Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies.

The endogenous opioid system is thought to play an important role in the regulation of mood. Buprenorphine/samidorphan (BUP/SAM) combination is an investigational opioid system modulator for adjunctive treatment of major depressive disorder (MDD). To confirm results from early studies, we report the efficacy and safety of BUP/SAM as adjunctive treatment in patients with MDD and an inadequate response to antidepressant therapy (ADT) in FORWARD-4 and FORWARD-5: two phase 3, randomized, double-blind, placebo-controlled studies that utilized the same sequential parallel-comparison design. Efficacy was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS). FORWARD-5 achieved the primary endpoint and demonstrated that adjunctive BUP/SAM 2 mg/2 mg was superior to placebo (average difference change from baseline to week 3 through end of treatment [EOT] in MADRS-6 and -10 versus placebo: -1.5, P = 0.018; -1.9, P = 0.026, respectively). FORWARD-4 did not achieve the primary endpoint (change from baseline in MADRS-10 at week 5 versus placebo: -1.8, P = 0.109), although separate analyses showed significant treatment differences at other timepoints using traditional, regulatory-accepted endpoints such as reduction in MADRS-10 at EOT. The pooled analysis of the two studies demonstrated consistently greater reduction in MADRS-10 scores from baseline for BUP/SAM 2 mg/2 mg versus placebo at multiple timepoints including EOT and average change from baseline to week 3 through EOT (-1.8, P = 0.010; -1.8, P = 0.004, respectively). The overall effect size (Hedges' g) in the pooled analyses for MADRS-10 change from baseline to EOT was 0.22. Overall, BUP/SAM was generally well tolerated, with most adverse events (AEs) being mild or moderate in severity. The most common AEs, occurring in ≥5% of patients in the BUP/SAM 2 mg/2 mg treatment group, which was more frequently than the placebo group, included nausea, constipation, dizziness, vomiting, somnolence, fatigue, and sedation. There was minimal evidence of abuse, and no evidence of dependence or opioid withdrawal by AEs or objective measures. This report describes adjunctive BUP/SAM 2 mg/2 mg combination, a therapy with a novel opioidergic mechanism of action, as a potential new treatment option for patients with MDD who have an inadequate response to currently available ADT.

Mitigation of Olanzapine-Induced Weight Gain With Samidorphan, an Opioid Antagonist: A Randomized Double-Blind Phase 2 Study in Patients With Schizophrenia.

OBJECTIVE: Preclinical evidence and data from a proof-of-concept study in healthy volunteers suggest that samidorphan, an opioid antagonist, mitigates weight gain associated with olanzapine. This study prospectively compared combination therapy of olanzapine plus either samidorphan or placebo for the treatment of schizophrenia. METHODS: This was an international, multicenter, randomized phase 2 study of olanzapine plus samidorphan in patients with schizophrenia. The study had a 1-week open-label olanzapine lead-in period followed by a 12-week double-blind treatment phase in which patients were randomly assigned in a 1:1:1:1 ratio to receive olanzapine plus placebo (N=75) or olanzapine plus 5 mg (N=80), 10 mg (N=86), or 20 mg (N=68) of samidorphan. The primary aims were to confirm that the antipsychotic efficacy of olanzapine plus samidorphan was comparable to olanzapine plus placebo, to assess the effect of combining olanzapine with samidorphan on olanzapine-induced weight gain, and to assess the overall safety and tolerability of olanzapine plus samidorphan. RESULTS: Antipsychotic efficacy, as assessed by total score on the Positive and Negative Syndrome Scale (PANSS), was equivalent across all treatment groups. Treatment with olanzapine plus samidorphan resulted in a statistically significant lower weight gain (37% lower weight gain compared with olanzapine plus placebo). The least square mean percent change from baseline in body weight was 4.1% (2.9 kg) for the olanzapine plus placebo group and 2.6% (1.9 kg) for the olanzapine plus samidorphan group (2.8% [2.1 kg] for the 5 mg group, 2.1% [1.5 kg] for the 10 mg group, and 2.9% [2.2 kg] for the 20 mg group). Adverse events reported at a frequency ≥5% in any of the olanzapine plus samidorphan groups and occurring at a rate ≥2 times greater than in the olanzapine plus placebo group were somnolence, sedation, dizziness, and constipation. Other safety measures were comparable between the olanzapine plus samidorphan groups and the olanzapine plus placebo group. CONCLUSIONS: The antipsychotic efficacy of olanzapine plus samidorphan was equivalent to that of olanzapine plus placebo, and olanzapine plus samidorphan was associated with clinically meaningful and statistically significant mitigation of weight gain compared with olanzapine plus placebo. Olanzapine plus samidorphan was generally well tolerated, with a safety profile similar to olanzapine plus placebo.

