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Clinical safety and hypothalamic-pituitary-adrenal axis effects of the arginine vasopressin type 1B receptor antagonist ABT-436

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Abstract

Rationale

Arginine vasopressin type 1B receptor (V1B) receptor antagonism is considered a potential therapeutic for diseases with hypothalamic-pituitary-adrenal (HPA) axis dysregulation.

Objectives

The aim of the present study was to evaluate the safety and pharmacodynamics of ABT-436, a selective V1B antagonist, in healthy adults.

Methods

Healthy adults received daily oral doses of ABT-436 in two clinical trials. In a dose escalation trial, nine subjects received each of 100, 500, or 800 mg ABT-436, or placebo, in the morning for 7–14 days. In a crossover trial on two 7-day regimens, 20 subjects received 200 mg ABT-436 each morning or each evening. Pharmacokinetics, measures of basal HPA axis activity, and safety were assessed in both trials.

Results

Mild gastrointestinal intolerance was more common with ABT-436 treatment, compared to placebo, and showed dose dependence. Mean increases and decreases of systolic blood pressure (at different times), and mean pulse increases, were observed in subjects who received 800 mg ABT-436. Mean decreases of plasma adrenocorticotrophic hormone (ACTH), serum cortisol, urine total glucocorticoids, and urine cortisol, compared to placebo, were observed following 7 daily doses of 500 and 800 mg ABT-436. Statistically significant mean differences of plasma ACTH, serum cortisol, and urine total glucocorticoids were observed between morning and evening regimens of 200 mg ABT-436. The largest observed differences were near the times of maximum post-dose ABT-436 plasma concentrations.

Conclusions

ABT-436 regimens of 200–800 mg once daily (QD) for 7 days attenuated basal HPA axis activity. The results support further evaluation of ABT-436 for treatment of disorders in which HPA axis dysregulation may have an etiologic role.

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Acknowledgments

The authors wish to thank the site investigators, site staff, and AbbVie colleagues who contributed to the conduct of the clinical studies. Each author contributed to study design, data collection, analysis, and interpretation. All authors provided intellectual input to the manuscript and approved the final version. These studies comply with the current laws in the country in which they were performed.

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Authors and Affiliations

  1. AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA

    David A. Katz, Wei Liu, Charles Locke, Sandeep Dutta & Katherine A. Tracy

  2. 222 West Merchandise Mart Plaza, Suite 1230, Chicago, IL, 60654, USA

    David A. Katz

Authors
  1. David A. Katz
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  2. Wei Liu
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  3. Charles Locke
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  4. Sandeep Dutta
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  5. Katherine A. Tracy
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Corresponding author

Correspondence to David A. Katz.

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Conflict of interest

These studies were funded by AbbVie Inc. AbbVie participated in the study design, research, data collection, analysis and interpretation of data, writing, reviewing, and approving the publication. All authors are (or were at the time of the studies) employees of, and may own AbbVie Inc. stock or options. David A. Katz is currently an employee of Sparrow Pharmaceuticals, Inc. Katherine A. Tracy is currently an employee of Astellas Pharma.

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Katz, D.A., Liu, W., Locke, C. et al. Clinical safety and hypothalamic-pituitary-adrenal axis effects of the arginine vasopressin type 1B receptor antagonist ABT-436. Psychopharmacology 233, 71–81 (2016). https://doi.org/10.1007/s00213-015-4089-5

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  • DOI: https://doi.org/10.1007/s00213-015-4089-5

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