Continuous dopaminergic stimulation

Continuous dopaminergic stimulation Angelo Antonini Milan, Italy GPSRC CNS 172 173 0709 RTG 1

As PD progresses patient mobility becomes increasingly dependent on bioavailability of peripheral levodopa Dyskinesia Dyskinesia Dyskinesia on on on off off off Antonini. Parkinsonism Relat Disord 2007;13(Suppl 3):S446 9. GPSRC CNS 172 173 0709 RTG 2

Evidence for effectiveness of continuous dopaminergic stimulation in early disease Early continuous dopaminergic stimulation can delay or prevent motor fluctuations and dyskinesia in patients with early PD Proven? GPSRC CNS 172 173 0709 RTG 3

COMT-inhibitors improve levodopa pharmacokinetics but not sufficiently to stabilize plasma levels Levodopa Concentration n (nmol/ml) 20 15 10 5 0 With Entacapone Without Entacapone Levodopa Administration 6 10 14 18 22 Time of day Levodopa ncentration (µg/l) con CURS SΣ Fig 2. Concentration-time profile (top) and effect-time profile (bottom) of levodopa over 4 consecutive dosage intervals before and during coadministration of tolcapone 100mg 3 times daily for 7 days. Values are means ± SD. Nutt. Neurology 2000;55:S33 7. *Baas et al. Clin Pharmacokinet 2001;40:383 93. COMT, catecholamine O-methyl transferase To view abstract, click pause then click Abstracts link above GPSRC CNS 172 173 0709 RTG 4

Reduced dyskinesias with ropinirole in a naturalistic 10-year follow-up of early PD patients who had initially received ropinirole or L-dopa Development of dyskinesias Development of dyskinesias Median time to develop dyskinesias Patien nts (%) 80 60 40 20 p = 0.0299 42% 71% Time (years) 10 9 8 7 6 8.3 p = 0.0025 7.3 0 5 Ropirinole Levodopa Ropirinole Levodopa Hauser et al. Mov Disord 2007;22:2409 17. To view abstract, click pause then click Abstracts link above GPSRC CNS 172 173 0709 RTG 5

Comparison of the agonist pramipexole versus levodopa on motor complications of Parkinson's disease (CALM-PD): 6-year prospective evaluation Endpoint Initial Pramipexole Initial Levodopa p Mean Schwab and England ADL Scale score (SD) 79.9 (16.2) 82.5 0.19 (14.6) Dopaminergic motor complications (%) 50.0 68.4 0.002 Mean Epworth Sleepiness Scale score (SD) 11.3 (5.8) 8.6 (4.7) <0.001 Mean change from baseline in UPDRS score (SD) 2.4 (17.4) 0.5 (17.1) 0.11 Parkinson Study Group CALM Cohort Investigators. Arch Neurol 2009;66:563 70. To view notes, click pause and then click on notes tab GPSRC CNS 172 173 0709 RTG 6

Potential for continuous dopaminergic stimulation in early Parkinson s s disease: clinical evidence Dopamine agonists vs levodopa: 29 studies, 5247 patients Adapted from: Stowe RL, et al. Cochrane Database of Systematic Reviews 2008;Issue 2. To view notes, click pause and then click on notes tab GPSRC CNS 172 173 0709 RTG 7

Evidence for effectiveness of continuous dopaminergic stimulation in advanced disease Continuous dopaminergic stimulation can reverse motor fluctuations and dyskinesia in patients with advanced PD Proven? GPSRC CNS 172 173 0709 RTG 8

Continuous dopaminergic stimulation widens therapeutic window in advanced PD on Infusion begins GPSRC CNS 172 173 0709 RTG 9

Rotigotine patch reduced off time in advanced PD LeWitt et al. Neurology 2007;68:1262 7. To view abstract, click pause then click Abstracts link above GPSRC CNS 172 173 0709 RTG 10

Rotigotine patch in advanced PD Study Dose Mean daily dose Levodopa Off (h) baseline Off (h) change from baseline Responders % LeWitt et al. ROT 8 760 6.7-2.7 56.6 ROT 12 740 6.3-2.1 55.1 Placebo 753 6.4-0.9 34.5 Poewe et al. ROT 4 16 795 6.2-2.5 59.7 PPX 0.5 4.5 813 6.0-2.8 67.0 Placebo 814 6.6-0.9 35.0 A significant amount of off time still remained after the introduction of rotigotine/pramipexole Placebo responder rate was very high LeWitt et al. Neurology 2007;68:1262 7; Poewe et al. Lancet Neurol 2007;6:513 20. To view abstract, click pause then click Abstracts link above GPSRC CNS 172 173 0709 RTG 11

