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A Population Pharmacokinetic and Pharmacodynamic Modelling Approach to Support the Clinical Development of RBP-6000, a New, Subcutaneously Injectable, Long-Acting, Sustained-Release Formulation of Buprenorphine, for the Treatment of Opioid Dependence

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Abstract

Background and Objectives

This study implemented pharmacokinetic/pharmacodynamic modelling to support the clinical development of RBP-6000, a new, long-acting, sustained-release formulation of buprenorphine for the treatment of opioid dependence. Such a formulation could offer advantages over existing buprenorphine pharmacotherapy by improving patient compliance and reducing the diversion of the product.

Methods

A population pharmacokinetic model was developed using 36 opioid-dependent subjects who received single subcutaneous doses of RBP-6000. Another pharmacokinetic/pharmacodynamic model was developed using μ-opioid receptor occupancy (µORO) data to predict efficacy of RBP-6000 after repeated doses. It was also assessed how buprenorphine plasma concentrations were correlated with opioid withdrawal symptoms and hydromorphone agonist blockade data from 15 heroin-dependent subjects.

Results

The resulting pharmacokinetic model accurately described buprenorphine and norbuprenorphine plasma concentrations. A saturable maximum effect (E max) model with 0.67 ng/mL effective concentration at 50 % of maximum (EC50) and 91 % E max best described µORO versus buprenorphine plasma concentrations. Linear relationships were found among µORO, withdrawal symptoms and blockade of agonist effects.

Conclusion

Previously published findings have demonstrated µORO ≥70 % is needed to achieve withdrawal suppression and blockade of opioid agonist subjective effects. Model simulations indicated that a 200 mg RBP-6000 dose should achieve 2–3 ng/mL buprenorphine average concentrations and desired efficacy.

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Acknowledgments

The authors would like to acknowledge Bradley Vince, DO, President and Medical Director at Vince & Associates (10103 Metcalf Avenue, Overland Park, KS 66212, USA) for patient recruitment in this study.

Conflict of Interest/Disclosure

At the time this manuscript was submitted for publication, A.F. Nasser, C. Heidbreder, P.J. Fudala and B. Zheng were full-time employees of Reckitt Benckiser Pharmaceuticals Inc. M.K. Greenwald was a full-time employee of Wayne State University, and was a paid consultant for Reckitt Benckiser Pharmaceuticals Inc. R. Gomeni was a paid consultant for Reckitt Benckiser Pharmaceuticals Inc.

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Authors and Affiliations

  1. Reckitt Benckiser Pharmaceuticals Inc., 10710 Midlothian Turnpike, Suite 430, Richmond, VA, 23235, USA

    Azmi F. Nasser, Christian Heidbreder, Paul J. Fudala & Bo Zheng

  2. Alleantis, Research Triangle Park, NC, 27709, USA

    Roberto Gomeni

  3. Wayne State University, Detroit, MI, 48202, USA

    Mark K. Greenwald

Authors
  1. Azmi F. Nasser
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  2. Christian Heidbreder
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  3. Roberto Gomeni
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  4. Paul J. Fudala
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  5. Bo Zheng
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  6. Mark K. Greenwald
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Correspondence to Azmi F. Nasser.

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Nasser, A.F., Heidbreder, C., Gomeni, R. et al. A Population Pharmacokinetic and Pharmacodynamic Modelling Approach to Support the Clinical Development of RBP-6000, a New, Subcutaneously Injectable, Long-Acting, Sustained-Release Formulation of Buprenorphine, for the Treatment of Opioid Dependence. Clin Pharmacokinet 53, 813–824 (2014). https://doi.org/10.1007/s40262-014-0155-0

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  • DOI: https://doi.org/10.1007/s40262-014-0155-0

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