Deutetrabenazine (Austedo, Teva Pharmaceuticals) is a deuterated form of tetrabenazine. It is the first deuterated drug to receive US regulatory approval and is approved for treatment of chorea in Huntington’s disease and tardive dyskinesia. Two oral single dose studies comparing deutetrabenazine (25 mg) with tetrabenazine (25 mg) in healthy volunteers evaluated the impact of deuteration on pharmacokinetics of the active metabolites, alpha‐dihydrotetrabenazine (α‐HTBZ) and beta‐dihydrotetrabenazine (β‐HTBZ), metabolite profile, safety, and tolerability. In the two‐way, cross‐over study, the mean elimination half‐life of deuterated total (α + β)‐HTBZ was doubled compared with nondeuterated total (α + β)‐HTBZ, with a twofold increase in overall mean exposure (area under the concentration‐time curve from zero to infinity (AUC 0–inf )) and a marginal increase in mean peak plasma concentration (C max ). In the mass balance and metabolite profiling study, there were no novel plasma or urinary metabolites of [ 14 C]‐deutetrabenazine relative to [ 14 C]‐tetrabenazine. Specific deuteration in deutetrabenazine resulted in a superior pharmacokinetic profile and an increased ratio of active‐to‐inactive metabolites, attributes considered to provide significant benefits to patients.

Deutetrabenazine (Austedo, Teva), an approved treatment of chorea in Huntington's disease and tardive dyskinesia in adult patients, is a rationally designed deuterated form of tetrabenazine. Two studies assessed the pharmacokinetics and safety of deutetrabenazine compared with tetrabenazine, and the effects of food on absorption of the deuterated active metabolites, α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). One study was an open-label 2-part study in healthy volunteers; the first part included a crossover single dose of two 15 mg candidate deutetrabenazine formulations in fed and fasted states compared with tetrabenazine 25 mg in the fasted state, and the second part included single and repeated dosing of the commercial formulation of deutetrabenazine (7.5, 15, and 22.5 mg) compared with tetrabenazine 25 mg. The second study was an open-label 5-way crossover study in healthy volunteers (n = 32) to evaluate relative bioavailability of 4 dose levels of the commercial formulation of deutetrabenazine (6, 12, 18, and 24 mg) with a standard meal and 18 mg with a high-fat meal.Both studies confirmed longer half-lives for active metabolites and lower peak-to-trough fluctuations for the sum of the metabolites (total [α+β]-HTBZ) following deutetrabenazine compared with tetrabenazine (3-to 4-fold and 11-fold, respectively) in steady-state conditions. Deutetrabenazine doses estimated to provide total (α+β)-HTBZ exposure comparable to tetrabenazine 25 mg were 11.4-13.2 mg. Food had no effect on exposure to total (α+β)-HTBZ, as measured by AUC. Although the total (α+β)-HTBZ C max of deutetrabenazine was increased by ≈50% in the presence of food, it remained lower than that of tetrabenazine.

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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 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).ResultsGeometric 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 < 0.0001) for Cmax and AUC0–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 Cmax and AUC0–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 Cmax and AUC0–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.