitive changes


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Strategies to improve levodopa delivery

Levodopa dose manipulations

increase size of levodopa dose

smaller, more frequent doses

Sustained-release levodopa preparations Enteral infusion of levodopa

Dual inhibition of DDC and COMT metabolic pathways


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A) Levodopa Modification1. Increase Dose

ClinicalEffect

Increased likelihood of peak-dose dyskinesia


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Find Many troughs

*Data from different fluctuating patients

* *

A) Levodopa Modification2. Increase Dose Frequency


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The challenge of CDS with CR levodopa

A) Levodopa Modification3. CR Preparations

Erratic/Variable AbsorptionSlow time to ONAbsent ON


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Combination of Carbidopa+Levodopa+Entacapone


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Stalevo: Mechanism of Action

With dual inhibition, significantly more levodopa reaches the

brain, with a 30-50% reduction in plasma variability

Gordin et al. 2006


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Pharmacokinetics of LCE compared withconventional LC in patients with PD

*(1.5, 2.0)

*(1.6, 2.2)

*(1.6, 2.1)

*(1.8, 2.4)

LCE LC

Group II: LCE versus LC 150 mg,3.5-hour intervals (n=9)

0

200

400

600

800

1000

Dose 1(8:00 am)

Dose 2(11:30 am)

Dose 3(3:00 pm)

Dose 4(6:30 pm)

Mean

plasmalevodopaCmin

levels

(ng/mL)

Group I: LCE versus LC 100 mg,3.5-hour intervals (n=10)

0

200

400

600

800

1000

1200

1400

M

eanplasmalevodopaCmin

levels(ng/mL)

Dose 1(8:00 am)

Dose 2(11:30 am)

Dose 3(3:00 pm)

Dose 4(6:30 pm)

*(1.7, 2.5)

*

(1.6, 2.5)

*(1.6, 2.4)

*(1.6, 2.5)

*p


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FIRST-STEP: Change from baseline in totalUPDRS Part II and III scores

Change

intotalUPDRSPartII

andIIIscores

*p


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Stalevo: Minimizing Pulsatilitity


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Repeated daily dosing of levodopa/DDCI/entacapone extends thebioavailable levodopa while reducing peaktrough variations

Stalevo: Minimizing Pulsatilitity

0

500

1000

1500

2000

2500

3000

3500

7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

Administration

Levodopaplasm

alevels(ng/ml) After 4 weeks levodopa/DDCI/entacapone treatmentLevodopa


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Stalevo: Sustained Duration of Efficacyor Long Duration Dose Stability

NOMESAFE Study- Larsen et al. (2003)

Long term safety and efficacy of Stalevo

3 yr extension trial of registration trial(6 month Nordic- NOMECOMT Study)

Mean duration of benefit improved from2.1 to 2.8 hrs at 3 months (P


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Earlier management of wearing-off improves long-term patient function

Delayed start analysis of 3 long-term studies

Over 5 years, early initiation of levodopa with a DDCI and entacaponeresulted in a significant benefit compared with a delayed start in treatment

-6.0

0.0

6.0

12.0

18.0

Baseline(N=484)

1(N=410)

2(N=101)

3(N=90)

4(N=44)

5(N=37)

Years

UPDRSIIIscores

Levodopa with DDCI and entacapone

Traditional levodopa plus placebo

Stalevo: Sustained Duration of Efficacyor Long Duration Dose Stability

Nissinen et al (2006 Feb)- Early initiation of entacapone leads to superior 5 year efficacy compared to delayed initiation in PD patients receiving traditional ldopa/DDCI therapyWorld Parkinson Congress- Poster, Washington


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Stalevo:Fluctuators- Quality of Life

Significant improvement inPDQ-39 versus baseline at 20weeks

IB-01 Gershanik et al. (2003) Opticom. Onofrj et al. (2004)

Significant improvements in PDQ-8independent of dosing frequency

Significant improvement in quality of life with Stalevo

1. Gershanik et al (2003) Efficacy and safety of levodopa with entacapone in parkinsons disease patients suboptimally controlled with levodopa alone, Prog Neuro-Psych & Bio-Psych, 27: 963-971

2. Onofrj et al. (2004) Combining entacapone with levodopa/DDCI improves clinical status and quality of life regarless of dosing frequency, J Neurol Transam, 111: 1053-1063


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Mean ADL UPDRS scores improved by 0.92.2

Daily levodopa dosage reduced by 2240 mg relative to placebo

Stalevo Levodopa/DDCI plus placebo

*p


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STALEVO switching guide line


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Add entacapone first. Once the appropriate dose of levodopa, DDCI isdetermined switch to Stalevo.

Except for entacapone other standard anti-Parkinsons drug may be usedconcomitantly with Stalevo

Only one Stalevo tablet should be administered at each dosing interval

Stalevo 200 mg can be dosed up to 7 times Per day


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STALEVO 200mg is now available

Stalevo 200 mg is suitable for patients who are receiving

Levodopa therapy >400mg & facing wearing-off


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THANK YOU

A Final Management of PD

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