Open-label investigation of rapid initiation of extended-release buprenorphine in patients using fentanyl and fentanyl analogs.

BACKGROUND AND OBJECTIVES: Synthetic opioids, including fentanyl and fentanyl analogs, account for over 70,000 annual overdose deaths in the United States, but there is limited information examining methods of induction and maintenance outcomes for buprenorphine treatment of patients with opioid use disorder (OUD) using these opioids. METHODS: A secondary analysis of results grouped by fentanyl use status was completed for an open-label study with rapid induction of extended-release buprenorphine in the inpatient research unit. Eligible participants received a single 4 mg dose of transmucosal buprenorphine (BUP-TM) followed by an extended-release buprenorphine 300 mg injection ([BUP-XR]) after approximately 1 h. An extension study continued follow-up up to 6 months (6 monthly injections). RESULTS: Among participants with fentanyl-positive urine samples (FEN+; n = 19), all received BUP-TM, 17 received BUP-XR, 13 elected to receive a second BUP-XR injection, and 10 received all six scheduled injections. Among participants with fentanyl-negative samples (FEN-; n = 7), all received BUP-TM and BUP-XR, four elected to receive a second injection, and two participants received all six scheduled injections. Induction day clinical opioid withdrawal scale (COWS) scores were similar for FEN+ and FEN- groups. In the FEN+ group, mean COWS scores fell to below 5 within 24 h of BUP-XR injection. DISCUSSION AND CONCLUSIONS: The treatment of individuals with OUD using fentanyl with a rapid 1-day induction to BUP-XR 300 mg injection is feasible and well-tolerated. SCIENTIFIC SIGNIFICANCE: A prospective trial of participants grouped by fentanyl use status at induction demonstrates comparable patient retention and clinical response following single-day induction of BUP-XR in participants who are FEN+ and FEN-.

Anti-IL-7 receptor α monoclonal antibody (GSK2618960) in healthy subjects - a randomized, double-blind, placebo-controlled study.

AIM: Interleukin (IL)-7 signalling modulates T cell activity and is implicated in numerous autoimmune diseases. The present study investigated the safety, pharmacokinetics, target engagement, pharmacodynamics and immunogenicity of GSK2618960, an IL-7 receptor-α subunit (CD127) monoclonal antibody. METHODS: A double-blind (sponsor-unblind) study of a single intravenous infusion of either GSK2618960 (0.6 mg kg-1 or 2.0 mg kg-1 ) or placebo was carried out in 18 healthy subjects over 24 weeks. RESULTS: GSK2618960 was well tolerated; there were no serious or significant adverse events. The observed half-life was 5 (±1) days (2.0 mg kg-1 ), with nonlinear pharmacokinetics. Full receptor occupancy (>95%) was observed until day 8 (0.6 mg kg-1 ) and day 22 (2.0 mg kg-1 ). Maximal inhibition of IL-7-mediated signal transducer and activator of transcription 5 (STAT5) phosphorylation was observed in 5/6 subjects until day 22 (2.0 mg kg-1 ). Mean circulating IL-7 and soluble receptor (CD127) levels were increased above baseline during days 2 and 15 (0.6 mg kg-1 ) and days 2 and 22 (2.0 mg kg-1 ). No meaningful changes were observed in absolute numbers or proportions of immune cell populations or inflammatory cytokine profiles (IL-6, tumour necrosis factor-α, interferon-γ, IL-2). Persistent antidrug antibodies (ADAs) were detected in 5/6 subjects administered a dose of 0.6 mg kg-1 (neutralizing in 2/6) and in 6/6 subjects administered 2.0 mg kg-1 (neutralizing in 5/6). CONCLUSION: GSK2618960 was well tolerated and blocked IL-7 receptor signalling upon full target engagement. Although there was no discernible impact on peripheral T cell subsets in healthy subjects, GSK2618960 may effectively modulate the autoinflammatory activity of pathogenic T cells in diseased tissue. A relatively short half-life is likely the result of target-mediated rather than ADA-mediated clearance.

