Pharmacokinetics and pharmacodynamics of a pasireotide subcutaneous depot (CAM4071) and comparison with immediate and long-acting release pasireotide.

PURPOSE: To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of subcutaneous depot CAM4071, a novel, ready-to-use pasireotide formulation. METHODS: This was a phase 1, randomised, open-label study in healthy volunteers. After a single 600 µg dose of pasireotide immediate release (IR), participants were randomised to one of eight groups to receive either a CAM4071 upper thigh (5, 10, 20, 40 or 80 mg) or buttock (20 mg) injection or multiple pasireotide IR 900 µg upper thigh injections twice daily or a single pasireotide long-acting release (LAR) 60 mg intramuscular buttock injection. RESULTS: Ninety-four participants were randomised. For all CAM4071 doses, initial pasireotide release was relatively rapid compared to pasireotide LAR and sustained over the 2-month observation period, with a slow decay in plasma concentrations. CAM4071 maximum plasma concentrations increased slightly greater than dose proportionally; area under the curve extrapolated to infinity increased approximately dose proportionally. Relative bioavailability of pasireotide for different doses of CAM4071 versus pasireotide IR 600 µg ranged from 0.752 (90% confidence interval [CI]: 0.58, 0.98) to 1.68 (1.32, 2.14), and versus pasireotide LAR: 0.517 (0.37, 0.72) to 1.15 (0.84, 1.58). CAM4071 doses >5 mg exhibited rapid initial reductions of insulin-like growth factor 1 (IGF-1) compared to pasireotide LAR. Maximum IGF-1 inhibition was greatest for CAM4071 80 mg. CAM4071 injections ≤40 mg were well tolerated and comparable with currently available pasireotide formulations. CONCLUSION: CAM4071 provided long-acting release of pasireotide over at least one month, with high bioavailability and onset and duration of IGF-1 suppression similar to pasireotide LAR. TRIAL REGISTRATION: EudraCT: 2014-003783-20.

Pharmacokinetic-pharmacodynamic analysis of drug liking blockade by buprenorphine subcutaneous depot (CAM2038) in participants with opioid use disorder.

Buprenorphine is used to treat opioid use disorder (OUD). Weekly and monthly subcutaneous long-acting buprenorphine injections (CAM2038) provide more stable buprenorphine plasma levels and reduce the treatment burden, misuse, and diversion associated with sublingual transmucosal buprenorphine formulations. To characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship, a maximum inhibition (Imax) model was developed relating CAM2038 buprenorphine plasma concentration to drug liking maximum effect (Emax) visual analog scale (VAS; bipolar) score after intramuscular hydromorphone administration. Data included time-matched observations of buprenorphine plasma concentration and drug liking Emax VAS score after hydromorphone 18 mg administration in 47 non-treatment-seeking adults with moderate to severe OUD in a phase 2 study. Analysis used non-|linear mixed-effects modeling (NONMEM®). The final Imax model adequately described the PK/PD relationship between buprenorphine plasma concentration and drug liking Emax VAS score. Simulations showed drug liking was effectively blocked at low buprenorphine plasma concentrations (0.4 ng/mL) where the upper 95% confidence interval of the drug liking Emax VAS score was below the pre-defined 11-point complete blockade threshold. The buprenorphine plasma concentration required to achieve 90% of the maximal effect (IC90) of drug liking was 0.675 ng/mL. Interindividual variability in responses to buprenorphine was observed; some participants experienced fluctuating responses, and a few did not achieve drug liking blockade even with higher buprenorphine plasma concentrations. This affirms the need to individualize treatment and titrate doses for optimal treatment outcomes. PK/PD models were also developed for desire to use VAS and Clinical Opiate Withdrawal Scale (COWS) scores, with results aligned to those for drug liking.

Methodology of the SORENTO clinical trial: a prospective, randomised, active-controlled phase 3 trial assessing the efficacy and safety of high exposure octreotide subcutaneous depot (CAM2029) in patients with GEP-NET.

