Brasofensine treatment for Parkinson's disease in combination with levodopa/carbidopa.
OBJECTIVE
To investigate the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of the dopamine transporter antagonist brasofensine (BMS-204756) in patients with Parkinson's disease receiving levodopa/carbidopa treatment.


METHODS
A 4-period crossover study was performed in 8 men (mean age 66 y) with moderate Parkinson's disease (Hoehn-Yahr stage II-IV). A dose escalation study was used in which each patient was given a single oral dose of brasofensine 0.5, 1, 2, or 4 mg, which was coadministered with the patient's usual dose of levodopa/carbidopa.


RESULTS
The maximum concentration (Cmax) values of brasofensine observed in plasma after oral administration were 0.35, 0.82, 2.14, and 3.27 ng/mL for the 0.5-, 1-, 2-, and 4-mg doses, respectively; these concentrations occurred 4 hours (time to Cmax) after administration in all cases. Exposure to brasofensine (based on AUC0-infinity) increased at a rate greater than proportional to dose. Based on the motor performance subscale of the Unified Parkinson's Disease Rating Scale, no change in patient disability was observed at any dose level.


CONCLUSIONS
Brasofensine was safe and well tolerated in the patient cohort studied at daily doses of up to 4 mg. Adverse events were generally mild in intensity, and included headache, insomnia, phlebitis, dizziness, ecchymosis, and vomiting.
Frackiewicz
Edyta J
EJ
Briston-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ, USA. edyta.frackiewicz@cctrials.com
Jhee
Stanford S
SS
Shiovitz
Thomas M
TM
Webster
Jonathan
J
Topham
Christine
C
Dockens
Randy C
RC
Whigan
Daisy
D
Salazar
Daniel E
DE
Cutler
Neal R
NR
D000368:Aged; D000369:Aged, 80 and over; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D002230:Carbidopa / Q000627:therapeutic use*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D006574:Heterocyclic Compounds, 2-Ring / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D006801:Humans; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010091:Oximes / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D010300:Parkinson Disease / Q000188:drug therapy*; D016896:Treatment Outcome
D000978:Antiparkinson Agents; D006574:Heterocyclic Compounds, 2-Ring; D010091:Oximes; C415103:brasofensine; D007980:Levodopa; D002230:Carbidopa