Endogenous opioid system dysregulation in depression: implications for new therapeutic approaches.

The United States is in the midst of an opioid addiction and overdose crisis precipitated and exacerbated by use of prescription opioid medicines. The majority of opioid prescriptions are dispensed to patients with comorbid mood disorders including major depressive disorder (MDD). A growing body of research indicates that the endogenous opioid system is directly involved in the regulation of mood and is dysregulated in MDD. This involvement of the endogenous opioid system may underlie the disproportionate use of opioids among patients with mood disorders. Emerging approaches to address endogenous opioid dysregulation in MDD may yield novel therapeutics that have a low or absent risk of abuse and addiction relative to µ-opioid agonists. Moreover, agents targeting the endogenous opioid system would be expected to yield clinical benefits qualitatively different from conventional monaminergic antidepressants. The development of safe and effective agents to treat MDD-associated endogenous opioid dysregulation may represent a distinct and currently underappreciated means of addressing treatment resistant depression with the potential to attenuate the on-going opioid crisis.

Abuse Potential of Buprenorphine/Samidorphan Combination Compared to Buprenorphine and Placebo: A Phase 1 Randomized Controlled Trial.

Buprenorphine/samidorphan combination (BUP/SAM) is an opioid system modulator being investigated as adjunctive treatment for major depressive disorder. BUP/SAM is a fixed-dose combination of buprenorphine, a partial µ-opioid receptor agonist and κ-opioid receptor antagonist, and samidorphan, a µ-opioid receptor antagonist added to address the abuse and dependence potential of buprenorphine. In this study, we assessed the effect of samidorphan on the abuse potential of buprenorphine in the BUP/SAM combination in nondependent, recreational, adult opioid users (ClinicalTrials.gov ID: NCT02413281). Participants were randomized to 6 treatments in a blinded, Williams crossover design: placebo, BUP/SAM at the intended therapeutic dose (2 mg/2 mg), at 4-fold (8 mg/8 mg) and 8-fold (16 mg/16 mg) the therapeutic dose, and buprenorphine alone (8 mg and 16 mg). The primary end point was maximum effect (Emax ) on the visual analog scale for "at the moment" Drug Liking. Emax of Drug Liking for the BUP/SAM 2 mg/2 mg dose was similar to that for placebo (median within-subject difference [90% confidence interval]: 2.5 [0.0-9.0]). The supratherapeutic doses of BUP/SAM showed differences of small magnitude on Drug Liking Emax compared to placebo. Drug Liking Emax for all BUP/SAM doses were significantly lower than those observed for either buprenorphine dose alone. Fewer participants reported adverse events associated with abuse potential with BUP/SAM than with buprenorphine alone, and the overall safety profile of BUP/SAM was consistent with prior reports in healthy volunteers. These findings indicate that samidorphan substantially reduces the abuse potential of buprenorphine in the BUP/SAM combination.

Abuse Potential of Samidorphan: A Phase I, Oxycodone-, Pentazocine-, Naltrexone-, and Placebo-Controlled Study.

Samidorphan is a µ-opioid receptor antagonist in development for the treatment of schizophrenia, in combination with olanzapine, and major depressive disorder, in combination with buprenorphine, at proposed therapeutic doses of samidorphan 10 mg and 2 mg, respectively. A double-blind, double-dummy, active- and placebo-controlled, crossover study evaluated the abuse potential of samidorphan in healthy, nondependent, recreational opioid users. Following a qualification phase, participants were randomized to 1 of 6 treatment sequences of study drugs: placebo, samidorphan (10 or 30 mg), oxycodone (40 mg), pentazocine (30 mg), and naltrexone (100 mg) in a 6 × 6 Williams design. The primary end point was maximum effect (Emax ) for "at-the-moment" Drug Liking visual analog scale scores. Secondary end points included Emax visual analog scale scores for Take Drug Again and Overall Drug Liking and safety assessments. Among 47 participants, at-the-moment Emax Drug Liking scores for positive study controls oxycodone and pentazocine were significantly higher than placebo (P < .001) and samidorphan (both doses; P < .001). Both samidorphan doses had Emax Drug Liking scores similar to placebo and naltrexone (median within-subject differences of 0.0). Emax Take Drug Again scores for samidorphan (both doses) were higher than placebo, but similar to naltrexone, an unscheduled µ-opioid receptor antagonist. Adverse events to evaluate abuse potential occurred less frequently with samidorphan, naltrexone, and placebo than with oxycodone and pentazocine. Findings from this study support a lack of abuse potential with samidorphan at doses up to 30 mg and a safety profile consistent with previous samidorphan clinical studies.