Rotigotine patch in advanced PD Study Dose No off periods On (h) without troublesome dyskinesia UPRDS ADL change UPDRS motor change LeWitt et al. ROT 8-1.5 +3.5-3.1-6.8 ROT 12-1.3 +2.2-3.2-8.7 Placebo -0.7 +1.1-0.5-3.4 Poewe et al. ROT 4 16-1.4 +2.8-4.2-8.7 PPX 0.5 4.5-1.4 +2.7-4.6-10.3 Placebo -0.6 +1.4-2.0-4.3 Quality of life (ADL) improved much less than motor function ADL, activities of daily living; UPRDS, Unified Parkinson s Disease Rating Scale LeWitt et al. Neurology 2007;68:1262 7; Poewe et al. Lancet Neurol 2007;6:513 20. GPSRC CNS 172 173 0709 RTG 12

Subcutaneous apomorphine infusion The speaker has requested that t this slide is not shown for copyright reasons GPSRC CNS 172 173 0709 RTG 13

Continuous subcutaneous waking day apomorphine in the long term treatment of levodopa-induced interdose dyskinesias in PD o off hours (% of wak king hours ) OFF HOURS e) UPDRS score DYSKINESIA p < 0.01 p < 0.01 *** baseline 1 year Dy yskinesia disablity (U *** baseline 1 year Apomorphine monotherapy (waking day) Colzi et al. J Neurol Neurosurg Psychiatry 1998;64:573 6. To view abstract, click pause then click Abstracts link above GPSRC CNS 172 173 0709 RTG 14

Changes in 15 patients after apomorphine infusion for 1 year Significant reduction in off time but little effect on dyskinesia Levodopa dose equivalents De Gaspari et al. J Neurol Neurosurg Psychiatry 2006;77:450 3. To view abstract, click pause then click Abstracts link above GPSRC CNS 172 173 0709 RTG 15

Continuous apomorphine reduced dyskinesia severity on acute challenge Baseline 6-month Change Levodopa challenge AIM dyskinesia scale 89 8.9 ± 46 4.6 49 4.9 ± 28 2.8 44% Goetz dyskinesia scale 2.2 ± 0.7 1.3 ± 0.8 40% Apomorphine challenge AIM dyskinesia scale 9.7 ± 4.9 5.9 ± 2.9 39% Goetz dyskinesia scale 2.2 ± 0.8 1.4 ± 0.8 36% AIM, abnormal involuntary movement Katzenschlager et al. Mov Disord 2005;20:151 7. To view abstract, click pause then click Abstracts link above GPSRC CNS 172 173 0709 RTG 16

Long-term lisuride infusion reduces Off hours and dyskinesia compared to standard oral levodopa therapy Stocchi et al Brain 2002;125:2058 66. To view abstract, click pause then click Abstracts link above GPSRC CNS 172 173 0709 RTG 17

Widening the levodopa therapeutic window using continuous lisuride infusion for 3 months Baronti et al. Ann Neurol 1992;32:776 81. To view abstract, click pause then click Abstracts link above GPSRC CNS 172 173 0709 RTG 18

Intrajejunal levodopa titration Patient 2 (P.T.) Oral medical treatment Baseline +3 +2 +1 0-1 -2-3 +3 +2 +1 0-1 -2-3 Day 3 - Naso-duodenal tube, infusion begins 1\2 levodopa oral 125 mg 00.00 h + 05.00 h Time of day (h) 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Time of day (h) Madopar 200 50mg: 3/4cp x 3 + 1/2cp x 3 Levomet:1 puff x 4 Apofin stylo: 5 mg x 3 s.c. Mirapexin 0.7 mg: 1/2cp x 3 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Daily dose Continuous dose rate (ml/h) Dose extra (ml) 1.2 1.5 1.8 2.3 2.2 Other treatment 0.5 0.5 0.5 1.0 1.0 1.0 Week 1 +3 +2 +1 0-1 -2-3 6 months +3 +2 +1 0-1 -2-3 Time of day (h) Daily dose Continuous dose rate (ml/h) Dose extra (ml) 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Time of day (h) 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 6.0 3.0 1.0 1.0 Daily dose Continuous dose rate (ml/h) Dose extra (ml) 4.5 2.7 2.5 Benefit occurred after withdrawal of all oral medications, personal data GPSRC CNS 172 173 0709 RTG 19

Intrajejunal infusion is possible through a gastrostomy and levodopa is delivered by a pump The speaker has requested that t this slide is not shown for copyright reasons GPSRC CNS 172 173 0709 RTG 20

Duodenal infusion makes levodopa bioavailability and plasma levels more predictable compared with oral tablets 47% decrease in plasma levodopa variability (p = 0.01) Kurth et al. Neurology 1993;43:1698 703. To view abstract, click pause then click Abstracts link above GPSRC CNS 172 173 0709 RTG 21

