title: Donepezil Plus Solifenacin (CPC-201) Treatment for Alzheimer's Disease.
abstract: Available cholinergic drugs for treating Alzheimer's disease (AD) provide modest symptomatic benefit. We hypothesized that co-administration of a peripheral anticholinergic to reduce dose-limiting adverse effects (AEs) would enable the safe/tolerable use of higher cholinesterase inhibitor doses and thus improve their antidementia efficacy. A modified single-blind, ascending-dose, phase IIa study of donepezil plus solifenacin (CPC-201) lasting 26 weeks was conducted in 41 patients with probable AD of moderate severity. Entry criteria included the use of donepezil at a dose of 10 mg/day during the preceding 3 months. The primary outcome measure was the maximum tolerated dose (MTD) of donepezil achieved (to protocol limit of 40 mg/day) when administered with the anticholinergic solifenacin 15 mg/day. Secondary measures included assessments of cognitive and global function, as well as of AEs. The mean ± SD donepezil MTD increased to 38 ± 0.74 mg/day (median 40 mg/day; p < 0.001); 88% of the study population safely attained this dose at the end of titration. Markedly reduced donepezil AE frequency, especially gastrointestinal, allowed this dose increase. There were no drug-related serious AEs or clinically significant laboratory abnormalities. At 26 weeks, Alzheimer's Disease Assessment Scale Cognitive Component scores in the efficacy evaluable population improved by 0.35 ± 0.85 points over baseline (p < 0.05), an estimated 2.5 ± 0.84 points above 10 mg/day donepezil and 5.4 ± 0.84 points above historic placebo (both p < 0.05). Clinical Global Impression of Improvement scores improved by 0.94 ± 0.20 to 3.1 ± 0.20 points (p < 0.001). The findings suggest that limiting donepezil AEs by co-administration of solifenacin allows the safe administration of substantially higher cholinesterase inhibitors doses that may augment cognitive and global benefits in patients with AD.
authors.affiliation: Chase Pharmaceuticals, Inc, 1825 K Street NW, Washington, DC, 20006, USA. tchase@chasetherapeutics.com.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Chase
authors.affiliation: Department of Neurology, Indiana University School of Medicine, 541 Clinical Drive, CL299, Indianapolis, IN, 46202, USA.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Farlow
authors.affiliation: Chase Pharmaceuticals, Inc, 1825 K Street NW, Washington, DC, 20006, USA.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Clarence-Smith
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000188:drug therapy*; D002800:Cholinesterase Inhibitors / Q000627:therapeutic use*; D000077265:Donepezil; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007189:Indans / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000627:therapeutic use*; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016037:Single-Blind Method; D000069464:Solifenacin Succinate / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D018727:Muscarinic Antagonists; D010880:Piperidines; D000077265:Donepezil; D000069464:Solifenacin Succinate
keywords: Dementia; anticholinergic.; cholinesterase inhibitor; clinical trial; donepezil; solifenacin