Effects of the Opioid System Modulator, Samidorphan, on Measures of Alcohol Consumption and Patient-Reported Outcomes in Adults with Alcohol Dependence.

BACKGROUND: Demonstrating clinically meaningful benefits of alcohol use disorder treatments is challenging. METHODS: We report findings from a 12-week, phase 2, randomized, double-blind, placebo-controlled study of samidorphan (1, 2.5, or 10 mg/d) in adults with alcohol use disorder (NCT00981617). The primary end point was percentage of subjects with no heavy drinking days (PSNHDD) during weeks 5 to 12; secondary end points included alcohol consumption measures, craving, and patient-rated outcomes. RESULTS: Altogether, 406 patients were included in the full analysis set (101, 104, 100, and 101 in the placebo, samidorphan 1, 2.5, and 10 mg treatment groups, respectively). There was no statistical difference between samidorphan and placebo groups on PSNHDD during weeks 5 to 12. However, dose-dependent reductions in cumulative rate of heavy drinking days were observed (-41%, p < 0.001 for samidorphan 10 mg/d vs. placebo; -30 and -32% for samidorphan 2.5 and 1 mg, p < 0.05 for both). A higher percentage of samidorphan- than placebo-treated patients had a ≥2-category downshift in World Health Organization (WHO) risk levels of drinking. There were significant reductions from baseline with samidorphan versus placebo in alcohol craving (for samidorphan 10 mg: -38.2 [standard error: 2.9] vs. placebo: -30.2 [2.8]; p = 0.044). On a Patient Global Assessment of Response to Therapy (PGART), samidorphan 10 mg was superior to placebo at 4, 8, and 12 weeks (p < 0.001, p < 0.001, p < 0.01, respectively). Improvement in PGART correlated with a reduction in craving and a decrease in WHO risk level. CONCLUSIONS: Results for the primary outcome measure PSNHDD were negative, but at variance with other measures and patient treatment perceptions that may be relevant for interventional studies. These findings highlight the importance of understanding the most relevant outcomes to patients and incorporating and prioritizing patient-centered outcomes when assessing interventions for alcohol use disorder.

Efficacy and safety of aripiprazole lauroxil in schizophrenic patients presenting with severe psychotic symptoms during an acute exacerbation.

Aripiprazole lauroxil (AL), a new long-acting injectable antipsychotic, demonstrated safety and efficacy in treating acute exacerbation symptoms of schizophrenia in a 12-week placebo-controlled trial of two doses of AL (441mg and 882mg) administered every 4weeks. We performed a post hoc analysis of this trial to evaluate the efficacy of AL in the subgroup of patients with severe psychotic symptoms, defined as those with baseline Positive and Negative Syndrome Scale (PANSS) Total score above the median score of 92 (n=309). Change from baseline to Day 85 in PANSS Total score; Positive, Negative, and General Psychopathology subscale scores; and overall response rate were assessed. Statistically significant and clinically meaningful improvements in PANSS Total score were demonstrated with AL 441mg and AL 882mg, with placebo-adjusted differences of -14.7 (p<0.0001) and -16.6 (p<0.0001), respectively. Significant and clinically meaningful findings with both doses of AL were also demonstrated for the PANSS subscales and responder rates. Overall responder rates at Day 85 were significantly greater for AL 441mg (49%; p<0.001) and 882 mg (61%; p<0.001) groups vs. placebo (18%). Common adverse events (>5%) were schizophrenia, akathisia, headache, insomnia, and anxiety. AL demonstrated robust efficacy in treatment of the subgroup of patients experiencing severe psychotic symptoms. Both doses (441mg and 882mg) were effective, with numerically greater improvement in symptoms and proportion of responders favoring the higher dose arm. Both doses had a side effect profile consistent with the known safety profile of aripiprazole.

Effect of Aripiprazole Lauroxil on Metabolic and Endocrine Profiles and Related Safety Considerations Among Patients With Acute Schizophrenia.