BACKGROUND: The current standard of care (SoC) for the initial treatment of unresectable or metastatic well-differentiated gastroenteropancreatic neuroendocrine tumours (GEP-NET) requires initiation of first-generation somatostatin receptor ligand (SRL) therapy, octreotide and lanreotide, which provide safe and efficacious tumour/symptom control in most patients. However, disease progression can occur with SoC SRL treatment and the optimal dose response of SRL remains unknown. Octreotide subcutaneous depot (CAM2029) is a novel, long-acting, high-exposure formulation that has shown greater bioavailability and improved administration than octreotide long-acting release (LAR) with a well-tolerated safety profile. Retrospective data have highlighted a potential benefit of high-exposure SRL for improved disease control in patients who did not adequately respond to the current SoC SRL treatment. This trial will investigate the efficacy and tolerability of CAM2029 compared to the current SoC, including octreotide LAR and lanreotide autogel (ATG). METHODS: SORENTO is a prospective, multicentre, randomised, active-controlled, open-label phase 3 trial aiming to demonstrate superiority of treatment with 20 mg octreotide subcutaneous depot (CAM2029) every 2 weeks (Q2W) compared to treatment with the Investigator's choice of SRL therapy at standard doses for tumour control (octreotide LAR 30 mg or lanreotide ATG 120 mg every 4 weeks [Q4W]) as assessed by progression-free survival (PFS) in approximately 300 patients with unresectable/metastatic and well-differentiated GEP-NET. Upon confirmation of disease progression (determined by a Blinded Independent Review Committee [BIRC] and defined as per RECIST 1.1), patients may enter an open-label extension treatment period with once weekly dosing, to investigate the effects of higher frequency dosing. Overall survival follow-up will end a maximum of 2 years after primary analysis. The primary endpoint will be analysed after 194 confirmed PFS events. DISCUSSION: This is the first trial investigating the efficacy of CAM2029 versus SoC SRL therapy using a head-to-head, superiority trial design. It is expected to be the first trial to investigate the efficacy of increased dosing frequency of a high-exposure SRL. A BIRC will limit bias and measurement variability and ensure high-quality efficacy data. Additionally, inclusion of patients with well-differentiated Grade 3 NET may elucidate treatment strategies for this rarely investigated patient population. TRIAL REGISTRATION: ClinicalTrials.gov NCT05050942. Registered on 21st September 2021.

Population Pharmacokinetic Analysis Supports Initiation Treatment and Bridging from Sublingual Buprenorphine to Subcutaneous Administration of a Buprenorphine Depot (CAM2038) in the Treatment of Opioid Use Disorder.

BACKGROUND AND OBJECTIVE: In treating opioid use disorder (OUD), subcutaneous (SC) extended-release buprenorphine (BPN) depots, e.g., CAM2038, have been shown to provide smaller and less frequent fluctuations in BPN plasma concentrations and pharmacodynamic responses, improve outcomes, reduce treatment burden, and lower risks of misuse and diversion compared to daily sublingual (SL) BPN. This analysis characterized the pharmacokinetics (PK) of BPN following intravenous and SL administration, and administration of SC CAM2038 weekly and monthly. METHODS: Pharmacokinetic data from two Phase 1 and two Phase 2 trials in healthy participants and participants with OUD, respectively, were used to develop a population PK model using non-linear mixed effects modelling. The analysis included data from 252 participants and 10,658 BPN observations. RESULTS: The disposition of BPN was best described by a three-compartment model with first-order elimination, and absorption of SL BPN and SC CAM2038 weekly and monthly by dual parallel absorption pathways. Model diagnostics indicated good predictive performance of BPN concentrations. Buprenorphine plasma concentration-time profiles were simulated for treatment initiation, switching from SL BPN to CAM2038 weekly and monthly, and tapering after interrupting treatment with CAM2038. Simulations predicted CAM2038 weekly and monthly doses that provided BPN plasma maximum concentration (Cmax) and trough concentration (Ctrough) values at steady state within those observed following SL BPN administration. CONCLUSIONS: This population PK model supports the use of CAM2038 doses as individualized treatment for OUD across different treatment stages, including initiation, switching from SL BPN according to established dose conversion schedules, and tapering. TRIAL REGISTRATIONS: ISRCTN41550730 (05/19/2014), ISRCTN24987553 (07/29/2014), NCT02611752 (11/23/2015), NCT02710526 (03/16/2016).

