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Clinical Pharmacokinetics

, Volume 53, Issue 9, pp 813–824 | Cite as

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

  • Azmi F. Nasser
  • Christian Heidbreder
  • Roberto Gomeni
  • Paul J. Fudala
  • Bo Zheng
  • Mark K. Greenwald
Original Research Article

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.

Keywords

Buprenorphine Withdrawal Symptom Hydromorphone Opioid Dependence Objective Function Value 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Azmi F. Nasser
    • 1
  • Christian Heidbreder
    • 1
  • Roberto Gomeni
    • 2
  • Paul J. Fudala
    • 1
  • Bo Zheng
    • 1
  • Mark K. Greenwald
    • 3
  1. 1.Reckitt Benckiser Pharmaceuticals Inc.RichmondUSA
  2. 2.AlleantisResearch Triangle ParkUSA
  3. 3.Wayne State UniversityDetroitUSA

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