OBJECTIVE: Aripiprazole lauroxil, a long-acting injectable antipsychotic, demonstrated safety and efficacy in treating symptoms of schizophrenia in a double-blind, placebo-controlled trial. Because the metabolic profile of antipsychotics is an important safety feature, the effects of aripiprazole lauroxil on body weight, endocrine and metabolic profiles, and safety were examined in a secondary analysis. METHODS: Patients with schizophrenia (DSM-IV-TR criteria) were randomly assigned to aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, or placebo intramuscularly once monthly between December 2011 and March 2014. Changes in body weight, body mass index, fasting blood glucose and serum lipids, glycosylated hemoglobin (HbA1c), and prolactin over 12 weeks were assessed. The incidence of treatment-emergent adverse events (AEs) was evaluated. RESULTS: Among 622 randomized patients, no clinically relevant changes from baseline to week 12 were observed for any serum lipid, lipoprotein, plasma glucose, or HbA1c value with placebo or either dose of aripiprazole lauroxil. Both doses of aripiprazole lauroxil were associated with reductions in mean prolactin levels, whereas placebo treatment was not. The mean (standard deviation) change from baseline for body weight was 0.74 (3.9) kg, 0.86 (3.7) kg, and 0.01 (3.6) kg for aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, and placebo groups, respectively. AEs related to metabolic parameters were reported in 2.4%, 1.4%, and 2.4% of patients in the aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, and placebo groups, respectively. CONCLUSIONS: Aripiprazole lauroxil was well tolerated, with a low-risk metabolic profile relative to published data for other antipsychotics. Changes similar to those observed with placebo were observed in the aripiprazole lauroxil groups for metabolic parameters, with modest weight gain in the active treatment groups over the 12-week course. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01469039.

Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial.

OBJECTIVE: Major depressive disorder has been associated with dysregulation of the endogenous opioid system. The authors sought to determine whether opioid modulation achieved through administration of ALKS 5461, a combination of a µ- and κ-opioid partial agonist, buprenorphine, and a µ-opioid antagonist, samidorphan, would exhibit antidepressant activity in patients with major depression. METHOD: A multicenter, randomized, double-blind, placebo-controlled, two-stage sequential parallel comparison design study was conducted in adults with major depression who had an inadequate response to one or two courses of antidepressant treatment. Participants were randomly assigned to receive adjunctive treatment with 2 mg/2 mg of buprenorphine/samidorphan (the 2/2 dosage group), 8 mg/8 mg of buprenorphine/samidorphan (the 8/8 dosage group), or placebo. Antidepressant effect was measured based on change from baseline to the end of 4 weeks of treatment on the 17-item Hamilton Depression Rating Scale (HAM-D), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Clinical Global Impressions severity scale (CGI-S). RESULTS: Compared with the placebo group, there were significantly greater improvements in the 2/2 dosage group across the three depression outcome measures (HAM-D: -2.8, 95% CI=-5.1, -0.6; MADRS: -4.9, 95% CI=-8.2, -1.6; CGI-S: -0.5, 95% CI=-0.9, -0.1). There was also evidence of improvement in the 8/8 dosage group, although it did not achieve statistical significance. Overall, the buprenorphine/samidorphan combinations were well tolerated, and there was no evidence of opioid withdrawal on treatment discontinuation. CONCLUSIONS: The buprenorphine/samidorphan combination is a novel and promising candidate for treatment of major depressive disorder in patients who have an inadequate response to standard antidepressants.

Effect of aripiprazole lauroxil on agitation and hostility in patients with schizophrenia.

This study aimed to evaluate the effects of aripiprazole lauroxil on hostility and aggressive behavior in patients with schizophrenia. Patients aged 18-70 years with a diagnosis of schizophrenia and currently experiencing an acute exacerbation or relapse were randomized to intramuscular (IM) aripiprazole lauroxil 441 mg (n=207), 882 mg (n=208), or placebo (n=207) for 12 weeks. In post-hoc analyses, hostility and aggression were assessed by the Positive and Negative Syndrome Scale (PANSS) Hostility item (P7) and a specific antihostility effect was assessed by adjusting for positive symptoms of schizophrenia, somnolence, and akathisia. The PANSS excited component score [P4 (Excitement), P7 (Hostility), G4 (Tension), G8 (Uncooperativeness), and G14 (Poor impulse control)], and the Personal and Social Performance scale disturbing and aggressive behavior domain were also assessed. Of the 147 patients who received aripiprazole lauroxil 882 mg and with a baseline PANSS Hostility item P7 more than 1, there was a significant (P<0.05) improvement versus placebo on the PANSS Hostility item P7 score by mixed-model repeated-measures at the end of the study, which remained significant when PANSS-positive symptoms and somnolence or akathisia were included as additional covariates. The proportion with PANSS Hostility item P7 more than 1 at endpoint was significantly (P<0.05) lower with aripiprazole lauroxil versus placebo (53.6, 46.1, and 66.3% for 441, 882 mg, and placebo). A significant (P<0.05) improvement was found with aripiprazole lauroxil versus placebo for change from baseline in the PANSS excited component score. The proportion of patients with aggressive behavior on the Personal and Social Performance scale was significantly (P<0.05) lower for aripiprazole lauroxil: 30.0% for 441 mg versus 44.1% for placebo (P=0.006) and 22.2% for 881 mg (P<0.001 versus placebo). Treatment with aripiprazole lauroxil resulted in decreases in agitation and hostility in patients with schizophrenia and this antihostility effect appears to be independent of a general antipsychotic effect.

