Pharmacokinetics, Metabolism and Safety of Deuterated L-DOPA (SD-1077)/Carbidopa (CD) Compared to L-DOPA/CD following single oral dose administration in Healthy Subjects.

AimsSD-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. MethodsPlasma and urine PK of drug and metabolites and safety after a single oral 150mg SD-1077 dose were compared to 150mgL-DOPA, each in combination with 37.5mg carbidopa (CD) in a double-blind, two-period, crossover study in healthy volunteers (n=16). ResultsGeometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD-1077 vs. L-DOPA for C-max, AUC(0-t), and AUC(0-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<0.0001) for C-max and AUC(0-t) and a concomitant reduction in the ratio of 3,4-dihydroxyphenylacetic acid/DA confirming slower metabolic breakdown of DA by monoamine oxidase (MAO). There were increases in systemic exposures to metabolites of catechol O-methyltransferase (COMT) reaction, 3-methoxytyramine (3-MT) and 3-O-methyldopa (3-OMD) with GMRs (90% CI) for SD-1077/CD to L-DOPA/CD for 3-MT exposure of 1.33 (1.14-1.56; P=0.0077) and 1.66 (1.42-1.93; P<0.0001) for C-max and AUC(0-t), respectively and GMRs (90% CI) for 3-OMD of 1.19 (1.15, 1.23; P<0.0001) and 1.31 (1.27, 1.36; P<0.0001) for C-max and AUC(0-t). SD-1077/CD exhibited comparable tolerability and safety to L-DOPA/CD. ConclusionsSD-1077/CD demonstrated the potential to prolong exposure to central DA at comparable peripheral PK and safety to the reference L-DOPA/CD combination. A single dose of SD-1077 is safe for further clinical development in Parkinson's disease patients.