Dataset Information

Evaluation of the Effects of a Monthly Buprenorphine Depot Subcutaneous Injection on QT Interval During Treatment for Opioid Use Disorder.

ABSTRACT: Extensive 12-lead electrocardiogram monitoring and drug concentrations were obtained during development of BUP-XR, a monthly subcutaneous injection for the treatment of opioid use disorder (OUD). Matched QT and plasma drug concentrations (11,925) from 1,114 subjects were pooled from 5 studies in OUD. A concentration-QT model was developed, which accounted for confounding factors (e.g., comedications) affecting heart rate and heart rate-corrected QT interval (QTc). Bias-corrected nonparametric two-sided 90% confidence intervals (CIs) were derived for the mean predicted effect of BUP-XR on QTc (?QTc) at therapeutic and supratherapeutic doses. Changes in QTc were associated with age, central vs. noncentral reading, sex, methadone, and barbiturates. The upper 90% CI of ?QTc was 0.29, 0.67, and 1.34 ms at the steady-state peak concentration (Cmax ) for 100, 300, and 2 × 300 mg doses, respectively. An effect of BUP-XR on QT can be ruled out at therapeutic and supratherapeutic doses of BUP-XR, after accounting for covariates that may influence heart rate and QT interval in OUD.

SUBMITTER: Schmith VD

PROVIDER: S-EPMC6766787 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Evaluation of the Effects of a Monthly Buprenorphine Depot Subcutaneous Injection on QT Interval During Treatment for Opioid Use Disorder.

Schmith Virginia D VD Curd Laura L Lohmer Lauren R L LRL Laffont Celine M CM Andorn Anne A Young Malcolm A MA

Clinical pharmacology and therapeutics 20190408 3

Extensive 12-lead electrocardiogram monitoring and drug concentrations were obtained during development of BUP-XR, a monthly subcutaneous injection for the treatment of opioid use disorder (OUD). Matched QT and plasma drug concentrations (11,925) from 1,114 subjects were pooled from 5 studies in OUD. A concentration-QT model was developed, which accounted for confounding factors (e.g., comedications) affecting heart rate and heart rate-corrected QT interval (QTc). Bias-corrected nonparametric tw ...[more]

PMID: 30801681

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Project description:Importance:Buprenorphine treatment for opioid use disorder may be improved by sustained-release formulations. Objective:To determine whether treatment involving novel weekly and monthly subcutaneous (SC) buprenorphine depot formulations is noninferior to a daily sublingual (SL) combination of buprenorphine hydrochloride and naloxone hydrochloride in the treatment of opioid use disorder. Design, Setting, and Participants:This outpatient, double-blind, double-dummy randomized clinical trial was conducted at 35 sites in the United States from December 29, 2015, through October 19, 2016. Participants were treatment-seeking adults with moderate-to-severe opioid use disorder. Interventions:Randomization to daily SL placebo and weekly (first 12 weeks; phase 1) and monthly (last 12 weeks; phase 2) SC buprenorphine (SC-BPN group) or to daily SL buprenorphine with naloxone (24 weeks) with matched weekly and monthly SC placebo injections (SL-BPN/NX group). Main Outcomes and Measures:Primary end points tested for noninferiority were response rate (10% margin) and the mean proportion of opioid-negative urine samples for 24 weeks (11% margin). Responder status was defined as having no evidence of illicit opioid use for at least 8 of 10 prespecified points during weeks 9 to 24, with 2 of these at week 12 and during month 6 (weeks 21-24). The mean proportion of samples with no evidence of illicit opioid use (weeks 4-24) evaluated by a cumulative distribution function (CDF) was an a priori secondary outcome with planned superiority testing if the response rate demonstrated noninferiority. Results:A total of 428 participants (263 men [61.4%] and 165 women [38.6%]; mean [SD] age, 38.4 [11.0] years) were randomized to the SL-BPN/NX group (n = 215) or the SC-BPN group (n = 213). The response rates were 31 of 215 (14.4%) for the SL-BPN/NX group and 37 of 213 (17.4%) for the SC-BPN group, a 3.0% difference (95% CI, -4.0% to 9.9%; P < .001). The proportion of opioid-negative urine samples was 1099 of 3870 (28.4%) for the SL-BPN/NX group and 1347 of 3834 (35.1%) for the SC-BPN group, a 6.7% difference (95% CI, -0.1% to 13.6%; P < .001). The CDF for the SC-BPN group (26.7%) was statistically superior to the CDF for the SL-BPN/NX group (0; P = .004). Injection site adverse events (none severe) occurred in 48 participants (22.3%) in the SL-BPN/NX group and 40 (18.8%) in the SC-BPN group. Conclusions and Relevance:Compared with SL buprenorphine, depot buprenorphine did not result in an inferior likelihood of being a responder or having urine test results negative for opioids and produced superior results on the CDF of no illicit opioid use. These data suggest that depot buprenorphine is efficacious and may have advantages. Trial Registration:ClinicalTrials.gov Identifier: NCT02651584.