A randomized, double-blind, placebo-controlled trial of aripiprazole lauroxil in acute exacerbation of schizophrenia.

OBJECTIVE: This study evaluated the efficacy, safety, and tolerability of aripiprazole lauroxil, a novel long-acting injectable atypical antipsychotic, for the treatment of schizophrenia. METHOD: An international multicenter, randomized, double-blind, placebo-controlled trial was conducted between December 2011 and March 2014. Patients (N = 623) aged 18 to 70 years with schizophrenia (DSM-IV-TR criteria), experiencing an acute exacerbation, were randomized in a 1:1:1 ratio to receive gluteal intramuscular injection of aripiprazole lauroxil 441 mg, aripiprazole lauroxil 882 mg, or matching placebo once monthly for 12 weeks. The primary efficacy outcome was change in Positive and Negative Syndrome Scale (PANSS) total score from baseline to day 85. The Clinical Global Impressions-Improvement scale (CGI-I) score at day 85 was the secondary efficacy outcome. Safety and tolerability were assessed. RESULTS: The PANSS total score (mean ± standard error [SE]) improved significantly from baseline to day 85 in the aripiprazole lauroxil 441 mg and 882 mg groups, with placebo-adjusted differences of -10.9 ± 1.8 (P < .001) and -11.9 ± 1.8 (P < .001), respectively. Significant (P ≤ .004) improvements in both active treatment groups were demonstrated as early as day 8 and continued throughout the treatment period. The proportion of patients who were very much or much improved on the CGI-I was significantly greater with aripiprazole lauroxil 441 mg and 882 mg treatment versus placebo (P < .001). The most common treatment-emergent adverse events were insomnia, akathisia, headache, and anxiety. The incidence of injection site reactions was low, predominantly described as injection site pain, and was associated with the first injection. CONCLUSIONS: Aripiprazole lauroxil demonstrated robust efficacy for treatment of patients experiencing acute exacerbation of schizophrenia. The improvement in psychotic symptoms was statistically significant and clinically meaningful. Symptom improvement occurred rapidly after initiation of aripiprazole lauroxil treatment and was maintained throughout the study. Both aripiprazole lauroxil 441 mg and 882 mg doses were well tolerated. These results support aripiprazole lauroxil as an important new treatment option for schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01469039; Clinicaltrialsregister.eu identifier: 2012-003445-15.

Use of Remifentanil in a Novel Clinical Paradigm to Characterize Onset and Duration of Opioid Blockade by Samidorphan, a Potent µ-Receptor Antagonist.

A novel clinical study design was used to evaluate the blockade of a selective short-acting µ-opioid agonist (remifentanil) in 24 opioid-experienced subjects. Samidorphan (3-carboxamido-4-hydroxynaltrexone) is a novel opioid modulator with µ-antagonist properties. Objective (pupil diameter) and subjective (visual analog scale) responses to repeated remifentanil and saline infusion challenges were assessed after single oral administration of placebo (day 1) and samidorphan (day 2). Complete blockade persisted with samidorphan for 24 hours for pupil miosis and 48 hours for the drug liking visual analog scale. Samidorphan effects persisted beyond measurable samidorphan exposure (t½ = 7 hours). Samidorphan was associated with complete blockade of remifentanil, and the duration supports daily administration. This study used a novel approach with multiple administrations of remifentanil to successfully demonstrate a durable effect with samidorphan and a rapid and potent blockade of physiological and subjective µ-opioid effects.

Single- and multiple-dose pharmacokinetics of samidorphan, a novel opioid antagonist, in healthy volunteers.

