Limits...
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 KR, Bursi R, Dogterom P, Ereshefsky L, Gertsik L, Mant T, Schipper J - Drugs R D (2012)

Bottom Line: No clinically relevant safety issues associated with Org 26576 were noted.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.

View Article: PubMed Central - PubMed

Affiliation: Merck Sharp Dohme Corp., Whitehouse Station, NJ, USA.

ABSTRACT

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 100-600 mg 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.

Show MeSH

Related in: MedlinePlus

Demographic and baseline characteristics of randomized subjects
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3585695&req=5

Tab1: Demographic and baseline characteristics of randomized subjects

Mentions: A total of 36 and 54 subjects were randomized in the HV and patient studies, respectively (see table I). All received at least one dose of study medication and therefore qualified for the all-subjects-treated population. All participants in the HV study were male, as were the majority (65%) in the patient study. The patient study sample was more racially diverse and somewhat older than the HV sample. Weight and body mass index (BMI) were comparable between studies. In the patient study, the majority of patients (76%) were diagnosed with recurrent depression, and the number of lifetime episodes was 4.4; the mean QIDS-C total score at baseline was 15.1 (standard deviation [SD] 2.26), reflecting moderately severe depression.[31]


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 KR, Bursi R, Dogterom P, Ereshefsky L, Gertsik L, Mant T, Schipper J - Drugs R D (2012)

Demographic and baseline characteristics of randomized subjects
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585695&req=5

Tab1: Demographic and baseline characteristics of randomized subjects
Mentions: A total of 36 and 54 subjects were randomized in the HV and patient studies, respectively (see table I). All received at least one dose of study medication and therefore qualified for the all-subjects-treated population. All participants in the HV study were male, as were the majority (65%) in the patient study. The patient study sample was more racially diverse and somewhat older than the HV sample. Weight and body mass index (BMI) were comparable between studies. In the patient study, the majority of patients (76%) were diagnosed with recurrent depression, and the number of lifetime episodes was 4.4; the mean QIDS-C total score at baseline was 15.1 (standard deviation [SD] 2.26), reflecting moderately severe depression.[31]

Bottom Line: No clinically relevant safety issues associated with Org 26576 were noted.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.

View Article: PubMed Central - PubMed

Affiliation: Merck Sharp Dohme Corp., Whitehouse Station, NJ, USA.

ABSTRACT

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 100-600 mg 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.

Show MeSH
Related in: MedlinePlus