BORDEAUX MDS WINTER SCHOOL FOR YOUNG NEUROLOGISTS INFUSION THERAPIES IN PARKINSON S DISEASE Apomorphine, T. Henriksen Tove Henriksen, MD MDS Clinic University Hospital of Bispebjerg, Copenhagen
MOTOR FLUCTUATIONS Levodopacarbidopa intestinal gel (LCIG) Erratic gastric emptying Bloating Late on No on Hyperkinesias T Henriksen, PD Unit Apomorphine DBS
Duodenal carbidopa/ levodopa gel infusion Device aided treatments Advanced treatment Complex treatment CDS CDD Deep brain stimulation Subcutaneous apomorphine infusion
INSUFFICIENT EVIDENCE FROM HEAD-TO- HEAD COMPARISONS Small study of four patients showed Improved off rating for levodopa versus apomorphine Improved quality of life for levodopa versus apomorphine according to PDQ-39 BUT the authors of a systematic review concluded: Clinical judgement remains the only tool to determine whether DBS, apomorphine infusion or levodopa infusion would be of benefit to a particular patient with advanced PD and complex motor symptoms Where possible, patient preference should form a significant part of the decision-making process Nyholm D, et al. Acta Neurol Scand 2009;119:345-8.Clarke CE, et al. Parkinsonism Relat Disord. 2009;15:728-41.
ALGORITHM FOR THE SELECTION OF PATIENTS WHO ARE CANDIDATES FOR CDS TREATMENTS Age <65 70 years with prominent motor fluctuations and moderate dyskinesia STN-DBS Subcutaneous apomorphine Levodopa/carbidopa duodenal infusion Cancer or similar Severe dementia GI problems Age <65 70 years with very severe dyskinesia (no therapeutic window) Parkinson s disease age >65 70 years STN-DBS Levodopa/carbidopa duodenal infusion Fluctuations ± dyskinesia Subcutaneous apomorphine Levodopa/carbidopa duodenal infusion Modified, Antonini A, Tolosa E. Expert Rev Neurother. 2009;9:859-67. Reproduced with permission of Expert Review Ltd.
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DUODENAL CARBIDOPA/LEVODOPA GEL INFUSION (DUODOPA ) Stable plasma concentrations of l-dopa attenuate severe On-off fluctuations in advanced PD (Shoulson 1975) i.v. trials large infusion volume, irritation of veins 1990s SM Aquilonius University of Uppsala
CARBIDOPA/LEVODOPA GEL INFUSION THERAPY Levodopa/carbidopa (2 g/day) in gel suspension 100 ml cassette (2000 mg) PEG with intestinal tube Ambulatory pump Mono therapy Morning bolus dose Continuous maintenance infusion over 16 hr
Change in Hours From Baseline to Week 12 5 4 3 2 1 0 P =.0059 4.11 2.24 P =.0142 3.37 P =.3294 LCIG LC-IR 1.09 1.5 0.81-0.11-0.03 1 2 3 4 5 6-4.04-2.14 P =.0015 "Off" Time Primary Endpoint "On" Time Without Troublesome Dyskinesia Key Secondary Endpoint SECONDARY EFFICACY: PD SYMPTOM DIARY ANALYSIS "On" Time Without Dyskinesia "On"Time With Nontroublesome Dyskinesia P =.8574 "On" Time With Troublesome Dyskinesia LCIG, levodopa-carbidopa intestinal gel; LC- IR,immediate-release levodopa-carbidopa. Olanow et al., (2014) Lancet Neurol, 141-149. 9
LCIG (n = 35) LC-IR (n = 31) Treatment Difference (95% CI) SECONDARY EFFICACY: QOL/CAREGIVER BURDEN P Value PDQ-39 summary index 10.9 (3.3) 3.9 (3.2) 7.0 ( 12.6 to 1.4).0155 Mean CGI-I score at final assessment 2.3 (0.4) 3.0 (0.4) 0.7 ( 1.4 to 0.1).0258 UPDRS part II b 1.8 (1.3) 1.3 (1.3) 3.0 ( 5.3 to 0.8).0086 UPDRS part III b 1.5 (2.4) 2.9 (2.4) 1.4 ( 2.8 to 5.6).5020 EQ-5D 0.05 (0.04) 0.02 (0.04) 0.07 ( 0.01 to 0.15).0670 Zarit Burden Interview 2.8 (3.7) 1.7 (3.3) 4.5 ( 10.7 to 1.7).1501 Levodopa total daily dose, mg 91.7 (96.6) 249.7 (94.9) 158.0 ( 324.5 to 8.5).0625 Overall mean (SD) levodopa rescue dose, mg 139.8 (20.3) 180.6 (21.9 ) 40.8 ( 100.4 to 18.8).1762 Patients treated with LCIG showed significant improvement (compared with patients receiving standard oral LC-IR) in the activities of daily living subscale of the UPDRS (part II) and measures of QoL 10 Data are the least squares mean change from baseline to week 12 (SE) unless otherwise stated. CGI-I, Clinical Global Impression Improvement; EQ-5D, EuroQol quality-of-life-5 Dimensions; LCIG, levodopa-carbidopa intestinal gel; LC-IR, immediate-release levodopa-carbidopa; PDQ-39, Parkinson Disease Questionnaire-39 items; QoL, quality of life; UPDRS, Unified Parkinson s Disease Rating Scale. a For CGI-I, 1 is very much improved, 2 is much improved, 3 is minimally improved, 4 is no change, 5 is minimally worse, 6 is much worse, and 7 is very much worse. b UPDRS was completed in the on state. Olanow CW, et al. (2014) Lancet Neurol, 141-149.
