Portal de Periódicos da CAPES

Pharmacokinetics, metabolism and safety of deuterated L-DOPA (SD-1077)/carbidopa compared to L-DOPA/carbidopa following single oral dose administration in healthy subjects

2018; Wiley; Volume: 84; Issue: 10 Linguagem: Inglês

10.1111/bcp.13702

1365-2125

Frank Schneider, Lavi Erisson, Hooman Beygi, Margaret Bradbury, Orit Cohen‐Barak, Igor D. Grachev, Serge Guzy, Pippa S. Loupe, Micha Levi, Mirna McDonald, Juha‐Matti Savola, Spyros Papapetropoulos, William Tracewell, Maria Velinova, Ofer Spiegelstein,

Chemical Reactions and Isotopes

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 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. Conclusions SD‐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.