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

Mean dose-normalized plasma concentrations of Org 26576 on days 1, 4, and 27 for (a) the 100 mg twice-daily dose and (b) the 400 mg twice-daily dose in MDD patients.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3585695&req=5

Fig3: Mean dose-normalized plasma concentrations of Org 26576 on days 1, 4, and 27 for (a) the 100 mg twice-daily dose and (b) the 400 mg twice-daily dose in MDD patients.

Mentions: The mean dose-normalized plasma concentrations observed in part II of this study at days 1, 4, and 27 for the 100 mg and 400 mg bid treatment groups are displayed in figure 3a and 3b, respectively. The mean dn-Cmax and dn-AUC values for days 4 and 27 in the 100 mg bid treatment group (see table III) were approximately 30% higher than for day 1 (data not shown). For the 400 mg bid treatment group, similar mean dn-Cmax and dn-AUC values were found for all days. The mean dose-normalized exposure values for the 400 mg bid group tended to be somewhat higher than those for the 100 mg bid group (see table III). An explorative ANOVA on all subjects in part II showed no statistically significant overall ‘Dose’, ‘Day’, or ‘Dose*Day’ effects on dn-Cmax, tmax, dn-AUC, and t1/2. No major deviations from the dose proportionality and time independence of the kinetics of Org 26576 were observed in this study in the titration schemes and dose range tested. For cohort D of part I, the mean Org 26576 exposure and concentration values in plasma and CSF were similar, both on day 1 (100 mg single dose) and on day 10 (300 mg steady state). The CSF tmax followed the plasma tmax by approximately 15 minutes with single doses and by approximately 1.5 hours with multiple doses.


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)

Mean dose-normalized plasma concentrations of Org 26576 on days 1, 4, and 27 for (a) the 100 mg twice-daily dose and (b) the 400 mg twice-daily dose in MDD patients.
© Copyright Policy
Related In: Results  -  Collection

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

Fig3: Mean dose-normalized plasma concentrations of Org 26576 on days 1, 4, and 27 for (a) the 100 mg twice-daily dose and (b) the 400 mg twice-daily dose in MDD patients.
Mentions: The mean dose-normalized plasma concentrations observed in part II of this study at days 1, 4, and 27 for the 100 mg and 400 mg bid treatment groups are displayed in figure 3a and 3b, respectively. The mean dn-Cmax and dn-AUC values for days 4 and 27 in the 100 mg bid treatment group (see table III) were approximately 30% higher than for day 1 (data not shown). For the 400 mg bid treatment group, similar mean dn-Cmax and dn-AUC values were found for all days. The mean dose-normalized exposure values for the 400 mg bid group tended to be somewhat higher than those for the 100 mg bid group (see table III). An explorative ANOVA on all subjects in part II showed no statistically significant overall ‘Dose’, ‘Day’, or ‘Dose*Day’ effects on dn-Cmax, tmax, dn-AUC, and t1/2. No major deviations from the dose proportionality and time independence of the kinetics of Org 26576 were observed in this study in the titration schemes and dose range tested. For cohort D of part I, the mean Org 26576 exposure and concentration values in plasma and CSF were similar, both on day 1 (100 mg single dose) and on day 10 (300 mg steady state). The CSF tmax followed the plasma tmax by approximately 15 minutes with single doses and by approximately 1.5 hours with multiple doses.

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