Ordinary people, criminals, addicts and recreational users: Swedish court of law descriptions of persons sentenced for online drug purchases.

Background: The aim of this study was to analyze how Swedish courts describe persons sentenced for purchasing illicit drugs online. Methods: Qualitative analysis of naturally occurring data through 201 sentences that included 248 individuals sentenced for having purchased drugs online between January 1 2010 and January 1 2020. Results: The analysis resulted in the construction of four ideal types regarding the described characteristics of the sentenced persons; the ordinary person, the recreational user, the addict and the criminal. The courts operate with a notable dichotomy between traditional drug markets and online drug markets, that can be understood in relation to descriptions of Bourdieusian capital forms, specifically street capital and digital capital. Conclusion: Descriptions relating to street capital were of larger interest to the courts compared to digital capital, although there were examples of when the courts argued that uses of digital capital should be viewed as an aggravating circumstance. The courts largely held a dichotomous view of online and offline drug markets that focus on street-based criminality, which may have implications for how emerging digital drug markets are responded to by drug law enforcement and judicial systems.

Patient-Reported Outcomes of Treatment of Opioid Dependence With Weekly and Monthly Subcutaneous Depot vs Daily Sublingual Buprenorphine: A Randomized Clinical Trial.

Importance: Patient-reported outcomes in the treatment of opioid dependence may differ between subcutaneously administered depot buprenorphine and daily sublingual buprenorphine. Objective: To compare patient satisfaction between depot buprenorphine and sublingual buprenorphine in adult outpatients with opioid dependence. Design, Setting, and Participants: This 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. Interventions: Participants were randomized to receive treatment with weekly or monthly depot buprenorphine or daily sublingual buprenorphine over 24 weeks. Main Outcomes and Measures: The 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. Results: A 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 Relevance: In 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 Registration: anzctr.org.au Identifier: ANZCTR12618001759280.

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

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.

Long-term safety of a weekly and monthly subcutaneous buprenorphine depot (CAM2038) in the treatment of adult out-patients with opioid use disorder.

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.

Octreotide SC depot in patients with acromegaly and functioning neuroendocrine tumors: a phase 2, multicenter study.

PURPOSE: Octreotide SC depot is a novel, ready-to-use formulation administered via a thin needle. In a phase 1 study in healthy volunteers, this formulation provided higher bioavailability of octreotide with faster onset and stronger suppression of IGF-1 in healthy volunteers versus long-acting intramuscular (IM) octreotide. This phase 2 study evaluated the pharmacokinetics, efficacy, and safety of octreotide SC depot in patients with acromegaly and functioning NETs, previously treated with octreotide IM. METHODS: Adult patients with acromegaly or functioning NETs treated for ≥ 2 months with octreotide IM [10/20/30 mg every 4 weeks (q4w)] received the last dose of octreotide IM treatment in study period 0 and were randomized 28 days later to receive octreotide SC depot 10 mg q2w, or 20 mg q4w for 3 months (period 1). The primary objective was to characterize the PK profile of octreotide SC depot after each injection vs PK for octreotide IM (period 0). RESULTS: Twelve patients were randomized to receive octreotide SC depot 10 mg q2w (acromegaly n = 3; NET n = 1) or 20 mg q4w (acromegaly n = 4; NET n = 4). Plasma levels of octreotide were higher with octreotide SC depot as compared to octreotide IM. Adverse events were reported in 6 and 8 patients during period 0 and period 1, respectively; most common in period 1 were gastrointestinal disorders. CONCLUSION: Octreotide SC depot provided higher exposure (AUC) than octreotide IM, maintained biochemical control in patients with acromegaly and symptom control in patients with functioning NETs, and was well tolerated with a safety profile consistent with octreotide IM. CLINICALTRIALS. GOV IDENTIFIER: NCT02299089.

Weekly and Monthly Subcutaneous Buprenorphine Depot Formulations vs Daily Sublingual Buprenorphine With Naloxone for Treatment of Opioid Use Disorder: A Randomized Clinical Trial.

