1. Pharmacokinetics, metabolism and safety of deuterated L-DOPA (SD-1077)/carbidopa compared to L-DOPA/carbidopa following single oral dose administration in healthy subjects
- Author
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Hooman Beygi, Igor D. Grachev, Juha-Matti Savola, Micha Levi, Serge Guzy, Margaret Bradbury, Pippa S. Loupe, Lavi Erisson, Ofer Spiegelstein, Maria Velinova, Spyros Papapetropoulos, William Tracewell, Mirna McDonald, Orit Cohen-Barak, and Frank Schneider
- Subjects
0301 basic medicine ,Pharmacology ,business.industry ,Monoamine oxidase ,Cmax ,Urine ,Crossover study ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Tolerability ,Pharmacokinetics ,Dopamine ,Carbidopa ,Medicine ,Pharmacology (medical) ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
AIMS SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD-1077. METHODS Plasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD-1077 dose were compared to 150 mg L-DOPA, each in combination with 37.5 mg carbidopa (CD) in a double-blind, two-period, crossover study in healthy volunteers (n = 16). RESULTS Geometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD-1077 vs. L-DOPA for Cmax , AUC0-t , and AUC0-inf were 88.4 (75.9-103.1), 89.5 (84.1-95.3), and 89.6 (84.2-95.4), respectively. Systemic exposure to DA was significantly higher after SD-1077/CD compared to that after L-DOPA/CD, with GMRs (90% CI) of 1.8 (1.45-2.24; P = 0.0005) and 2.06 (1.68-2.52; P
- Published
- 2018