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184 Insulin Sensitivity and Glucose Metabolism of Olanzapine and Combination Olanzapine and Samidorphan: A Phase 1 Exploratory Study in Healthy Volunteers

  • William Martin (a1), Christine Graham (a2), Linda Morrow (a3), Carine Beysen (a4), Frederico G.S. Toledo (a5), Daiva Bajorunas (a6), Ying Jiang (a7), Bernard Silverman (a8), David McDonnell (a9), Mark N. Namchuk (a10) and John W. Newcomer (a11)...

Abstract:

Background:

A combination of olanzapine and samidorphan (OLZ/SAM) is in development for schizophrenia to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. The objective of this phase 1 exploratory study was to assess metabolic treatment effects of OLZ/SAM.

Methods:

Healthy, non-obese adults (18–40 years) were randomized 2:2:1 to once-daily OLZ/SAM, olanzapine, or placebo for 21 days. Assessments included oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, weight gain, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance.

Results:

Sixty subjects were randomized (OLZ/SAM, n=24; olanzapine, n=24; placebo, n=12); 19 (79.2%), 22 (91.7%), and 11 (91.7%), respectively, completed the study. In the OGTT, olanzapine led to significant hyperinsulinemia (P<0.0001) and significantly reduced insulin sensitivity (2-hour Matsuda index) at day 19 vs baseline (P=0.0012), changes not observed with OLZ/SAM. No significant between-group differences were observed for change from baseline in clamp-derived insulin sensitivity index at day 21. Least squares mean weight change from baseline was similar with OLZ/SAM (3.16 kg) and olanzapine (2.87 kg); both were significantly higher than placebo (0.57 kg; both P<0.01). Caloric intake significantly decreased from baseline to day 22 with OLZ/SAM (P=0.015) but not with olanzapine or placebo. Forty-nine subjects (81.7%) experienced ≥1 AE (OLZ/SAM, 87.5%; olanzapine, 79.2%; placebo, 75.0%).

Conclusions:

In this exploratory study, hyperinsulinemia and decreased insulin sensitivity were observed in the OGTT with olanzapine but not with OLZ/SAM or placebo. Clamp-derived insulin sensitivity index and weight changes were similar with OLZ/SAM and olanzapine in healthy subjects during the 3-week study.

Funding Acknowledgements:

This study was funded by Alkermes, Inc.

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184 Insulin Sensitivity and Glucose Metabolism of Olanzapine and Combination Olanzapine and Samidorphan: A Phase 1 Exploratory Study in Healthy Volunteers

  • William Martin (a1), Christine Graham (a2), Linda Morrow (a3), Carine Beysen (a4), Frederico G.S. Toledo (a5), Daiva Bajorunas (a6), Ying Jiang (a7), Bernard Silverman (a8), David McDonnell (a9), Mark N. Namchuk (a10) and John W. Newcomer (a11)...

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