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.

The lipolytic degradation of highly structured cubic micellar nanoparticles of soy phosphatidylcholine and glycerol dioleate by phospholipase A2 and triacylglycerol lipase.

The effects of different lipolytic enzymes on the structure of lipid liquid crystalline nano-particles (LCNP) have been investigated by cryogenic transmission electron microscopy (cryo-TEM) and synchrotron small angle X-ray diffraction (SAXD). Here we used highly structured cubic micellar (Fd3m) nanoparticles of 50/50 (wt%/wt%) soy phosphatidyl choline (SPC)/glycerol dioleate (GDO) as substrate. Two types of lipolytic enzymes were used, phospholipase A2 (PLA2) that catalyses degradation of the phospholipid component, SPC, and porcine pancreatic triacylglycerol lipase (TGL) that facilitate the hydrolysis of the diglyceride, GDO. Evolution of the structure was found to be very different and linked to specificity of the two types of enzymes. PLA2, which hydrolyses the lamellar forming component, SPC, induces a reversed micellar lipid phase, while TGL which hydrolysis the reverse phase forming compound, GDO, induces a lamellar phase.

Effect of Buprenorphine Weekly Depot (CAM2038) and Hydromorphone Blockade in Individuals With Opioid Use Disorder: A Randomized Clinical Trial.

Importance: Buprenorphine is an efficacious, widely used treatment for opioid use disorder (OUD). Daily oral transmucosal formulations can be associated with misuse, diversion, and nonadherence; these limitations may be obviated by a sustained release formulation. Objective: To evaluate the ability of a novel, weekly, subcutaneous buprenorphine depot formulation, CAM2038, to block euphorigenic opioid effects and suppress opioid withdrawal in non-treatment-seeking individuals with OUD. Design, Setting, and Participants: This multisite, double-blind, randomized within-patient study was conducted at 3 controlled inpatient research facilities. It involved 47 adults with DSM-V moderate-to-severe OUD. The study was conducted from October 12, 2015 (first patient enrolled), to April 21, 2016 (last patient visit). Interventions: A total of five 3-day test sessions evaluated the response to hydromorphone (0, 6, and 18 mg intramuscular in random order; 1 dose/session/day). After the first 3-day session (ie, qualification phase), participants were randomized to either CAM2038 weekly at 24 mg (n = 22) or 32 mg (n = 25); the assigned CAM2038 dose was given twice, 1 week apart (day 0 and 7). Four sets of sessions were conducted after randomization (days 1-3, 4-6, 8-10, and 11-13). Main Outcomes and Measures: The primary end point was maximum rating on the visual analog scale for drug liking. Secondary end points included other visual analog scale (eg, high and desire to use), opioid withdrawal scales, and physiological and pharmacokinetic outcomes. Results: A total of 46 of 47 randomized participants (mean [SD] age, 35.5 [9] years; 76% male [n = 35]) completed the study. Both weekly CAM2038 doses produced immediate and sustained blockade of hydromorphone effects (liking maximum effect, CAM2038, 24 mg: effect size, 0.813; P < .001, and CAM2038, 32 mg: effect size, 0.753; P < .001) and suppression of withdrawal (Clinical Opiate Withdrawal Scale, CAM2038, 24 mg: effect size, 0.617; P < .001, and CAM2038, 32 mg: effect size, 0.751; P < .001). CAM2038 produces a rapid initial rise of buprenorphine in plasma with maximum concentration around 24 hours, with an apparent half-life of 4 to 5 days and approximately 50% accumulation of trough concentration from first to second dose (trough concentration = 0.822 and 1.23 ng/mL for weeks 1 and 2, respectively, with 24 mg; trough concentration = 0.993 and 1.47 ng/mL for weeks 1 and 2, respectively, with 32 mg). Conclusions and Relevance: CAM2038 weekly, 24 and 32 mg, was safely tolerated and produced immediate and sustained opioid blockade and withdrawal suppression. The results support the use of this depot formulation for treatment initiation and stabilization of patients with OUD, with the further benefit of obviating the risk for misuse and diversion of daily buprenorphine while retaining its therapeutic benefits. Trial Registration: Clinicaltrials.gov Identifier: NCT02611752.

