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Laffont C.M.,Indivior Inc. | Gomeni R.,Pharmacometrica | Heidbreder C.,Indivior Inc. | Jones J.P.,Indivior Inc. | Nasser A.F.,Indivior Inc.
Journal of Clinical Pharmacology | Year: 2016

RBP-6000 is a novel sustained-release formulation of buprenorphine for the treatment of opioid use disorder, which has been designed for once-monthly (28 days) subcutaneous (SC) injections. A population pharmacokinetic (PK) model was developed to describe the time course of buprenorphine plasma concentrations after repeated SC injections of RBP-6000 at 50 mg, 100 mg, 200 mg, or 300 mg in treatment-seeking opioid-dependent subjects previously on sublingual buprenorphine (Subutex®) treatment. The μ-opioid receptor occupancy was predicted using a previously developed PK/PD Emax model. The results of the population PK analysis jointly with the predicted level of μ-opioid receptor occupancy provided quantitative criteria for clinical dose selection for RBP-6000: the dose of 300 mg every 28 days seems appropriate for immediately achieving an effective exposure after the first SC injection and to maintain effective levels of exposure during chronic treatment. Furthermore, simulations conducted to evaluate the potential impact of a holiday in drug intake indicated that in the unexpected event of a 2-week holiday, levels of μ-opioid receptor occupancy remained consistently above 70% with no significant loss of drug efficacy. This analysis indicated that RBP-6000 has the potential for becoming an effective treatment for opioid-dependent subjects by addressing compliance issues associated with the current once-a-day treatments. © 2016, The American College of Clinical Pharmacology


Micheli F.,Aptuit S.r.l. | Bernardelli A.,Aptuit S.r.l. | Bianchi F.,Aptuit S.r.l. | Braggio S.,Aptuit S.r.l. | And 14 more authors.
Bioorganic and Medicinal Chemistry | Year: 2016

A novel series of 1,2,4-triazolyl octahydropyrrolo[2,3-b]pyrroles showing high affinity and selectivity at the DA D3 receptor is reported here. Compounds endowed with high selectivity over the hERG channel were identified and their pharmacokinetic properties thoroughly analyzed. A few derivatives with appropriate developability characteristics were selected for further studies and progression along the screening cascade. In particular, derivative 60a, (DA D3 pK i =8.4, DA D2 pK i =6.0 and hERG fpK i =5.2) showed a balanced profile and further refinements are in progress around this molecule. © 2016 Elsevier Ltd.


Janoff S.L.,Kaiser Permanente | Perrin N.A.,Kaiser Permanente | Coplan P.M.,Purdue Pharma | Chilcoat H.D.,Indivior Inc. | And 2 more authors.
BMC Pharmacology and Toxicology | Year: 2016

Background: Addiction, overdoses and deaths resulting from prescription opioids have increased dramatically over the last decade. In response, several manufacturers have developed formulations of opioids with abuse-deterrent properties. For many of these products, the Food and Drug Administration (FDA) recognized the formulation with labeling claims and mandated post-marketing studies to assess the abuse-deterrent effects. In response, we assess differences in rates of opioid-related overdoses and poisonings prior to and following the introduction of a formulation of OxyContin® with abuse-deterrent properties. Methods/Design: To assess effects of this formulation, electronic medical record (EMR) data from Kaiser Permanente Northwest (KPNW) and Kaiser Permanente Northern California (KPNC) are linked to state death data and compared to chart audits. Overdose and poisoning events will be categorized by intentionality and number of agents involved, including illicit drugs and alcohol. Using 6-month intervals over a 10-year period, trends will be compared in rates of opioid-related overdoses and poisoning events associated with OxyContin® to rates of events associated with other oxycodone and opioid formulations. Qualitative interviews with patients and relatives of deceased patients will be conducted to capture circumstances surrounding events. Discussion: This study assesses and tracks changes in opioid-related overdoses and poisoning events prior to and following the introduction of OxyContin® with abuse-deterrent properties. Public health significance is high because these medications are designed to reduce abuse-related behaviors that lead to important adverse outcomes, including overdoses and deaths. © 2016 Janoff et al.


Micheli F.,Aptuit S.r.l. | Cremonesi S.,Aptuit S.r.l. | Semeraro T.,Aptuit S.r.l. | Tarsi L.,Aptuit S.r.l. | And 9 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2016

A new series of morpholine derivatives has been identified as selective DA D3 receptor antagonists; their in vitro profile and pharmacokinetic data are provided. © 2016 Elsevier Ltd. All rights reserved.


Nasser A.F.,Indivior Inc. | Greenwald M.K.,Wayne State University | Vince B.,Vince and Associates Clinical Research Inc. | Fudala P.J.,Indivior Inc. | And 4 more authors.
Journal of Clinical Psychopharmacology | Year: 2016

A major goal for the treatment of opioid use disorder is to reduce or eliminate the use of illicit opioids. Buprenorphine, a ì-opioid receptor partial agonist and kappa opioid receptor antagonist, is now being developed as a monthly, sustained-release formulation (RBP-6000). The objective of this study was to demonstrate that RBP-6000 blocks the subjective effects and reinforcing efficacy of the μ-opioid receptor agonist hydromorphone (intramuscularly administered) in subjects with moderate or severe opioid use disorder. Subjects were first inducted and dose stabilized on sublingual buprenorphine/naloxone (8-24 mg daily; dose expressed as the buprenorphine component), then received two subcutaneous injections of RBP-6000 (300 mg) on Day 1 and Day 29. Hydromorphone challenges (6 mg, 18 mg or placebo administered in randomized order) occurred on 3 consecutive days of each study week before and after receiving RBP-6000. Subjects reported their responses to each challenge on various 100-mm Visual Analogue Scales (VAS). Subjects also completed a choice task to assess the reinforcing efficacy of each hydromorphone dose relative to money. At baseline, mean "drug liking" VAS scores for hydromorphone 18 mg and 6 mg versus placebo were 61 mm (95% confidence interval, 52.3-68.9) and 45 mm (95% confidence interval, 37.2-53.6), respectively. After 300 mg RBP-6000 was administered, mean VAS score differences from placebo were less than 10 mm through week 12. The reinforcing efficacy of hydromorphone decreased in a parallel manner. This study demonstrated that RBP-6000 at a 300 mg dose provides durable and potent blockade of the subjective effects and reinforcing efficacy of hydromorphone in subjects with moderate or severe opioid use disorder. © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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