title: Double-blind study of the actively transported levodopa prodrug XP21279 in Parkinson's disease.
abstract: The objective of this study was to assess the efficacy, safety, and pharmacokinetics of XP21279-carbidopa in patients with Parkinson's disease who experience motor fluctuations compared with immediate-release carbidopa-levodopa tablets. XP21279 is a levodopa prodrug that is actively absorbed by high-capacity nutrient transporters expressed throughout the gastrointestinal tract and then rapidly converted to levodopa by carboxylesterases. XP21279-carbidopa sustained-release bilayer tablets were developed to overcome pharmacokinetic limitations of levodopa by providing more continuous exposure. Patients with motor fluctuations who required carbidopa-levodopa four or five times daily were optimized for 2 weeks each on carbidopa-levodopa four or five times daily and XP21279-carbidopa three times daily in a randomized sequence. Next, they received each optimized treatment for 2 weeks in a double-blind/double-dummy, randomized sequence. The primary outcome measure was change from baseline in daily off time at the end of each double-blind treatment period. All patients at 2 sites underwent pharmacokinetic analyses. Twenty-eight of 35 enrolled patients completed both double-blind treatments. The mean total daily off time was reduced from baseline by a mean (± standard error) of 2.7 hours (± 0.48 hours) for immediate-release carbidopa-levodopa and 3.0 hours (± 0.57 hours) for XP21279-carbidopa (P = 0.49). Among 11 patients who completed pharmacokinetic sampling on each optimized treatment, the percentage deviation from the mean levodopa concentration was lower (P < 0.05) for XP21279-carbidopa than carbidopa-levodopa. Both treatments had a similar incidence of new or worsening dyskinesias. XP21279-carbidopa administered three times daily produced a reduction in off time similar to that of carbidopa-levodopa administered four or five times daily, and the difference was not statistically significant. XP21279-carbidopa significantly reduced variability in levodopa concentrations compared with carbidopa-levodopa.
authors: Department of Neurology, Henry Ford Hospital, West Bloomfield, Michigan, USA; Department of Neurology, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors: Peter A
authors: PA
authors: LeWitt
authors: F Jacob
authors: FJ
authors: Huff
authors: Robert A
authors: RA
authors: Hauser
authors: Dan
authors: D
authors: Chen
authors: Dmitri
authors: D
authors: Lissin
authors: Katie
authors: K
authors: Zomorodi
authors: Kenneth C
authors: KC
authors: Cundy
mesh_terms: D000978:Antiparkinson Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002230:Carbidopa / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007980:Levodopa / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy*; D011355:Prodrugs / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000978:Antiparkinson Agents; D004338:Drug Combinations; D011355:Prodrugs; C009265:carbidopa, levodopa drug combination; D007980:Levodopa; D002230:Carbidopa
keywords: Parkinson's disease; XP21279; dyskinesias; levodopa; motor fluctuations; pharmacokinetics