Pharmacokinetics and pharmacodynamics of a buprenorphine subcutaneous depot formulation (CAM2038) for once-weekly dosing in patients with opioid use disorder.

INTRODUCTION: Sublingual buprenorphine is effective for opioid dependence treatment but associated with misuse, abuse, and diversion. The present Phase I/II study evaluated a novel buprenorphine subcutaneous depot formulation for once-weekly dosing (CAM2038 q1w) in patients receiving maintenance treatment for opioid use disorder with daily sublingual buprenorphine. METHODS: After discontinuation of buprenorphine for 48h, patients received a single CAM2038 q1w dose based on their pre-study daily sublingual maintenance dose. CAM2038 q1w doses of 7.5, 15, 22.5, and 30mg were administered in a sequential dose-escalating design. The following assessments were performed: pharmacokinetics of buprenorphine and norbuprenorphine, pharmacodynamics (evaluated using the Subjective and Clinical Opiate Withdrawal Scales), and time to intake of rescue sublingual buprenorphine medication. RESULTS: Single doses of CAM2038 q1w indicated dose-proportional buprenorphine pharmacokinetics (Cmax and AUC0-7d), with time to Cmax ~20h and an apparent terminal half-life of 3-5days, supporting once-weekly dosing. On average, patients showed a rapid and extended decrease in opiate-withdrawal symptoms from baseline, with zero or very low SOWS and COWS values measured at least up to 7days after dosing of CAM2038 q1w. The median time to first use of rescue buprenorphine was 10days. No dose dependence was seen in the pharmacodynamics, attributable to the selection of CAM2038 q1w doses based on patients' pre-study maintenance doses. CAM2038 q1w was safe and generally well tolerated. CONCLUSIONS: Pharmacokinetics and pharmacodynamics of a novel buprenorphine subcutaneous depot formulation for once-weekly dosing was evaluated, suggesting utility in maintenance treatment of patients with opioid use disorder.

Pharmacokinetic Evaluation of Once-Weekly and Once-Monthly Buprenorphine Subcutaneous Injection Depots (CAM2038) Versus Intravenous and Sublingual Buprenorphine in Healthy Volunteers Under Naltrexone Blockade: An Open-Label Phase 1 Study.

INTRODUCTION: CAM2038 q1w (once weekly) and q4w (once monthly) are investigational buprenorphine subcutaneous (SC) formulations based on FluidCrystal® injection depot technology. These two drug products are being developed for opioid dependence treatment, with a target for once-weekly and once-monthly SC dosing. The rationale for developing two products with different dosing frequencies is that treatment strategies/routines, and hence different treatment preferences, can vary between patients, different stages of opioid maintenance treatment, and countries. This study evaluated the pharmacokinetics and safety of buprenorphine and norbuprenorphine following administration of CAM2038 q1w or q4w versus active controls. METHODS: Healthy volunteers were randomized to five treatment groups. All received a single intravenous dose of buprenorphine 600 µg, followed post-washout by a single dose of CAM2038 q4w 96 mg, a single dose of CAM2038 q4w 192 mg, or sublingual buprenorphine 8, 16, or 24 mg daily for 7 days, followed post-washout by a single dose of CAM2038 q4w 64 or 128 mg or four repeated weekly doses of CAM2038 q1w 16 mg. All subjects received daily naltrexone. RESULTS: Eighty-seven subjects were randomized. Median buprenorphine t max after CAM2038 q4w was 4-10 h (24 h for CAM2038 q1w); mean terminal half-life was 19-25 days (5 days for CAM2038 q1w). CAM2038 q4w showed dose-proportional buprenorphine release, with similar exposure to repeat-dose CAM2038 q1w at comparable monthly dose level. Both CAM2038 formulations showed complete absolute bioavailability of buprenorphine and 5.7- to 7.7-fold greater buprenorphine bioavailability versus sublingual buprenorphine. CAM2038 q1w and q4w were well tolerated; subjects' acceptance was higher for CAM2038 than for sublingual buprenorphine 1 h post-dose. CONCLUSIONS: The pharmacokinetic profiles of CAM2038 q1w and q4w versus sublingual buprenorphine support expected treatment efficacy with once-weekly and once-monthly dosing, respectively. CAM2038 formulations were safe and showed good local tolerability. TRIAL REGISTRATION: ISRCTN24987553. FUNDING: Camurus AB.