Evaluation of the safety, pharmacokinetics, pharmacodynamics, and drug-drug interaction potential of a selective Lp-PLA2 inhibitor (GSK2647544) in healthy volunteers
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OBJECTIVE: To evaluate in healthy volunteers the safety, pharmacokinetics (PK), pharmacodynamics (PD), and drug-drug interaction (DDI) potential of GSK2647544, (a selective lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor). METHODS: Study 1 was a single-blind, randomized, placebo-controlled, crossover study with healthy male volunteers randomized to receive single escalating oral doses (0.5 - 750 mg) of GSK2647544. Study 2 was a single-blind, randomized, placebo-controlled study with healthy volunteers randomized to receive repeat doses (80 mg) of GSK2647544. The drug-drug interaction of GSK2647544 with simvastatin was also evaluated in study 2. RESULTS: Across both studies GSK2647544 doses were generally well tolerated with no GSK2647544-related clinically significant findings. GSK2647544 was readily absorbed and its plasma concentration declined bi-exponentially with a terminal half-life ranging from 8 to 16 hours. Plasma exposure of GSK2647544 increased approximately dose-proportionally. There was GSK2647544 dose-dependent inhibition of plasma Lp-PLA2 activity, with a trough inhibition (12 hours after dose) of 85.6% after 7-day twice daily dosing. The administration of simvastatin concomitantly with GSK2647544 increased the overall exposure (area under the plasma concentration-time curve and maximum plasma concentration) of simvastatin and simvastatin acid by 3.6- to 4.3-fold and 1.5- to 3.1-fold, respectively. CONCLUSIONS: GSK2647544 was generally well tolerated and had a reasonable PK-PD profile. The clinically significant drug-drug interaction led to an early termination of study 2.
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GSK356278, a potent, selective, brain-penetrant phosphodiesterase 4 inhibitor that demonstrates anxiolytic and cognition-enhancing effects without inducing side effects in preclinical species.

Small molecule phosphodiesterase (PDE) 4 inhibitors have long been known to show therapeutic benefit in various preclinical models of psychiatric and neurologic diseases because of their ability to elevate cAMP in various cell types of the central nervous system. Despite the registration of the first PDE4 inhibitor, roflumilast, for the treatment of chronic obstructive pulmonary disease, the therapeutic potential of PDE4 inhibitors in neurologic diseases has never been fulfilled in the clinic due to severe dose-limiting side effects such as nausea and vomiting. In this study, we describe the detailed pharmacological characterization of GSK356278 [5-(5-((2,4-dimethylthiazol-5-yl)methyl)-1,3,4-oxadiazol-2-yl)-1-ethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine], a potent, selective, and brain-penetrant PDE4 inhibitor that shows a superior therapeutic index to both rolipram and roflumilast in various preclinical species and has potential for further development in the clinic for the treatment of psychiatric and neurologic diseases. GSK356278 inhibited PDE4B enzyme activity with a pIC50 of 8.8 and bound to the high-affinity rolipram binding site with a pIC50 of 8.6. In preclinical models, the therapeutic index as defined in a rodent lung inflammation model versus rat pica feeding was >150 compared with 0.5 and 6.4 for rolipram and roflumilast, respectively. In a model of anxiety in common marmosets, the therapeutic index for GSK356278 was >10 versus <1 for rolipram. We also demonstrate that GSK356278 enhances performance in a model of executive function in cynomolgus macaques with no adverse effects, a therapeutic profile that supports further evaluation of GSK356278 in a clinical setting.

Monoamine transporter occupancy of a novel triple reuptake inhibitor in baboons and humans using positron emission tomography.