2 3 4 5 Daily dose of levodopa and equivalents administered did not change Me ean (SD) dai ily dose of levodopa (m mg/kg) 2000 1600 1200 800 400 0 1 1249±521 1246±516 1257±325 Baseline Month 6 * Month 12 * Min, Max n 825, 1825 780, 2125 780, 2100 7 7 7 * Includes morning bolus and one extra afternoon dose Antonini et al. Mov Disord 2007;22:1145 9. To view abstract, click pause then click Abstracts link above GPSRC CNS 172 173 0709 RTG 22

1 2 3 4 5 Total daily duration of off periods was reduced by over 80% ) Mean (SD) total daily durat tion off period ds (minutes of 450 400 350 300 250 200 150 100 50 0 266.8 ± 101 34.1 ± 15.1 30.0 ± 16.0 Baseline Month 6 ** Month 12 ** Min, Max 100, 400 20, 60 15, 60 n 7 7 7 **p < 0.01 vs baseline Antonini et al. Mov Disord 2007;22:1145 9. GPSRC CNS 172 173 0709 RTG 23

2 3 4 5 Total daily duration of moderate-severe dyskinesia was reduced by over 80% Mean (SD) total daily durat ion of moderate to severe dyskinesia (minutes) 250 200 150 100 50 152.6 ± 67.7 42.2 ± 24.3 40.7 ± 20.1 0 1 Baseline Month 6 ** Month 12 ** Min, Max 60, 250 20, 90 20, 80 n 7 7 7 **p < 0.01 vs baseline Antonini et al. Mov Disord 2007;22:1145 9. GPSRC CNS 172 173 0709 RTG 24

Patient video With permission from Dr Riboldazzi, Varese, Italy With permission from Dr Riboldazzi, Varese, Italy GPSRC CNS 092 1730509 0709 RTG 25

Benefit on quality of life (PDQ 39) after 1 year *p < 0.05 Baseline Year 1 *p < 0.05 **p < 0.01 **p < 0.01 Score (as sub-item of PDQ-39) PDQ, Parkinson s Disease Questionnaire Antonini et al. Mov Disord 2007;22:1145 9. GPSRC CNS 172 173 0709 RTG 26

Effect size of duodenal levodopa on non-motor symptoms 0-0.2 in health st tatus Change -0.4 Cognition -0.6-0.8-1 -1.2 Attention Mood Gastro- intestinali CVS Sleep Urinary Sex -1.4 Miscellaneous < 0.2 = negligible; 0.2 0.49 = small; 0.5 0.79 = moderate; > 0.8 = large (Kazis et al. Med Care 1989;27:S178 89) CVS: cardiovascular symptoms Honig et al. Mov Disord 2009;24:1468 74. To view abstract, click pause then click Abstracts link above GPSRC CNS 172 173 0709 RTG 27

Summary Motor complications (wearing-off and dyskinesia) i are frequently observed with disease progression and chronic pulsatile levodopa treatment Progressive denervation and fluctuations in plasma levodopa levels are likely to contribute to the development of motor complications Continuous dopaminergic stimulation can delay complications in early PD and reverse them in advanced patients with benefit extending to quality of life and non-motor symptoms GPSRC CNS 172 173 0709 RTG 28

PD treatment algorithm Add MAO-B inhibitor (i.e. rasagiline 1 mg/day) Raise dopamine agonist dose if tolerated Add amantadine up to 100 mg three times daily Untreated Insufficient motor control Wearing-off Dyskinesia Start with non- ergot agonist and raise to average effective dose Add levodopa three times daily Try not exceed 300 400 mg/day Increase frequency of levodopa administration Use entacapone Adjust levodopa dose Consider tolcapone Consider more invasive therapies (DBS apomorphine or levodopa duodenal infusion) DBS, deep brain stimulation; MAO-B, mono-amine oxidase B Antonini & Barone. Neurol Sci 2008;29:S371 4. GPSRC CNS 172 173 0709 RTG 29

Copyright statements Slide 6 2000, reproduced with permission from John Wiley & Son, Inc, and 2001, reproduced with permission from Wolters Kluwer Health Slide 11 2007, reproduced d with permission i from Wolters Kluwer Health Slide 15 1998, reproduced with permission from the BMJ Publishing Group Slide 17 2005, reproduced with permission from John Wiley & Sons, Inc Slide 18 Slide 19 2002, reproduced with permission from Oxford University Press 1992, reproduced with permission from John Wiley & Sons, Inc GPSRC CNS 172 173 0709 RTG 30

Copyright statements Slide 22 Slide 23 Slide 24 Slide 25 Slide 27 Slide 28 Slide 29 1993, reproduced with permission from Wolters Kluwer Health 2007, reproduced with permission from John Wiley & Sons, Inc 2007, reproduced with permission from John Wiley & Sons, Inc 2007, reproduced with permission from John Wiley & Sons, Inc 2007, reproduced with permission from John Wiley & Sons, Inc 2009, reproduced with permission from John Wiley & Sons, Inc 2008, reproduced with permission from Springer GPSRC CNS 172 173 0709 RTG 31