科研之友
微信
新浪微博
Facebook
分享链接
摘要
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 mu-opioid receptor occupancy (mu ORO) 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 mu ORO versus buprenorphine plasma concentrations. Linear relationships were found among mu ORO, withdrawal symptoms and blockade of agonist effects. Conclusion Previously published findings have demonstrated mu ORO >= 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.
- 出版日期2014-9