The selection of a therapeutically meaningful dose of a novel pharmaceutical is a crucial step in drug development. Positron emission tomography (PET) allows the in vivo estimation of the relationship between the plasma concentration of a drug and its target occupancy, optimizing dose selection and reducing the time and cost of early development. Triple reuptake inhibitors (TRIs), also referred to as serotonin-norepinephrine-dopamine reuptake inhibitors, enhance monoaminergic neurotransmission by blocking the action of the monoamine transporters, raising extracellular concentrations of those neurotransmitters. GSK1360707 [(1R,6S)-1-(3,4-dichlorophenyl)-6-(methoxymethyl)-4-azabicyclo[4.1.0]heptane] is a novel TRI that until recently was under development for the treatment of major depressive disorder; its development was put on hold for strategic reasons. We present the results of an in vivo assessment of the relationship between plasma exposure and transporter blockade (occupancy). Studies were performed in baboons (Papio anubis) to determine the relationship between plasma concentration and occupancy of brain serotonin reuptake transporter (SERT), dopamine reuptake transporter (DAT), and norepinephrine uptake transporter (NET) using the radioligands [(11)C]DASB [(N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine], [(11)C]PE2I [N-(3-iodoprop-2E-enyl)-2ß-carbomethoxy-3ß-(4-methylphenyl)nortropane], and [(11)C]2-[(2-methoxyphenoxy)phenylmethyl]morpholine (also known as [(11)C]MRB) and in humans using [(11)C]DASB and [(11)C]PE2I. In P. anubis, plasma concentrations resulting in half-maximal occupancy at SERT, DAT, and NET were 15.16, 15.56, and 0.97 ng/ml, respectively. In humans, the corresponding values for SERT and DAT were 6.80 and 18.00 ng/ml. GSK1360707 dose-dependently blocked the signal of SERT-, DAT-, and NET-selective PET ligands, confirming its penetration across the blood-brain barrier and blockade of all three monoamine transporters in vivo.

Pharmacokinetics and central nervous system effects of the novel dual NK1 /NK3 receptor antagonist GSK1144814 in alcohol-intoxicated volunteers.

AIMS: Antagonism of both NK1 and NK3 receptors may be an effective strategy in the pharmacotherapy of schizophrenia, drug addiction or depression. GSK1144814 is a novel selective dual NK1 /NK3 receptor antagonist. The potential influence of GSK1144814 on the effects of alcohol was investigated. METHODS: In a blinded, randomized, placebo-controlled, two period crossover study, the pharmacokinetics and central nervous system (CNS) effects of single oral doses of 200 mg GSK1144814 were evaluated in 20 healthy volunteers, using a controlled alcohol infusion paradigm to maintain stable alcohol concentrations with subsequent analysis of eye movements, adaptive tracking, body sway, visual analogue scales, Epworth sleepiness scale and the verbal visual learning test. RESULTS: Frequent adverse effects were mild somnolence, fatigue and headache. Plasma concentration of GSK1144814 in the presence of alcohol was maximal 1.5 h after dose administration. GSK1144814 did not affect alcohol pharmacokinetics. Co-administration of GSK1144814 and alcohol impaired saccadic reaction time and peak velocity, adaptive tracking, alertness, sleepiness, word recognition and recognition reaction time compared with administration of alcohol alone, but the size of the interaction was small. CONCLUSIONS: Administration of GSK1144814 in the presence of alcohol was generally well tolerated and not likely to produce clinically relevant additional impairments after alcohol consumption.

Effect of sustained high buprenorphine plasma concentrations on fentanyl-induced respiratory depression: A placebo-controlled crossover study in healthy volunteers and opioid-tolerant patients.