PURPOSE: Samidorphan (3-carboxamido-4-hydroxy naltrexone) is a novel opioid receptor antagonist that is currently in clinical development. The oral dose pharmacokinetics, safety, and tolerability of samidorphan were evaluated in 2 double-blind, placebo-controlled, randomized studies in healthy adults. METHODS: The first study investigated single, ascending doses of 3.7 to 55.7 mg of samidorphan in 16 healthy adults; the second study evaluated multiple ascending doses of 10 or 20 mg of samidorphan administered for 7 days in 30 healthy adults. FINDINGS: Across the two studies, 39 of 46 subjects were male; 32 were white, 11 were black, and 3 were hispanic. Mean age was 34.9 years and mean weight was 84.2 kg. In both studies, samidorphan was rapidly absorbed, with a Tmax of 1 hour, and AUC increased with increasing dose. Samidorphan plasma levels declined in a monoexponential manner, with a half-life of ~7 to 9 hours. After multiple doses, steady state was approached by day 6 and achieved by day 7 after the 10-mg dose, but steady state was not reached for the 20-mg dose. Accumulation was low, with accumulation ratios <1.65. In both studies, samidorphan was generally well tolerated, with somnolence reported as the most common adverse event. IMPLICATIONS: In these single- and multiple-dose studies in healthy volunteers, samidorphan exhibited a pharmacokinetic profile consistent with once-daily dosing. ClinicalTrials.gov identifier: NCT00800319.

Evaluation of opioid modulation in major depressive disorder.

Although opioids have known antidepressant activity, their use in major depressive disorder (MDD) has been greatly limited by risk of abuse and addiction. Our aim was to determine whether opioid modulation achieved through a combination of a µ-opioid partial agonist, buprenorphine (BUP), and a potent µ-opioid antagonist, samidorphan (SAM), would demonstrate antidepressant activity without addictive potential. A placebo-controlled crossover study assessed the opioid pharmacodynamic profile following escalating doses of SAM co-administered with BUP in opioid-experienced adults. A subsequent 1-week, placebo-controlled, parallel-group study was conducted in subjects with MDD and an inadequate response to standard antidepressant therapy. This second study evaluated safety and efficacy of ratios of BUP/SAM that were associated with partial and with maximal blockade of opioid responses in the initial study. Pupillometry, visual analog scale assessments, and self-reported questionnaires demonstrated that increasing amounts of SAM added to a fixed dose of BUP resulted in dose-dependent reductions in objective and subjective opioid effects, including euphoria and drug liking, in opioid-experienced adults. Following 7 days of treatment in subjects with MDD, a 1 : 1 ratio of BUP and SAM, the ratio associated with maximal antagonism of opioid effects, exhibited statistically significant improvement vs placebo in HAM-D17 total score (p=0.032) and nearly significant improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) total score (p=0.054). Overall, BUP/SAM therapy was well tolerated. A combination of BUP and SAM showed antidepressant activity in subjects with MDD. Balanced agonist-antagonist opioid modulation represents a novel and potentially clinically important approach to the treatment of MDD and other psychiatric disorders.

Relative bioavailability and safety of aripiprazole lauroxil, a novel once-monthly, long-acting injectable atypical antipsychotic, following deltoid and gluteal administration in adult subjects with schizophrenia.

Aripiprazole lauroxil is a linker lipid ester of aripiprazole for extended-release intramuscular (IM) injection. This multicenter, randomized, open-label study evaluated the pharmacokinetics (PK), relative bioavailability, and tolerability of a single IM deltoid or gluteal injection of aripiprazole lauroxil in adult subjects with chronic stable schizophrenia or schizoaffective disorder. Forty-six subjects were randomized 1:1 to aripiprazole lauroxil 441 mg IM in the deltoid or gluteal muscle. Samples were collected through 89 days post-dose to measure levels of aripiprazole lauroxil, N-hydroxymethyl aripiprazole, aripiprazole, and dehydro-aripiprazole. Forty-three (93.5%) subjects completed all study assessments; most were CYP2D6 extensive or immediate metabolizers (96%); two (4%) were poor metabolizers. The PK of aripiprazole following aripiprazole lauroxil was characterized by a steady rise in plasma concentrations (Tmax 44-50 days), a broad peak, and prolonged exposure attributable to the dissolution of aripiprazole lauroxil and formation rate-limited elimination of aripiprazole (t1/2=15.4-19.2 days). Deltoid vs. gluteal administration resulted in slightly higher Cmax aripiprazole concentrations [1.31 (1.02, 1.67); GMR 90% CI]; total exposure (AUCinf) was similar between sites of administration [0.84 (0.57, 1.24)]. N-hydroxymethyl-aripiprazole and dehydro-aripiprazole exposures were 10% and 33-36%, respectively, of aripiprazole exposure following aripiprazole lauroxil. The most common adverse events were injection site pain in 20 subjects (43.5%) and headache in 6 subjects (13.0%) of mild intensity occurring at a similar rate with deltoid and gluteal administration. Exposure ranges with deltoid and gluteal administration overlapped, suggesting that these sites may be used interchangeably. Despite a higher incidence of adverse events, deltoid muscle provides a more accessible injection site and could facilitate patient acceptance.