4 prospective, multicenter studies Safety data Already published 412 patients 911 days observation (range 1-1980) 2017, T Henriksen
Patients With Treatment-Emergent Adverse Events, % SAFETY: AES AND DEVICE COMPLICATIONS OVER TIME 55 50 45 40 35 30 25 20 15 10 5 0 Complication of device insertion Abdominal pain Procedural pain Constipation Nausea Flatulence Orthostatic hypotension 0 1 2 3 4 5-12 Weeks 12 AE, adverse event. Olanow CW, et al. (2014) Lancet Neurol, 141-149.
2017, T Henriksen
SUBCUTANEOUS APOMORPHINE INFUSION 1988 A Lees Stibe
Researches into the Constitution of the Opium Bases. On the Action of Hydrochloric Acid on Codeia. Matthiessen A, C. R. A. Wright. Proceedings of the Royal Soci.of London, Vol.18,1869, pp. 83-88 Schwab RS et al. Apomorphine in Parkinson s disease. Trans Am Neurol Assoc 1951 High hepatic first pass metabolism and poor oral bioavailability. Short duration Peripheral dopaminergic adverse effects: Nausea, postural hypotension, prerenal azotemia Apomorphine, T. Henriksen Domperidone (Agid, Lancet 1979), peripherally acting dopamine antagonist
1960S Non-ergoline dopamine agonist (D2, D3, D4, D1) Apomorphine: Improvement in tremor and rigidity (Schwab 1951, Trans Am Neurol Ass) Oral 600-1400 mg/day reduced on-off (Cotzias 1970, NEJM Catecholaminergic compound common to dopamine No opioid analgesic properties Short-acting potent agonist with effect on D 1 and D 2 receptors Latency to motor response 10 minutes Duration of action of a single injection 60 minutes Apomorphine, T. Henriksen
ROUTES OF ADMINISTRATION Per orally First pass effect Intravenous infusion Intra vascular thrombosis, crystals (3 of 6 patients) Sublingual New gel formulation on the way Intranasal spray Disabling nasal irritation Inhaled (Grosset KA et al 2013), rescue off A randomized, double-blind, 2:1 active: placebo, parallelgroup, 55 patients dose range 1.5 to 4.5 mg, significantly improved UPDRS 3 aborted a greater proportion of off periods at-home, compared to placebo. However, daily off time was not significantly reduced by the use of inhaled apomorphine Apomorphine, T. Henriksen
Ruiz PJG et al, Movement Disorders 2008 Apomorphine, T. Henriksen
Apomorphine, T. Henriksen From 148 adverse events collected: 93 (62.8%) were mild 44 (29.7%) moderate 11 (7.4%) severe, but did not lead to treatment dropout. No case of HA was reported in these 82 long-term-treated patients. MOVEMENT DISORDERS 2008
Apomorphine, T. Henriksen
2017, T Henriksen
STUDY DESIGN, 107 PATIENTS, 23 CENTRES 2017, T Henriksen
MOTOR STATUS BY PARKINSON DIARY 2017, T Henriksen
PATIENT GLOBAL IMPRESSION CHANGE FROM BASELINE TO WEEK 12 2017, T Henriksen
SIDE EFFECTS 2017, T Henriksen
WHEN? Apomorphine, T. Henriksen
Psychosocial impact of Parkinson s disease: Employment Method: survival analysis of employment Approx. 450 patients with onset of disease <65 y Loss of employment (including retirement) on average 4.9 years after Parkinson s disease onset: Parkinson s disease onset <45 y: 6.7 y Parkinson s disease onset >56 y: 1.7 y In young patients: Loss of professional career opportunities Greater economic impact of unemployment Schrag A, Banks P. Time of loss of employment in Parkinson's disease. Mov Disord 2006; 21:1839-43. Copyright (2006 Movement Disorder Society); Reproduced with permission of John Wiley & Sons, Inc.
WHY NOT EARLIER? LCIG Price Polyneuropathy Weight Apomorphine Nodules Price DBS Early Stim Disease duration 7.5 y, fluctuations 1.5 y, same improvement of QoL as 14 y disease duration. Are the patients ready? No, last resort (interview study, Sperens 2017) Change of IPG Risk of infection Apomorphine, T. Henriksen
CONCLUSION Main indication for advanced therapy: Motor fluctuations +/- dyskinesias in spite of optimized peroral/transdermal PD therapy. Non-motor symptoms can be part of the indication. Due to contraindications for DBS, large groups of patients are only suitable for pump therapy A special out patient set up with a PD nurse specialist Factors influencing the choice of advanced therapy: methodology and practical aspects, as well as, expected effects on motor- and non-motor symptoms Start thinking about advanced therapy already in the early complications phase of advanced Parkinson s disease