BACKGROUND: Opioid-induced respiratory depression driven by ligand binding to mu-opioid receptors is a leading cause of opioid-related fatalities. Buprenorphine, a partial agonist, binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects. The authors examined whether sustained buprenorphine plasma concentrations similar to those achieved with some extended-release injections used to treat opioid use disorder could reduce the frequency and magnitude of fentanyl-induced respiratory depression. METHODS: In this two-period crossover, single-centre study, 14 healthy volunteers (single-blind, randomized) and eight opioid-tolerant patients taking daily opioid doses ≥90 mg oral morphine equivalents (open-label) received continuous intravenous buprenorphine or placebo for 360 minutes, targeting buprenorphine plasma concentrations of 0.2 or 0.5 ng/mL in healthy volunteers and 1.0, 2.0 or 5.0 ng/mL in opioid-tolerant patients. Upon reaching target concentrations, participants received up to four escalating intravenous doses of fentanyl. The primary endpoint was change in isohypercapnic minute ventilation (VE). Additionally, occurrence of apnea was recorded. RESULTS: Fentanyl-induced changes in VE were smaller at higher buprenorphine plasma concentrations. In healthy volunteers, at target buprenorphine concentration of 0.5 ng/mL, the first and second fentanyl boluses reduced VE by [LSmean (95% CI)] 26% (13-40%) and 47% (37-59%) compared to 51% (38-64%) and 79% (69-89%) during placebo infusion (p = 0.001 and < .001, respectively). Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection. In opioid-tolerant patients, fentanyl reduced VE up to 49% (21-76%) during buprenorphine infusion (all concentration groups combined) versus up to 100% (68-132%) during placebo infusion (p = 0.006). In opioid-tolerant patients, the risk of experiencing apnea requiring verbal stimulation following fentanyl boluses was lower with buprenorphine than with placebo (odds ratio: 0.07; 95% CI: 0.0 to 0.3; p = 0.001). INTERPRETATION: Results from this proof-of-principle study provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids like fentanyl.

Pharmacokinetics of Sublingual Buprenorphine Tablets Following Single and Multiple Doses in Chinese Participants With and Without Opioid Use Disorder.

BACKGROUND: Two phase I studies assessed the pharmacokinetics of buprenorphine, its metabolite norbuprenorphine, and naloxone following administration of buprenorphine/naloxone sublingual tablets in Chinese participants. METHODS: In the first phase I, open-label, single ascending-dose (SAD) study, 82 opioid-naïve volunteers received a single buprenorphine/naloxone dose ranging from 2 mg/0.5 mg to 24 mg/6 mg while under naltrexone block. In a second phase I, open-label, multiple ascending-dose (MAD) study, 27 patients with opioid dependence in withdrawal received buprenorphine/naloxone doses of either 16 mg/4 mg or 24 mg/6 mg for 9 consecutive days. Serial blood samples were collected after a single dose (SAD study) and at steady-state (MAD study). Pharmacokinetic parameters were calculated using non-compartmental analysis. Safety assessments included adverse events monitoring and laboratory tests. RESULTS: The pharmacokinetic profiles of buprenorphine and naloxone were consistent between single- and multiple-dose studies. Peak plasma concentrations (Cmax) were reached early for buprenorphine (0.75-1.0 h) and naloxone (0.5 h), supporting rapid absorption. In the SAD study, increases in plasma exposures to buprenorphine and naloxone were less than dose proportional, in line with previous observations in Western populations. Buprenorphine-to-naloxone ratios for Cmax and area under the curve (AUC) were constant over the dose range investigated and also consistent with Western populations data. Steady state was reached within 7 days of daily dosing, with slight accumulation over repeated doses. No serious adverse events were observed. CONCLUSIONS: The present data suggest that buprenorphine/naloxone pharmacokinetic profiles in Chinese participants are consistent, overall, with those in Western populations, supporting no differences in dosing. CLINICAL TRIAL REGISTRATION: The protocols were registered on the official website of the China Food and Drug Administration (CFDA): http://www.chinadrugtrials.org.cn/ ; Registration numbers CTR20132963 (RB-CN-10-0012), CTR20140153 (RB-CN-10-0015).

Treatment of opioid dependence with buprenorphine/naloxone sublingual tablets: A phase 3 randomized, double-blind, placebo-controlled trial.