A placebo-controlled pilot study of the novel opioid receptor antagonist ALKS-33 in binge eating disorder.

OBJECTIVE: To assess preliminarily the effectiveness of a novel opioid antagonist, ALKS-33, in binge eating disorder (BED). METHOD: In this randomized, placebo-controlled, flexible dose, proof-of-concept trial, 62 outpatients with BED and obesity received ALKS-33 (N = 26) or placebo (N = 36) for 6 weeks. Outcome measures of binge eating, body weight, and eating pathology were assessed. RESULTS: A large decrease in binge eating episode frequency was observed following both ALKS-33 and placebo treatment. There was no significant difference between treatment groups in binge eating episode frequency or any other measure of binge eating, body weight, or eating pathology. DISCUSSION: In this preliminary proof-of-concept study in BED, ALKS-33 did not separate from placebo. Although a failed trial cannot be excluded, the finding is consistent with earlier observations in bulimia nervosa with other opioid antagonists and suggests ALKS-33, at least when administered daily for 6 weeks, may not be efficacious for BED.

Single- and multiple-dose pharmacokinetics of long-acting injectable naltrexone.

BACKGROUND: Oral naltrexone is effective in the treatment of alcohol dependence; however, a major limitation of its clinical utility is poor patient adherence to the daily dosing schedule. A biodegradable, long-acting naltrexone microsphere formulation was developed to achieve continuous naltrexone exposure for 1 month in the treatment of alcohol dependence. METHODS: The single- and multiple-dose safety and pharmacokinetics of a long-acting naltrexone microsphere preparation were evaluated in healthy subjects. One group of subjects (n = 28) received a single dose of oral naltrexone 50 mg followed by a single gluteal intramuscular (IM) injection of long-acting naltrexone 190 or 380 mg or placebo. A different group of subjects (n = 14) received oral naltrexone 50 mg daily for 5 days, followed by IM long-acting naltrexone 380 mg or placebo every 28 days for a total of 4 doses. A 7-day washout period separated oral and IM administrations. Blood samples were collected to determine plasma concentrations of naltrexone and the primary metabolite, 6beta-naltrexol. RESULTS: After a single IM injection of long-acting naltrexone 380 mg, naltrexone plasma concentrations were measurable in all subjects for at least 31 days postdose. The pharmacokinetics were proportional to the dose and multiple dose observations were consistent with single dose observations. Mean apparent elimination half-lives for naltrexone and 6beta-naltrexol ranged from 5 to 7 days. Exposure to 6beta-naltrexol was reduced with IM injection compared with that oral administration. No serious adverse events occurred. CONCLUSIONS: This study demonstrated that the long-acting naltrexone formulation was well tolerated, displayed predictable pharmacokinetics, and resulted in no meaningful drug accumulation upon multiple dosing. Intramuscular administration avoids first-pass metabolism and changes the exposure ratio of 6beta-naltrexol to naltrexone compared with oral administration. By providing continuous exposure to naltrexone for several weeks following IM injection, this long-acting naltrexone formulation may offer therapeutic benefit to those patients who experience difficulty adhering to the daily administration schedule necessitated by oral naltrexone therapy.

Pharmacokinetics of long-acting naltrexone in subjects with mild to moderate hepatic impairment.

