title: Pharmacokinetics and pharmacodynamics of gastroretentive delivery of levodopa/carbidopa in patients with Parkinson disease.
abstract: OBJECTIVE
  To investigate, in patients with Parkinson disease, the pharmacokinetics and pharmacodynamics of levodopa/carbidopa delivered via 3 different extended-release (ER) tablet formulations.
  
  
  METHODS
  This was a randomized, crossover study in patients with stable idiopathic Parkinson disease comparing a conventional ER tablet (C-ER) administered orally 3 times daily with 2 levodopa/carbidopa gastroretentive ER formulations administered orally twice daily, one with an immediate release (IR) component (IR/ER) and one without (ER). Blood samples were collected for pharmacokinetic (PK) analysis, and a finger-tapping test was performed to assess pharmacodynamics. Tolerability was evaluated by monitoring adverse events and measuring vital signs. PK modeling was performed to estimate steady-state levodopa concentrations.
  
  
  RESULTS
  Fourteen patients completed the study. Compared with C-ER, both gastroretentive ER tablets significantly extended the first maximum time (6.0 vs 2.5 h; P < 0.025) and had smoother plasma concentration-time profiles while achieving a similar maximum plasma concentration and area under the curve. The IR/ER formulation exhibited a significantly longer duration of concentration above the presumed efficacious threshold of 300 ng/mL (21 vs 18 h; P = 0.0027) compared with C-ER. PK modeling predicts a steady-state levodopa peak/trough ratio of 4 for both IR/ER and ER formulations and a ratio of 21 for C-ER. Furthermore, superior response in the finger tapping test was observed for the IR/ER and ER formulations compared with the C-ER formulation.
  
  
  CONCLUSIONS
  This study demonstrated that the gastroretentive ER formulations achieved more constant plasma levodopa concentrations and better pharmacodynamics with reduced dose frequency, potentially reducing the on-off phenomena that have been associated with fluctuations in plasma levodopa concentrations.
authors.affiliation: Depomed, Inc, Menlo Park, CA 94025, USA. cchen@depomed.com
authors.forename: Cuiping
authors.initials: C
authors.lastname: Chen
authors.forename: Verne E
authors.initials: VE
authors.lastname: Cowles
authors.forename: Michael
authors.initials: M
authors.lastname: Sweeney
authors.forename: Igor D
authors.initials: ID
authors.lastname: Stolyarov
authors.forename: Sergey N
authors.initials: SN
authors.lastname: Illarioshkin
mesh_terms: D000328:Adult; D000368:Aged; D002230:Carbidopa / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology; D007980:Levodopa / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D003692:Delayed-Action Preparations; D007980:Levodopa; D002230:Carbidopa