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.
Isitt J.J.,Indivior Inc. |
Nadipelli V.R.,Indivior Inc. |
Kouassi A.,Indivior Inc. |
Fava M.,Harvard University |
Heidbreder C.,Indivior Inc.
Schizophrenia Research | Year: 2016
Background: There is increased interest in the impact of new long-acting treatments on health-related quality of life (HRQoL) in patients with schizophrenia. The aim of this study was to evaluate the impact of treatment with subcutaneous injections of RBP-7000, a new sustained-release formulation of risperidone, compared with placebo on health status, subjective well-being, treatment satisfaction, and preference of medicine in subjects with acute schizophrenia. Methods: HRQoL data were derived from an 8-week double-blind, randomized, placebo-controlled, phase 3 study that assessed efficacy, safety, and tolerability of once monthly RBP-7000 (90 mg and 120 mg) compared with placebo in subjects with acute schizophrenia (n = 337). HRQoL was measured with the EuroQol EQ-5D-5L, well-being using the Neuroleptic Treatment-Short Version (SWN-S), satisfaction using the Medication Satisfaction Questionnaire (MSQ), and preference using the Preference of Medicine Questionnaire (POM). Results: The EQ-5D-5L VAS increased significantly in the RBP-7000 120 mg group compared to Placebo (p = 0.0212). In RBP-7000 120 mg, subjects reported significant improvements in SWN-S physical functioning (p = 0.0093), social integration (p = 0.0368), and total score (p = 0.0395). Subjects were significantly more satisfied with RBP-7000 versus placebo (90 mg p = 0.0009, 120 mg p = 0.0006) and preferred RBP-7000 over their previous medication (90 mg p < 0.0001, 120 mg p = 0.0619). Conclusions: Significantly greater improvements in HRQoL and overall well-being were demonstrated in patients randomized to RBP-7000 compared to placebo. The effect was more pronounced in the RBP-7000 120 mg group. Patient satisfaction improved significantly and patient preference for their medicine favored RBP-7000 90 mg and 120 mg versus Placebo. © 2016 Elsevier B.V.
Liu Y.,Indivior Inc. |
Li X.,Keystone Bioanalytical Inc. |
Xu A.,Keystone Bioanalytical Inc. |
Nasser A.F.,Indivior Inc. |
Heidbreder C.,Indivior Inc.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2016
A simple, sensitive and rapid liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for simultaneous quantification of naloxone, buprenorphine and its metabolite norbuprenorphine in human plasma. Human plasma samples were extracted using a single step liquid-liquid extraction, and then separated on an Imtakt Unison UK-C18 column (2.1×50 mm, 3 μm) using alkaline mobile phases with gradient elution. All of the analytes were detected in positive ion mode using multiple reaction monitoring (MRM). The method was validated and the specificity, linearity, lower limit of quantitation, precision, accuracy, recoveries and stability were determined. The linear range was 20-10000 pg/mL for buprenorphine and norbuprenorphine; and 1-500 pg/mL for naloxone. The correlation coefficient (R2) values for all three analytes were ≥0.995. The precision and accuracy for intra-day and inter-day were <11.0%. The recoveries were >63% and matrix effects were tracked by the deuterated internal standards (IS) with the IS-normalized matrix factor ranging from 0.96 to 1.33 for all three analytes. The validated method was successfully applied in a clinical pharmacokinetic study with low dose administration of sublingual buprenorphine and naloxone. © 2015 Elsevier B.V.
PubMed | Aptuit s.r.l and Indivior Inc
Type: Journal Article | Journal: Bioorganic & 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.
PubMed | Keystone Bioanalytical Inc. and Indivior Inc.
