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Maximum Tolerated Dose Evaluation of the AMPA Modulator Org 26576 in Healthy Volunteers and Depressed Patients: A Summary and Method Analysis of Bridging Research in Support of Phase II Dose Selection

BACKGROUND: A key challenge to dose selection in early central nervous system (CNS) clinical drug development is that patient tolerability profiles often differ from those of healthy volunteers (HVs), yet HVs are the modal population for determining doses to be investigated in phase II trials. Witho...

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Autores principales: Nations, Kari R., Bursi, Roberta, Dogterom, Peter, Ereshefsky, Larry, Gertsik, Lev, Mant, Tim, Schipper, Jacques
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585695/
https://www.ncbi.nlm.nih.gov/pubmed/22852579
http://dx.doi.org/10.2165/11634360-000000000-00000
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author Nations, Kari R.
Bursi, Roberta
Dogterom, Peter
Ereshefsky, Larry
Gertsik, Lev
Mant, Tim
Schipper, Jacques
author_facet Nations, Kari R.
Bursi, Roberta
Dogterom, Peter
Ereshefsky, Larry
Gertsik, Lev
Mant, Tim
Schipper, Jacques
author_sort Nations, Kari R.
collection PubMed
description BACKGROUND: A key challenge to dose selection in early central nervous system (CNS) clinical drug development is that patient tolerability profiles often differ from those of healthy volunteers (HVs), yet HVs are the modal population for determining doses to be investigated in phase II trials. Without clear tolerability data from the target patient population, first efficacy trials may include doses that are either too high or too low, creating undue risk for study participants and the development program overall. Bridging trials address this challenge by carefully investigating safety and tolerability in the target population prior to full-scale proof-of-concept trials. OBJECTIVE: Org 26576 is an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor positive allosteric modulator that acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. In preparation for phase II efficacy trials in major depressive disorder (MDD), two separate phase I trials were conducted to evaluate safety, tolerability, and pharmacokinetics in HVs and in the target patient population. METHODS: Both trials were randomized and placebo controlled, and included multiple rising-dose cohorts (HV range 100–400 mg bid; MDD range 100–600mg bid). HVs (n = 36) and patients with MDD (n = 54) were dosed under similarly controlled conditions in an inpatient facility, HVs for up to 14 days and MDD patients for up to 28 days. Safety, tolerability, and pharmacokinetics were assessed frequently. RESULTS: Despite comparable pharmacokinetic profiles, the maximum tolerated dose (MTD) in depressed patients was 450 mg bid, twice the MTD established in HVs. No clinically relevant safety issues associated with Org 26576 were noted. CONCLUSION: This article presents safety, tolerability, and pharmacokinetic data from two different populations examined under similar dosing conditions. The important implications of such bridging work in phase II dose selection are discussed, as are study design and data interpretation challenges.
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spelling pubmed-35856952013-03-04 Maximum Tolerated Dose Evaluation of the AMPA Modulator Org 26576 in Healthy Volunteers and Depressed Patients: A Summary and Method Analysis of Bridging Research in Support of Phase II Dose Selection Nations, Kari R. Bursi, Roberta Dogterom, Peter Ereshefsky, Larry Gertsik, Lev Mant, Tim Schipper, Jacques Drugs R D Original Research Article BACKGROUND: A key challenge to dose selection in early central nervous system (CNS) clinical drug development is that patient tolerability profiles often differ from those of healthy volunteers (HVs), yet HVs are the modal population for determining doses to be investigated in phase II trials. Without clear tolerability data from the target patient population, first efficacy trials may include doses that are either too high or too low, creating undue risk for study participants and the development program overall. Bridging trials address this challenge by carefully investigating safety and tolerability in the target population prior to full-scale proof-of-concept trials. OBJECTIVE: Org 26576 is an alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor positive allosteric modulator that acts by modulating ionotropic AMPA-type glutamate receptors to enhance glutamatergic neurotransmission. In preparation for phase II efficacy trials in major depressive disorder (MDD), two separate phase I trials were conducted to evaluate safety, tolerability, and pharmacokinetics in HVs and in the target patient population. METHODS: Both trials were randomized and placebo controlled, and included multiple rising-dose cohorts (HV range 100–400 mg bid; MDD range 100–600mg bid). HVs (n = 36) and patients with MDD (n = 54) were dosed under similarly controlled conditions in an inpatient facility, HVs for up to 14 days and MDD patients for up to 28 days. Safety, tolerability, and pharmacokinetics were assessed frequently. RESULTS: Despite comparable pharmacokinetic profiles, the maximum tolerated dose (MTD) in depressed patients was 450 mg bid, twice the MTD established in HVs. No clinically relevant safety issues associated with Org 26576 were noted. CONCLUSION: This article presents safety, tolerability, and pharmacokinetic data from two different populations examined under similar dosing conditions. The important implications of such bridging work in phase II dose selection are discussed, as are study design and data interpretation challenges. Springer International Publishing 2012-12-18 2012-09 /pmc/articles/PMC3585695/ /pubmed/22852579 http://dx.doi.org/10.2165/11634360-000000000-00000 Text en © Colau et al., publisher and licensee Springer International Publishing AG 2012
spellingShingle Original Research Article
Nations, Kari R.
Bursi, Roberta
Dogterom, Peter
Ereshefsky, Larry
Gertsik, Lev
Mant, Tim
Schipper, Jacques
Maximum Tolerated Dose Evaluation of the AMPA Modulator Org 26576 in Healthy Volunteers and Depressed Patients: A Summary and Method Analysis of Bridging Research in Support of Phase II Dose Selection
title Maximum Tolerated Dose Evaluation of the AMPA Modulator Org 26576 in Healthy Volunteers and Depressed Patients: A Summary and Method Analysis of Bridging Research in Support of Phase II Dose Selection
title_full Maximum Tolerated Dose Evaluation of the AMPA Modulator Org 26576 in Healthy Volunteers and Depressed Patients: A Summary and Method Analysis of Bridging Research in Support of Phase II Dose Selection
title_fullStr Maximum Tolerated Dose Evaluation of the AMPA Modulator Org 26576 in Healthy Volunteers and Depressed Patients: A Summary and Method Analysis of Bridging Research in Support of Phase II Dose Selection
title_full_unstemmed Maximum Tolerated Dose Evaluation of the AMPA Modulator Org 26576 in Healthy Volunteers and Depressed Patients: A Summary and Method Analysis of Bridging Research in Support of Phase II Dose Selection
title_short Maximum Tolerated Dose Evaluation of the AMPA Modulator Org 26576 in Healthy Volunteers and Depressed Patients: A Summary and Method Analysis of Bridging Research in Support of Phase II Dose Selection
title_sort maximum tolerated dose evaluation of the ampa modulator org 26576 in healthy volunteers and depressed patients: a summary and method analysis of bridging research in support of phase ii dose selection
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585695/
https://www.ncbi.nlm.nih.gov/pubmed/22852579
http://dx.doi.org/10.2165/11634360-000000000-00000
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