Long-acting naltrexone is an extended-release formulation developed with the goal of continuous naltrexone exposure for 1 month for the treatment of alcohol dependence. The influence of mild and moderate hepatic impairment on naltrexone pharmacokinetics following long-acting naltrexone 190-mg administration was assessed. Subjects with mild (Child-Pugh grade A) and moderate (Child-Pugh grade B) hepatic impairment (n = 6 per group) and matched control subjects (n = 13) were enrolled. Naltrexone and 6beta-naltrexol concentrations were determined over a period of 63 days following a single intramuscular dose. Naltrexone and 6beta-naltrexol concentrations were detected in all subjects through 28 days. Total exposure (AUC(0-infinity)) of naltrexone and 6beta-naltrexol was similar across all groups. The long apparent half-lives of naltrexone and 6beta-naltrexol (5-8 days) were attributed to the slow release of naltrexone (long-acting naltrexone exhibits absorption rate-limited elimination or "flip-flop" kinetics); elimination was not altered in subjects with hepatic impairment. Based on pharmacokinetic considerations, the dose of long-acting naltrexone does not need to be adjusted in patients with mild or moderate hepatic impairment.

Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial.

CONTEXT: Alcohol dependence is a common disorder associated with significant morbidity and mortality. Naltrexone, an opioid antagonist, has been shown to be effective for treatment of alcohol dependence. However, adherence to daily oral pharmacotherapy can be problematic, and clinical acceptance and utility of oral naltrexone have been limited. OBJECTIVE: To determine efficacy and tolerability of a long-acting intramuscular formulation of naltrexone for treatment of alcohol-dependent patients. DESIGN, SETTING, AND PARTICIPANTS: A 6-month, randomized, double-blind, placebo-controlled trial conducted between February 2002 and September 2003 at 24 US public hospitals, private and Veterans Administration clinics, and tertiary care medical centers. Of the 899 individuals screened, 627 who were diagnosed as being actively drinking alcohol-dependent adults were randomized to receive treatment and 624 received at least 1 injection. INTERVENTION: An intramuscular injection of 380 mg of long-acting naltrexone (n = 205) or 190 mg of long-acting naltrexone (n = 210) or a matching volume of placebo (n = 209) each administered monthly and combined with 12 sessions of low-intensity psychosocial intervention. MAIN OUTCOME MEASURE: The event rate of heavy drinking days in the intent-to-treat population. RESULTS: Compared with placebo, 380 mg of long-acting naltrexone resulted in a 25% decrease in the event rate of heavy drinking days (P = .02) [corrected] and 190 mg of naltrexone resulted in a 17% decrease (P = .07). Sex and pretreatment abstinence each showed significant interaction with the medication group on treatment outcome, with men and those with lead-in abstinence both exhibiting greater treatment effects. Discontinuation due to adverse events occurred in 14.1% in the 380-mg and 6.7% in the 190-mg group and 6.7% in the placebo group. Overall, rate and time to treatment discontinuation were similar among treatment groups. CONCLUSIONS: Long-acting naltrexone was well tolerated and resulted in reductions in heavy drinking among treatment-seeking alcohol-dependent patients during 6 months of therapy. These data indicate that long-acting naltrexone can be of benefit in the treatment of alcohol dependence.

A pilot evaluation of the safety and tolerability of repeat dose administration of long-acting injectable naltrexone (Vivitrex) in patients with alcohol dependence.

BACKGROUND: : Oral naltrexone is currently used as part of a treatment regimen for alcohol-dependent patients, but its clinical utility is hampered by poor patient adherence. A long-acting injectable naltrexone formulation (Vivitrex) was designed to facilitate patient adherence by providing an extended duration of therapeutic naltrexone over 1 month, thereby eliminating the need for daily dosing. METHODS: : A multicenter, randomized, double-blind, placebo-controlled pilot study was conducted to evaluate the safety and tolerability of intramuscular repeat dose administration of this extended-release naltrexone formulation in DSM-IV alcohol-dependent patients. Thirty patients were randomized to treatment with injectable naltrexone (400 mg; n = 25) or a matching placebo injection (n = 5) and were dosed once every 28 days over 4 months. Psychosocial treatment was offered to patients in both treatment groups. Outcome measures related to drinking activity and trough plasma concentrations of naltrexone and its primary metabolite, 6-beta-naltrexol, were evaluated. RESULTS: : Injectable naltrexone was generally safe and well tolerated. Reported adverse events were mild to moderate and resolved without intervention; only two patients discontinued due to adverse events. The most common adverse events (nausea and headache) occurred at a similar rate for patients in both treatment groups. Pharmacokinetic analysis confirmed that therapeutic levels of naltrexone were delivered throughout the four 1-month treatment cycles. CONCLUSIONS: : The results of this pilot study provide the basis and methods for a larger, more definitive trial to determine the utility of this long-acting injectable naltrexone formulation in the treatment of alcohol-dependent patients.