Type: | Journal: Journal of pharmaceutical and biomedical analysis | Year: 2016
A simple, sensitive and rapid liquid chromatography/electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for simultaneous quantification of naloxone, buprenorphine and its metabolite norbuprenorphine in human plasma. Human plasma samples were extracted using a single step liquid-liquid extraction, and then separated on an Imtakt Unison UK-C18 column (2.150mm, 3m) using alkaline mobile phases with gradient elution. All of the analytes were detected in positive ion mode using multiple reaction monitoring (MRM). The method was validated and the specificity, linearity, lower limit of quantitation, precision, accuracy, recoveries and stability were determined. The linear range was 20-10000pg/mL for buprenorphine and norbuprenorphine; and 1-500pg/mL for naloxone. The correlation coefficient (R(2)) values for all three analytes were 0.995. The precision and accuracy for intra-day and inter-day were <11.0%. The recoveries were >63% and matrix effects were tracked by the deuterated internal standards (IS) with the IS-normalized matrix factor ranging from 0.96 to 1.33 for all three analytes. The validated method was successfully applied in a clinical pharmacokinetic study with low dose administration of sublingual buprenorphine and naloxone.
PubMed | University of Parma, Indivior Inc. and Aptuit s.r.l.
Type: Journal Article | Journal: Journal of medicinal chemistry | Year: 2016
A novel series of 1,2,4-triazolyl 5-azaspiro[2.4]heptanes with high affinity and selectivity at the dopamine (DA) D3 receptor (D3R) is described. Some of these compounds also have high selectivity over the hERG channel and were characterized with respect to their pharmacokinetic properties both in vitro and in vivo during lead identification and early lead optimization phases. A few derivatives with overall favorable developability characteristics were selected for further late lead optimization studies.
PubMed | Kaiser Permanente, Purdue Pharma and Indivior Inc.
Type: Journal Article | Journal: BMC pharmacology & toxicology | Year: 2016
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.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.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.
PubMed | Aptuit s.r.l and Indivior Inc
Type: Journal Article | Journal: Bioorganic & 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 pKi=8.4, DA D2 pKi=6.0 and hERG fpKi=5.2) showed a balanced profile and further refinements are in progress around this molecule.
PubMed | University of Maryland Baltimore County and Indivior Inc.
Type: | Journal: British journal of clinical pharmacology | Year: 2017
A new, long-acting, subcutaneous (SC) formulation of risperidone (RBP-7000) has been developed for the treatment of schizophrenia to address issues of non-adherence associated with oral risperidone treatment. The objective of this work was to establish an exposure-response relationship between total active moiety plasma (AM) exposure (risperidone+9-OH-risperidone) and Positive and Negative Syndrome Scale (PANSS) or Clinical Global Impressions severity (CGI-S) scores using data from a registration trial.This was a phase 3 randomized, double-blind, placebo-controlled, multicenter study in 354 patients to evaluate the efficacy, safety and tolerability of RBP-7000 (90mg and 120mg). Non-linear mixed effects modeling was used to develop an integrated population pharmacokinetic/pharmacodynamic (PK/PD) model that included a joint PK model for risperidone and 9-hydroxy (OH)-risperidone with placebo and drug-effect models to establish the relation between total AM exposure and PANSS or CGI-S scores.CYP2D6 poor and intermediate metabolizers had lower formation rates of 9-OH risperidone (94% and 76% lower, respectively) compared to the extensive CYP2D6 metabolizers. The maximum placebo-corrected relative decrease in PANSS score from baseline following RBP-7000 treatment was 5.4 %, half of which could be achieved at plasma concentrations of 4.6ng/mL of the total AM. A proportional odds model for the CGI-S score related the total AM plasma concentration to the probability of improving/worsening scores over time.Exposure-response analysis was established between total AM concentrations and PANSS and CGI-S scores, with good precision in parameter estimates. CYP2D6 phenotype on risperidone metabolism was the only identified covariate.
Population Pharmacokinetic Modeling After Repeated Administrations of RBP-6000, a New, Subcutaneously Injectable, Long-Acting, Sustained-Release Formulation of Buprenorphine, for the Treatment of Opioid Use Disorder
PubMed | Indivior Inc and Pharmacometrica
Type: Journal Article | Journal: 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 -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 -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 -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.