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Population pharmacokinetic and pharmacodynamic analyses of safinamide in subjects with Parkinson's disease
Safinamide is an orally administered α‐aminoamide derivative with both dopaminergic and non‐dopaminergic properties. Nonlinear mixed effects models for population pharmacokinetic (PK) and pharmacokinetic–pharmacodynamic (PKPD) analyses were developed using records from, respectively, 623 and 668 pat...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045937/ https://www.ncbi.nlm.nih.gov/pubmed/27713822 http://dx.doi.org/10.1002/prp2.251 |
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author | Loprete, Luca Leuratti, Chiara Cattaneo, Carlo Thapar, Mita M. Farrell, Colm Sardina, Marco |
author_facet | Loprete, Luca Leuratti, Chiara Cattaneo, Carlo Thapar, Mita M. Farrell, Colm Sardina, Marco |
author_sort | Loprete, Luca |
collection | PubMed |
description | Safinamide is an orally administered α‐aminoamide derivative with both dopaminergic and non‐dopaminergic properties. Nonlinear mixed effects models for population pharmacokinetic (PK) and pharmacokinetic–pharmacodynamic (PKPD) analyses were developed using records from, respectively, 623 and 668 patients belonging to two Phase 3, randomized, placebo‐controlled, double‐blind efficacy studies. The aim was to estimate safinamide population PK parameters in patients with Parkinson's disease (PD) on stable levodopa therapy, and to develop a model of safinamide effect on the PD phase of normal functioning (ON‐time). The final models were internally evaluated using visual predictive checks (VPCs), prediction corrected‐VPC, and nonparametric bootstrap analysis. Safinamide profiles were adequately described by a linear one‐compartmental model with first‐order absorption and elimination. CL/F, Vd/F, and KA (95% confidence interval [CI]) were 4.96 (4.73–5.21) L/h, 166 (158–174) L, and 0.582 (0.335–0.829) h(−1), respectively. CL/F and Vd/F increased with body weight, while age, gender, renal function, and exposure to levodopa did not influence safinamide PK. The observed ON‐time values were adequately described by a linear model, with time in the study period as dependent variable, and rate of ON‐time change and baseline plus offset effect as slope and intercept parameters. Safinamide treatment resulted in an increase in ON‐time of 0.73 h (week 4), with further ON‐time increase with the same slope as placebo. The increase was not influenced by age, levodopa, or safinamide exposure. The population models adequately describe the population PK of safinamide and safinamide effect on ON‐time. No dose adjustments in elderly and mild to moderate renally impaired patients are requested. |
format | Online Article Text |
id | pubmed-5045937 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-50459372016-10-06 Population pharmacokinetic and pharmacodynamic analyses of safinamide in subjects with Parkinson's disease Loprete, Luca Leuratti, Chiara Cattaneo, Carlo Thapar, Mita M. Farrell, Colm Sardina, Marco Pharmacol Res Perspect Original Articles Safinamide is an orally administered α‐aminoamide derivative with both dopaminergic and non‐dopaminergic properties. Nonlinear mixed effects models for population pharmacokinetic (PK) and pharmacokinetic–pharmacodynamic (PKPD) analyses were developed using records from, respectively, 623 and 668 patients belonging to two Phase 3, randomized, placebo‐controlled, double‐blind efficacy studies. The aim was to estimate safinamide population PK parameters in patients with Parkinson's disease (PD) on stable levodopa therapy, and to develop a model of safinamide effect on the PD phase of normal functioning (ON‐time). The final models were internally evaluated using visual predictive checks (VPCs), prediction corrected‐VPC, and nonparametric bootstrap analysis. Safinamide profiles were adequately described by a linear one‐compartmental model with first‐order absorption and elimination. CL/F, Vd/F, and KA (95% confidence interval [CI]) were 4.96 (4.73–5.21) L/h, 166 (158–174) L, and 0.582 (0.335–0.829) h(−1), respectively. CL/F and Vd/F increased with body weight, while age, gender, renal function, and exposure to levodopa did not influence safinamide PK. The observed ON‐time values were adequately described by a linear model, with time in the study period as dependent variable, and rate of ON‐time change and baseline plus offset effect as slope and intercept parameters. Safinamide treatment resulted in an increase in ON‐time of 0.73 h (week 4), with further ON‐time increase with the same slope as placebo. The increase was not influenced by age, levodopa, or safinamide exposure. The population models adequately describe the population PK of safinamide and safinamide effect on ON‐time. No dose adjustments in elderly and mild to moderate renally impaired patients are requested. John Wiley and Sons Inc. 2016-08-08 /pmc/articles/PMC5045937/ /pubmed/27713822 http://dx.doi.org/10.1002/prp2.251 Text en © 2016 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Articles Loprete, Luca Leuratti, Chiara Cattaneo, Carlo Thapar, Mita M. Farrell, Colm Sardina, Marco Population pharmacokinetic and pharmacodynamic analyses of safinamide in subjects with Parkinson's disease |
title | Population pharmacokinetic and pharmacodynamic analyses of safinamide in subjects with Parkinson's disease |
title_full | Population pharmacokinetic and pharmacodynamic analyses of safinamide in subjects with Parkinson's disease |
title_fullStr | Population pharmacokinetic and pharmacodynamic analyses of safinamide in subjects with Parkinson's disease |
title_full_unstemmed | Population pharmacokinetic and pharmacodynamic analyses of safinamide in subjects with Parkinson's disease |
title_short | Population pharmacokinetic and pharmacodynamic analyses of safinamide in subjects with Parkinson's disease |
title_sort | population pharmacokinetic and pharmacodynamic analyses of safinamide in subjects with parkinson's disease |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045937/ https://www.ncbi.nlm.nih.gov/pubmed/27713822 http://dx.doi.org/10.1002/prp2.251 |
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