Sustained-Release Buprenorphine (RBP-6000) Blocks the Effects of Opioid Challenge With Hydromorphone in Subjects With Opioid Use Disorder

Nasser, Azmi; Greenwald, Mark K.; Vince, Bradley; Fudala, Paul J.; Twumasi‐Ankrah, Philip; Liu, Yongzhen; Jones, J. P.; Heidbreder, Christian

doi:10.1097/jcp.0000000000000434

Cited by 57 publications

(42 citation statements)

References 21 publications

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“…A US study demonstrated that a 300 mg dose of RBP-6000 provided a potent blockade of the subjective effects and reinforcing efficacy of hydromorphone in subjects with moderate or severe OUD. 74 In addition, pharmacokinetic analysis of RBP-6000 showed that a subcutaneous dose of 300 mg every 28 days rapidly achieved effective drug exposure after the initial injection and maintained effective levels during chronic treatment. A simulated 2-week drug holiday demonstrated μ-opioid receptor occupancy consistently above 80% without loss of drug efficacy.…”

Section: New Medication Delivery Approaches For Treating Oudmentioning

confidence: 99%

Advances in the delivery of buprenorphine for opioid dependence

Rosenthal¹,

Goradia²

2017

DDDT

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Opioid use disorders (OUDs) have long been a global problem, but the prevalence rates have increased over 20 years to epidemic proportions in the US, with concomitant increases in morbidity and all-cause mortality, but especially opioid overdose. These increases are in part attributable to a several-fold expansion in the prescription of opioid pain medications over the same time period. Opioid detoxification and psychosocial treatments alone have each not yielded sufficient efficacy for OUD, but μ-opioid receptor agonist, partial agonist, and antagonist medications have demonstrated the greatest overall benefit in OUD treatment. Buprenorphine, a μ-opioid receptor partial agonist, has been used successfully on an international basis for several decades in sublingual tablet and film preparations for the treatment of OUD, but the nature of formulation, which is typically self-administered, renders it susceptible to nonadherence, diversion, and accidental exposure. This article reviews the clinical trial data for novel buprenorphine delivery systems in the form of subcutaneous depot injections, transdermal patches, and subdermal implants for the treatment of OUD and discusses both the clinical efficacy of longer-acting formulations through increasing consistent medication exposure and their potential utility in reducing diversion. These new delivery systems also offer new dosing opportunities for buprenorphine and strategies for dosing intervals in the treatment of OUD.

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Section: New Medication Delivery Approaches For Treating Oudmentioning

confidence: 99%

Advances in the delivery of buprenorphine for opioid dependence

Rosenthal¹,

Goradia²

2017

DDDT

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“…The ability of BUP to block the effect of full opioid agonists on the lOR has been shown in pharmacological 'blockade' or 'challenge' studies where patients are first administered BUP at different doses and then challenged with drugs such as heroin or hydromorphone [4]. There are some authors of scientific publications claiming that an adequate opioid blockade requires an 'optimal exposure' with BUP plasma concentrations of 2-3 ng/ mL and that this is achieved with a daily sublingual (SL) dose of BUP or buprenorphine/naloxone (BUP-NLX) of 16 mg and higher [5][6][7]. However, others suggest that further research is needed to understand dose-response relationships in patients with this complex disorder [8,9].…”

Section: Introductionmentioning

confidence: 99%

Optimal dose of buprenorphine in opioid use disorder treatment: a review of pharmacodynamic and efficacy data

Hjelmström¹,

Nordbeck²,

Tiberg³

2020

Drug Development and Industrial Pharmacy

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Context: There is currently no consensus regarding optimal dose or dose-range of buprenorphine (BUP) for treatment of opioid use disorder (OUD). Objective: To elucidate the relationship between BUP dose and opioid receptor blockade, retention in treatment and illicit opioid drug use. Methods: Systematic review of the scientific literature through searches in the databases MEDLINE and PubMed. Results: The review of the opioid receptor blockade studies did not find evidence that a daily sublingual (SL) BUP tablet dose higher than 16 mg confers added blockade benefit, while doses under 8 mg are insufficient to produce opioid receptor blockade. The data are inconclusive regarding the relative effectiveness of an 8 mg SL BUP tablet dose versus a 16 mg SL BUP tablet dose in terms of opioid receptor blockade. The review did not establish any clear relationship between BUP dose and treatment retention or illicit opioid use. Conclusions: The BUP dose in treatment of OUD should be individualized based on a continuous clinical benefit-risk assessment. Further research is needed to better understand the relationship between dose and efficacy over time in patients with this complex disorder.

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“…A total of nine subcutaneous injections were simulated in 5000 subjects. The horizontal red dashed line indicates the 2-ng/mL minimum concentration required for opioid blockade, as established from modeling and simulation and confirmed by clinical data (Nasser et al [18]) SL buprenorphine in Study 2 (where genotypes were measured), the effect of genetic covariates on SL bioavailability was not assessed.…”

Section: Discussionmentioning

confidence: 87%

Population Pharmacokinetics of a Monthly Buprenorphine Depot Injection for the Treatment of Opioid Use Disorder: A Combined Analysis of Phase II and Phase III Trials

et al. 2020

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Background BUP-XR (a.k.a. RBP-6000 or SUBLOCADE™) is an extended-release subcutaneous buprenorphine formulation for the treatment of opioid use disorder. BUP-XR was designed to provide sustained buprenorphine exposure throughout the monthly dosing interval, at concentrations sufficient to control all aspects of the disease (withdrawal, craving, and blockade of opioid subjective effects). Objectives To characterize the population pharmacokinetics of BUP-XR based on phase II and phase III data and to evaluate whether target therapeutic concentrations were reached with the dosing regimens evaluated in the phase III program. Methods The population pharmacokinetic analysis included 570 subjects with opioid use disorder who received up to 12 monthly BUP-XR injections following induction with sublingual buprenorphine. Results In phase III studies, target therapeutic concentrations of buprenorphine were achieved from the first injection and maintained over the entire treatment duration. Buprenorphine plasma concentration-time profiles were well described by a two-compartment model, with first-order absorption for sublingual buprenorphine and a dual absorption submodel for BUP-XR. A covariate analysis evaluated the effects of subjects' demographic characteristics, laboratory data, and genetic status regarding buprenorphine-metabolizing enzymes. Only two covariates, body mass index and body weight, were retained in the final model. Overall, their effects were not of sufficient magnitude to justify a dose adjustment. Finally, pharmacokinetic simulations showed that buprenorphine plasma concentrations decreased slowly after discontinuation of treatment and that a 2-week occasional delay in dosing would not impact efficacy, which translated into labeling claims. Discussion In conclusion, the present analysis led to the development of a robust population pharmacokinetic model and confirms the ability of BUP-XR to deliver and maintain therapeutic plasma concentrations over the entire treatment duration.

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Sustained-Release Buprenorphine (RBP-6000) Blocks the Effects of Opioid Challenge With Hydromorphone in Subjects With Opioid Use Disorder

Cited by 57 publications

References 21 publications

Advances in the delivery of buprenorphine for opioid dependence

Advances in the delivery of buprenorphine for opioid dependence

Optimal dose of buprenorphine in opioid use disorder treatment: a review of pharmacodynamic and efficacy data

Population Pharmacokinetics of a Monthly Buprenorphine Depot Injection for the Treatment of Opioid Use Disorder: A Combined Analysis of Phase II and Phase III Trials

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