Interfacial properties of POPC/GDO liquid crystalline nanoparticles deposited on anionic and cationic silica surfaces.

Reversed lipid liquid crystalline nanoparticles (LCNPs) of the cubic micellar (I2) phase have high potential in drug delivery applications due to their ability to encapsulate both hydrophobic and hydrophilic drug molecules. Their interactions with various interfaces, and the consequences for the particle structure and integrity, are essential considerations in their effectiveness as drug delivery vehicles. Here, we have studied LCNPs formed of equal fractions of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine and glycerol dioleate in the presence of different fractions of the stabilizer Polysorbate 80. We have used a combination of ellipsometry, quartz crystal microbalance with dissipation monitoring and neutron reflectometry to reveal the structure and composition of the adsorbed layer on both anionic silica and cationic (aminopropyltriethoxysilane) silanized surfaces. For both types of surfaces, there is a spread near-surface layer comprising lipid and polymer as well as a sparse coverage of intact particles. The composition of the near-surface layer is very close to that of the particles, in contrast to the lipid bilayer observed with related systems. The interaction is stronger for cationic than anionic surfaces, which is rationalized in terms of the negative zeta potential of the LCNPs. The work shows that the attachment of and spreading from LCNPs is influenced by the properties of the surface, the internal structure, composition and stability of the particles as well as the nature of the stabilizer.

Octreotide s.c. depot provides sustained octreotide bioavailability and similar IGF-1 suppression to octreotide LAR in healthy volunteers.

AIMS: The aim was to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of octreotide subcutaneous (s.c.) depot, a novel octreotide formulation. METHODS: This was a phase I, randomized, open label study. After a single dose of octreotide immediate release (IR) 200 µg, subjects were randomized to one of eight groups to receive three monthly injections of octreotide s.c. depot A 10, 20 or 30 mg, B 30 mg, C 10, 20 or 30 mg or long acting octreotide (octreotide LAR) 30 mg. RESULTS: One hundred and twenty-two subjects were randomized. For all depot variants, onset of octreotide release was rapid and sustained for up to 4 weeks. The relative octreotide bioavailability of depot variants vs. octreotide IR ranged from 0.68 (90% confidence interval [CI] 0.61, 0.76) to 0.91 (90% CI 0.81, 1.02) and, vs. octreotide LAR, was approximately four- to five-fold greater: 3.97 (90% CI 3.35, 4.71) to 5.27 ng ml(-1) h (90% CI 4.43, 6.27). All depot variants showed relatively rapid initial reductions of insulin-like growth factor 1 (IGF-1) compared with octreotide LAR. A trend of octreotide dose dependence was also indicated from the plasma concentrations and suppression of IGF-1. Maximum inhibition of IGF-1 at steady-state was highest for depot B and C. All depot treatments were well tolerated. The most frequent adverse events were gastrointestinal related. CONCLUSIONS: Octreotide s.c. depot provides greater octreotide bioavailability with a more rapid onset and stronger suppression of IGF-1 than octreotide LAR in healthy volunteers.

Non-lamellar lipid liquid crystalline structures at interfaces.

