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Pharmacokinetic/Pharmacodynamic Correlation Analysis of Amantadine for Levodopa-Induced Dyskinesia.
Brigham, Elizabeth F; Johnston, Tom H; Brown, Carl; Holt, Jonathon D S; Fox, Susan H; Hill, Michael P; Howson, Patrick A; Brotchie, Jonathan M; Nguyen, Jack T.
Afiliación
  • Brigham EF; Adamas Pharmaceuticals, Inc., Emeryville, California (E.F.B., C.B., J.D.S.H., J.T.N.); Atuka Inc, Toronto, Ontario, Canada (T.H.J., M.P.H., P.A.H., J.M.B.); Krembil Research Institute, University Health Network, Toronto, Ontario, Canada (T.H.J., S.H.F., J.M.B.); and Morton and Gloria Shulman Movemen
  • Johnston TH; Adamas Pharmaceuticals, Inc., Emeryville, California (E.F.B., C.B., J.D.S.H., J.T.N.); Atuka Inc, Toronto, Ontario, Canada (T.H.J., M.P.H., P.A.H., J.M.B.); Krembil Research Institute, University Health Network, Toronto, Ontario, Canada (T.H.J., S.H.F., J.M.B.); and Morton and Gloria Shulman Movemen
  • Brown C; Adamas Pharmaceuticals, Inc., Emeryville, California (E.F.B., C.B., J.D.S.H., J.T.N.); Atuka Inc, Toronto, Ontario, Canada (T.H.J., M.P.H., P.A.H., J.M.B.); Krembil Research Institute, University Health Network, Toronto, Ontario, Canada (T.H.J., S.H.F., J.M.B.); and Morton and Gloria Shulman Movemen
  • Holt JDS; Adamas Pharmaceuticals, Inc., Emeryville, California (E.F.B., C.B., J.D.S.H., J.T.N.); Atuka Inc, Toronto, Ontario, Canada (T.H.J., M.P.H., P.A.H., J.M.B.); Krembil Research Institute, University Health Network, Toronto, Ontario, Canada (T.H.J., S.H.F., J.M.B.); and Morton and Gloria Shulman Movemen
  • Fox SH; Adamas Pharmaceuticals, Inc., Emeryville, California (E.F.B., C.B., J.D.S.H., J.T.N.); Atuka Inc, Toronto, Ontario, Canada (T.H.J., M.P.H., P.A.H., J.M.B.); Krembil Research Institute, University Health Network, Toronto, Ontario, Canada (T.H.J., S.H.F., J.M.B.); and Morton and Gloria Shulman Movemen
  • Hill MP; Adamas Pharmaceuticals, Inc., Emeryville, California (E.F.B., C.B., J.D.S.H., J.T.N.); Atuka Inc, Toronto, Ontario, Canada (T.H.J., M.P.H., P.A.H., J.M.B.); Krembil Research Institute, University Health Network, Toronto, Ontario, Canada (T.H.J., S.H.F., J.M.B.); and Morton and Gloria Shulman Movemen
  • Howson PA; Adamas Pharmaceuticals, Inc., Emeryville, California (E.F.B., C.B., J.D.S.H., J.T.N.); Atuka Inc, Toronto, Ontario, Canada (T.H.J., M.P.H., P.A.H., J.M.B.); Krembil Research Institute, University Health Network, Toronto, Ontario, Canada (T.H.J., S.H.F., J.M.B.); and Morton and Gloria Shulman Movemen
  • Brotchie JM; Adamas Pharmaceuticals, Inc., Emeryville, California (E.F.B., C.B., J.D.S.H., J.T.N.); Atuka Inc, Toronto, Ontario, Canada (T.H.J., M.P.H., P.A.H., J.M.B.); Krembil Research Institute, University Health Network, Toronto, Ontario, Canada (T.H.J., S.H.F., J.M.B.); and Morton and Gloria Shulman Movemen
  • Nguyen JT; Adamas Pharmaceuticals, Inc., Emeryville, California (E.F.B., C.B., J.D.S.H., J.T.N.); Atuka Inc, Toronto, Ontario, Canada (T.H.J., M.P.H., P.A.H., J.M.B.); Krembil Research Institute, University Health Network, Toronto, Ontario, Canada (T.H.J., S.H.F., J.M.B.); and Morton and Gloria Shulman Movemen
J Pharmacol Exp Ther ; 367(2): 373-381, 2018 11.
Article en En | MEDLINE | ID: mdl-30087157
Dyskinesia is a common motor complication associated with the use of levodopa to treat Parkinson's disease. Numerous animal studies in mice, rats, and nonhuman primates have demonstrated that the N-methyl-d-aspartate antagonist, amantadine, dose dependently reduces levodopa-induced dyskinesia (LID). However, none of these studies characterized the amantadine plasma concentrations required for a therapeutic effect. This study evaluates the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between amantadine plasma concentrations and antidyskinetic efficacy across multiple species to define optimal therapeutic dosing. The PK profile of amantadine was determined in mice, rats, and macaques. Efficacy data from the 6-hydroxydopamine rat and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine macaque model of LID, along with previously published antidyskinetic efficacy data, were used to establish species-specific PK/PD relationships using a direct-effect maximum possible effect model. Results from the PK/PD model were compared with amantadine plasma concentrations and antidyskinetic effect in a phase 2 study in patients with Parkinson's disease treated with ADS-5102, an extended-release amantadine capsule formulation. Outcomes from each of the species evaluated indicate that the EC50 of amantadine for reducing dyskinesia range from 1025 to 1633 ng/ml (1367 ng/ml for an all-species model). These data are consistent with the mean amantadine plasma concentrations observed in patients with Parkinson's disease (∼1500 ng/ml) treated with ADS-5102 at doses that demonstrated a statistically significant reduction in dyskinesia. These results demonstrate that the EC50 of amantadine for reducing dyskinesia is consistent across multiple species and supports a plasma concentration target of ∼1400 ng/ml to achieve therapeutic efficacy.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Amantadina / Levodopa / Discinesia Inducida por Medicamentos Límite: Animals Idioma: En Revista: J Pharmacol Exp Ther Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Amantadina / Levodopa / Discinesia Inducida por Medicamentos Límite: Animals Idioma: En Revista: J Pharmacol Exp Ther Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos