Published in:
01-09-2014 | Original Research Article
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
Published in: Clinical Pharmacokinetics | Issue 9/2014
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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.