title: 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.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Azmi F
authors.initials: AF
authors.lastname: Nasser
authors.forename: Christian
authors.initials: C
authors.lastname: Heidbreder
authors.forename: Roberto
authors.initials: R
authors.lastname: Gomeni
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fudala
authors.forename: Bo
authors.initials: B
authors.lastname: Zheng
authors.forename: Mark K
authors.initials: MK
authors.lastname: Greenwald
mesh_terms: D000328:Adult; D002047:Buprenorphine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D007267:Injections; D007279:Injections, Subcutaneous; D008297:Male; D008954:Models, Biological; D009293:Opioid-Related Disorders / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*
chemical_list: D003692:Delayed-Action Preparations; D017450:Receptors, Opioid, mu; D002047:Buprenorphine; C043585:norbuprenorphine