PMID- 29777529 OWN - NLM STAT- MEDLINE DCOM- 20200227 LR - 20220317 IS - 1179-1926 (Electronic) IS - 0312-5963 (Print) IS - 0312-5963 (Linking) VI - 58 IP - 1 DP - 2019 Jan TI - Pharmacokinetics of ADS-5102 (Amantadine) Extended Release Capsules Administered Once Daily at Bedtime for the Treatment of Dyskinesia. PG - 77-88 LID - 10.1007/s40262-018-0663-4 [doi] AB - BACKGROUND: Preclinical and clinical studies suggest amantadine immediate-release (IR) may reduce dyskinesia in Parkinson's disease (PD), although higher doses are associated with increased CNS adverse events (AEs). ADS-5102 is an extended release amantadine capsule formulation, designed for once-daily dosing at bedtime (qhs) to provide high concentrations upon waking and throughout the day, with lower concentrations in the evening. The pharmacokinetics (PK) of ADS-5102 were assessed in two phase I studies in healthy subjects, and a blinded, randomized phase II/III dose-finding study in PD patients. METHODS: The first phase I study assessed single ADS-5102 doses (68.5, 137, and 274 mg) in a crossover design, whereas the second phase I study evaluated ADS-5102 137 mg for 7 days followed by amantadine IR 81 mg twice daily (or reverse order). In the phase II/III double-blind study, PD patients with dyskinesia were randomized to ADS-5102 (210, 274, or 338 mg) or placebo for 8 weeks. RESULTS: Single ADS-5102 doses resulted in a slow initial rise in amantadine plasma concentration, with delayed time to maximum concentration (12-16 h). Amantadine plasma concentrations were higher in PD patients versus healthy volunteers. The steady-state profile of once-daily ADS-5102 was significantly different from that of twice-daily amantadine IR, such that the two formulations are not bioequivalent. PK modeling suggested the recommended daily ADS-5102 dosage (274 mg qhs) resulted in 1.4- to 2.0-fold higher amantadine plasma concentrations during the day versus amantadine IR. CONCLUSIONS: ADS-5102 can be administered once-daily qhs to achieve high amantadine plasma concentrations in the morning and throughout the day, when symptoms of dyskinesia occur. FAU - Hauser, Robert A AU - Hauser RA AD - USF Parkinson's Disease and Movement Disorders Center, Parkinson Foundation Center of Excellence, USF Health Byrd Institute, 4001 E. Fletcher Ave, 6th Floor, Tampa, FL, 33613, USA. rhauser@health.usf.edu. FAU - Pahwa, Rajesh AU - Pahwa R AD - Department of Neurology, University of Kansas Medical Center, 3599 Rainbow Boulevard, Mailstop 3042, Kansas City, KS, 66160, USA. FAU - Wargin, William A AU - Wargin WA AD - Nuventra Pharma Sciences, 2525 Meridian Parkway, Suite 280, Durham, NC, 27713, USA. FAU - Souza-Prien, Cindy J AU - Souza-Prien CJ AD - Adamas Pharmaceuticals, Inc, 1900 Powell Street, Suite 750, Emeryville, CA, 94608, USA. FAU - McClure, Natalie AU - McClure N AD - Adamas Pharmaceuticals, Inc, 1900 Powell Street, Suite 750, Emeryville, CA, 94608, USA. FAU - Johnson, Reed AU - Johnson R AD - Adamas Pharmaceuticals, Inc, 1900 Powell Street, Suite 750, Emeryville, CA, 94608, USA. FAU - Nguyen, Jack T AU - Nguyen JT AD - Adamas Pharmaceuticals, Inc, 1900 Powell Street, Suite 750, Emeryville, CA, 94608, USA. FAU - Patni, Rajiv AU - Patni R AD - Adamas Pharmaceuticals, Inc, 1900 Powell Street, Suite 750, Emeryville, CA, 94608, USA. rpatni@adamaspharma.com. FAU - Went, Gregory T AU - Went GT AD - Adamas Pharmaceuticals, Inc, 1900 Powell Street, Suite 750, Emeryville, CA, 94608, USA. LA - eng PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Clinical Trial, Phase III PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't PL - Switzerland TA - Clin Pharmacokinet JT - Clinical pharmacokinetics JID - 7606849 RN - 0 (Antiparkinson Agents) RN - 0 (Delayed-Action Preparations) RN - BF4C9Z1J53 (Amantadine) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - Amantadine/*administration & dosage/*pharmacokinetics MH - Antiparkinson Agents/*administration & dosage/*pharmacokinetics MH - Cross-Over Studies MH - Delayed-Action Preparations/administration & dosage/pharmacokinetics MH - Double-Blind Method MH - Drug Administration Schedule MH - Dyskinesias/drug therapy/*metabolism MH - Female MH - Humans MH - Male MH - Middle Aged MH - Parkinson Disease/drug therapy/*metabolism MH - Young Adult PMC - PMC6325984 COIS- CONFLICTS OF INTEREST: Robert A. Hauser is supported in part by a Center of Excellence grant from the National Parkinson Foundation. He received payment from Adamas Pharmaceuticals for participating as a Steering Committee member, and reports consulting fees from Teva Pharmaceuticals, UCB BioSciences, AbbVie, Novartis, Biotie Therapies, Lundbeck, Pfizer, Allergan Neuroscience, Neurocrine Biosciences, Chelsea Therapeutics, Auspex Pharmaceuticals, Acadia Pharmaceuticals, Michael J. Fox Foundation, GLG, AstraZeneca, Acorda Therapeutics, Impax Pharmaceuticals, Cynapsus Therapeutics, US WorldMeds, Neuropore, and Prexton Therapeutics. He is employed by the University of South Florida (Florida). Rajesh Pahwa is receiving, or has received, honoraria or payments for consulting from AbbVie, Acadia, Acorda, Adamas, Sunovion, Impax, Lundbeck, Neurocrine, Sage, St. Jude Medical, Teva Neuroscience, UCB, US WorldMeds, and Global Kinetics, and has also received research grants from Acadia, Acorda, Adamas, Avid, Biotie, Boston Scientific, Civitas, Cynapsus, Kyowa, NIH/NINDS, NPF, Pfizer, and PSG/University of Rochester. He has served on the Data Monitoring Committee for Ionis and has received personal compensation as the Co-Editor-in-Chief of the International Journal of Neuroscience. William Wargin is an employee of Nuventra Pharma Sciences. Cindy Souza-Prien, Rajiv Patni, Reed Johnson, Jack Nguyen, and Gregory T. Went are employees of, and own stock in, Adamas Pharmaceuticals. Natalie McClure was employed by Adamas Pharmaceuticals at the time this research was undertaken, and owns stock in Adamas. ETHICS APPROVAL: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. EDAT- 2018/05/20 06:00 MHDA- 2020/02/28 06:00 PMCR- 2018/05/18 CRDT- 2018/05/20 06:00 PHST- 2018/05/20 06:00 [pubmed] PHST- 2020/02/28 06:00 [medline] PHST- 2018/05/20 06:00 [entrez] PHST- 2018/05/18 00:00 [pmc-release] AID - 10.1007/s40262-018-0663-4 [pii] AID - 663 [pii] AID - 10.1007/s40262-018-0663-4 [doi] PST - ppublish SO - Clin Pharmacokinet. 2019 Jan;58(1):77-88. doi: 10.1007/s40262-018-0663-4.