The self-assembly of lipids leads to the formation of a rich variety of nano-structures, not only restricted to lipid bilayers, but also encompassing non-lamellar liquid crystalline structures, such as cubic, hexagonal, and sponge phases. These non-lamellar phases have been increasingly recognized as important for living systems, both in terms of providing compartmentalization and as regulators of biological activity. Consequently, they are of great interest for their potential as delivery systems in pharmaceutical, food and cosmetic applications. The compartmentalizing nature of these phases features mono- or bicontinuous networks of both hydrophilic and hydrophobic domains. To utilize these non-lamellar liquid crystalline structures in biomedical devices for analyses and drug delivery, it is crucial to understand how they interact with and respond to different types of interfaces. Such non-lamellar interfacial layers can be used to entrap functional biomolecules that respond to lipid curvature as well as the confinement. It is also important to understand the structural changes of deposited lipid in relation to the corresponding bulk dispersions. They can be controlled by changing the lipid composition or by introducing components that can alter the curvature or by deposition on nano-structured surface, e.g. vertical nano-wire arrays. Progress in the area of liquid crystalline lipid based nanoparticles opens up new possibilities for the preparation of well-defined surface films with well-defined nano-structures. This review will focus on recent progress in the formation of non-lamellar dispersions and their interfacial properties at the solid/liquid and biologically relevant interfaces.

Structural effects of the dispersing agent polysorbate 80 on liquid crystalline nanoparticles of soy phosphatidylcholine and glycerol dioleate.

Well-defined, stable and highly structured I2 (Fd3̅m) liquid crystalline nanoparticles (LCNP) of 50/50 (wt/wt) soy phosphatidylcholine (SPC)/glycerol dioleate (GDO), can be formed by using a low fraction (5-10 wt%) of the dispersing polymeric surfactant polyoxyethylene (20) sorbitan monooleate (polysorbate 80 or P80). In the present study we used small angle neutron scattering (SANS) and deuterated P80 (d-P80) to determine the location and concentration of P80 within the LCNP and small angle X-ray scattering (SAXS) to reveal the internal structure. SANS data suggests that some d-P80 already penetrates the particle core at 5%. However, the content of d-P80 is still low enough not to significantly change the internal Fd3̅m structure of the LCNP. At higher fractions of P80 a phase separation occurs, in which a SPC and P80 rich phase is formed at the particle surface. The surface layer becomes gradually richer in both solvent and d-P80 when the surfactant concentration is increased from 5 to 15%, while the core of the particle is enriched by GDO, resulting in loss of internal structure and reduced hydration. We have used neutron reflectometry to reveal the location of the stabiliser within the adsorbed layer on an anionic silica and cationic (aminopropyltriethoxysilane (APTES) silanized) surface. d-P80 is enriched closest to the supporting surface and slightly more so for the cationic APTES surface. The results are relevant not only for the capability of LCNPs as drug delivery vehicles but also as means of preparing functional surface coatings.

Formation of highly structured cubic micellar lipid nanoparticles of soy phosphatidylcholine and glycerol dioleate and their degradation by triacylglycerol lipase.

Lipid nanoparticles of reversed internal phase structures, such as cubic micellar (I2) structure show good drug loading ability of peptides and proteins as well as some small molecules. Due to their controllable small size and inner morphology, such nanoparticles are suitable for drug delivery using several different administration routes, including intravenous, intramuscular, and subcutaneous injection. A very interesting system in this regard, is the two component soy phosphatidylcholine (SPC)/glycerol dioleate (GDO) system, which depending on the ratio of the lipid components form a range of reversed liquid crystalline phases. For a 50/50 (w/w) ratio in excess water, these lipids have been shown to form a reversed cubic micellar (I2) phase of the Fd3m structure. Here, we demonstrate that this SPC/GDO phase, in the presence of small quantities (5-10 wt %) of Polysorbate 80 (P80), can be dispersed into nanoparticles, still with well-defined Fd3m structure. The resulting nanoparticle dispersion has a narrow size distribution and exhibit good long-term stability. In pharmaceutical applications, biodegradation pathways of the drug delivery vehicles and their components are important considerations. In the second part of the study we show how the structure of the particles evolves during exposure to a triacylglycerol lipase (TGL) under physiological-like temperature and pH. TGL catalyzes the lipolytic degradation of acylglycerides, such as GDO, to monoglycerides, glycerol, and free fatty acids. During the degradation, the interior phase of the particles is shown to undergo continuous phase transitions from the reversed I2 structure to structures of less negative curvature (2D hexagonal, bicontinuous cubic, and sponge), ultimately resulting in the formation of multilamellar vesicles.