Project description:AIMS:To assess the long-term safety of subcutaneous buprenorphine (CAM2038) weekly and monthly depots. DESIGN:Phase 3, open-label, observational, multi-centre 48-week trial (ClinicalTrials.gov NCT02672111). SETTING:Twenty-six out-patient sites (United States, United Kingdom, Hungary, Denmark, Sweden, Germany, Australia) between 14 December 2015 and 12 April 2017. PARTICIPANTS:Two hundred and twenty-eight adults with opioid use disorder; 227 received CAM2038 (37 initiated onto CAM2038 and 190 converted from sublingual buprenorphine). INTERVENTIONS:CAM2038 weekly (8, 16, 24 or 32 mg) or monthly (64, 96, 128 or 160 mg) with flexible dosing and individualized titration utilizing multiple CAM2038 weekly and monthly doses. MEASUREMENTS:Safety variables, urine toxicology samples and self-reported illicit opioid use were collected at each visit. Participants were administered a patient satisfaction survey at months 6 and 12, completed by 162 of 227 (71.4%) participants. FINDINGS:The study treatment period was completed by 167 of 227 (73.6%) participants. At least one treatment-emergent adverse event (TEAE) was reported by 143 of 227 (63.0%) participants, of whom 60 of 227 (26.4%) reported as being drug-related. Most of the TEAEs, reported by 128 of 227 (56.4%) of participants, were mild or moderate in intensity. Injection-site reactions were reported by 46 of 227 (20.3%) participants, with most [45 of 46 (97.8%)] reported as mild to moderate. Five participants (2.2%) discontinued the study drug due to a TEAE, two cases (0.9%) of which were injection-site-related. No serious adverse events were attributed to the study drug. Among those remaining in the study, the percentage of opioid-negative urine tests combined with self-reports was 63.0% (17 of 27) in new-to-treatment participants and 82.8% (111 of 134) for those converted from sublingual buprenorphine. Participants reported high levels of satisfaction with CAM2038. CONCLUSIONS:Subcutaneous buprenorphine delivered weekly or monthly (CAM2038) was well tolerated, with a systemic safety profile consistent with the known profile of sublingual buprenorphine. CAM2038 weekly and monthly was associated with high retention rates and low levels of illicit opioid use throughout this study.

Project description:BackgroundBUP-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).ObjectivesTo 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.MethodsThe population pharmacokinetic analysis included 570 subjects with opioid use disorder who received up to 12 monthly BUP-XR injections following induction with sublingual buprenorphine.ResultsIn 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.DiscussionIn 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.

Project description:ImportancePatient-reported outcomes in the treatment of opioid dependence may differ between subcutaneously administered depot buprenorphine and daily sublingual buprenorphine.ObjectiveTo compare patient satisfaction between depot buprenorphine and sublingual buprenorphine in adult outpatients with opioid dependence.Design, setting, and participantsThis open-label, randomized clinical trial was conducted among adult patients with opioid dependence at 6 outpatient clinical sites in Australia from October 2018 to September 2019. Data analysis was conducted from October 2019 to May 2020.InterventionsParticipants were randomized to receive treatment with weekly or monthly depot buprenorphine or daily sublingual buprenorphine over 24 weeks.Main outcomes and measuresThe primary end point was the difference in global treatment satisfaction, assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4 (range, 0-100; higher score indicates greater satisfaction) at week 24. Secondary end points included other patient-reported outcomes, including quality of life, treatment burden, and health-related outcomes, as well as measures of opioid use, retention in treatment, and safety.ResultsA total of 119 participants (70 [58.8%] men; mean [SD] age, 44.4 [10.5] years) were enrolled, randomized to, and received either depot buprenorphine (60 participants [50.4%]) or sublingual buprenorphine (59 participants [49.6%]). From the initial sample of 120, a participant (0.8%) in the sublingual buprenorphine group withdrew consent and did not receive study treatment. All participants were receiving sublingual buprenorphine when enrolled. The mean TSQM global satisfaction score was significantly higher for the depot group compared with the sublingual group at week 24 (mean [SE] score, 82.5 [2.3] vs 74.3 [2.3]; difference, 8.2; 95% CI, 1.7 to 14.6; P = .01). Improved outcomes were also observed for several secondary end points after treatment with depot buprenorphine (eg, mean [SE] treatment burden assessed by the Treatment Burden Questionnaire global score, on which lower scores indicate lower burden: 13.2 [2.6] vs 28.6 [2.5]; difference, -15.4; 95% CI, -22.6 to -8.2; P < .001). Thirty-nine participants (65.0%) in the depot buprenorphine group experienced 117 adverse drug reactions, mainly injection site reactions of mild intensity following subcutaneous administration, and 12 participants (20.3%) in the sublingual buprenorphine group experienced 21 adverse drug reactions. No participants withdrew from the trial medication or the trial due to adverse events.Conclusions and relevanceIn this study, participants receiving depot buprenorphine reported improved treatment satisfaction compared with those receiving sublingual buprenorphine. The results highlight the application of patient-reported outcomes as alternative end points to traditional markers of substance use in addiction treatment outcome studies.Trial registrationanzctr.org.au Identifier: ANZCTR12618001759280.

Dataset Information

Evaluation of the Effects of a Monthly Buprenorphine Depot Subcutaneous Injection on QT Interval During Treatment for Opioid Use Disorder.

Publications

Evaluation of the Effects of a Monthly Buprenorphine Depot Subcutaneous Injection on QT Interval During Treatment for Opioid Use Disorder.

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