INTRODUCTION: The purpose of the study is to evaluate the efficacy and safety of buprenorphine/naloxone sublingual tablets for the treatment of opioid dependence in Chinese adults. METHODS: This multicenter, double-blind, placebo-controlled study included four periods: induction (3-5 days), stabilization (7-21 days), randomization/treatment (6 weeks), and postmedication follow-up (1 week). A total of 442 participants with opioid dependence were enrolled; 260 were randomized to buprenorphine/naloxone or placebo. The primary outcome was retention in treatment, defined as the time from randomization to treatment completion or treatment failure. Secondary outcomes included maximum consecutive days of abstinence from opioids, self-reported craving and opioid withdrawal symptoms, and urine drug screen results. Safety assessments included adverse event reporting, electrocardiograms, clinical laboratory tests, vital signs, and prior/concomitant medications. RESULTS: The median treatment retention time (95% confidence internal) with buprenorphine/naloxone was 32 days (26-38) versus 6 days (5-8) for placebo, with a Cox hazard ratio of 0.28 (95% confidence interval, 0.21-0.38; P < 0.0001). The median maximum consecutive days of abstinence (95% confidence interval) was: buprenorphine/naloxone, 21 days (26-38); placebo, 5 days (5-8) with a Cox hazard ratio of 0.38 (95% confidence interval, 0.25-0.60; P < 0.0001). Withdrawal and craving symptoms were significantly milder with buprenorphine/naloxone versus placebo (P < 0.001). Urine drug screen results indicated significantly lower opioid usage in the buprenorphine/naloxone group compared with placebo (P < 0.001). The most commonly reported adverse events in the buprenorphine/naloxone group during treatment were aspartate aminotransferase increased and nasopharyngitis. DISCUSSION: Efficacy and safety results from this clinical trial support a positive benefit-risk ratio for buprenorphine/naloxone sublingual tablet use in the treatment of an opioid-dependent Chinese population.

Quantification of human brain PDE4 occupancy by GSK356278: A [11C](R)-rolipram PET study.

We characterized the relationship between the plasma concentration of the phospodiesterase (PDE)-4 inhibitor GSK356278 and occupancy of the PDE4 enzyme in the brain of healthy volunteers, using the positron emission tomography (PET) tracer [11C](R)-rolipram. To this end, PET scans were acquired in eight male volunteers before and at 3 and 8 h after a single 14 mg oral dose of GSK356278. A metabolite-corrected arterial input function was used in conjunction with the dynamic PET emission data to estimate volumes of distribution (VT) from a two-tissue compartment model. The administration of GSK356278 reduced [11C](R)-rolipram whole brain VT by 17% at 3 h post-dose (p = 0.01) and by 4% at 8 h post-dose. The mean plasma Cmax was 42.3 ng/ml, leading to a PDE4 occupancy of 48% at Tmax. The in vivo affinity of GSK356278 was estimated as EC50 = 46 ± 3.6 ng/ml. We present the first report of a direct estimation of PDE4 blockade in the living human brain. In vivo affinity of GSK356278 for the PDE4, estimated in this early phase study, was combined with GSK356278 safety and tolerability data to decide on a therapeutic dose for future clinical development.

Safety, pharmacokinetics, pharmacodynamics, and bioavailability of GSK2018682, a sphingosine-1-phosphate receptor modulator, in healthy volunteers.

The tolerability, pharmacokinetics, and pharmacodynamics of single (SD) and repeat (RD) doses of GSK2018682, a selective S1P1 receptor modulator, were evaluated in healthy volunteers. The bioavailability (BA) of different formulations and effects of food were also evaluated. SD of up to 24 mg and RD of up to 6 mg/day for 28 days were reasonably tolerated, despite higher incidences of gastrointestinal and cardiovascular adverse events compared to placebo. There was a linear relationship between dose and systemic exposure with a dose-independent half-life (t1/2 ) between 44.9 and 63.3 hours. GSK2018682 induced acute, transient and non-symptomatic decreases in heart rate and blood pressure. Dose-dependent reduction in absolute lymphocyte count (ALC), and all tested subsets, was observed to various degrees, up to a nadir of over 70% reduction from baseline. There was no difference in major pharmacokinetic parameters among three formulations of GSK2018682 and between fasted and fed subjects. However, there was a reduction in the extent of bradycardia following dosing in the fed state. Additionally, exercise induced robust increase in heart rate in subjects who had bradycardia following RD of GSK2018682 up to 6 mg, suggesting possible physiological methods of reducing the extent of S1P mediated bradycardia and subsequent AV-block.

Characterising the plasma-target occupancy relationship of the neurokinin antagonist GSK1144814 with PET.

GSK1144814 is a potent, insurmountable antagonist at human NK1 and NK3 receptors. Understanding the relationship between plasma pharmacokinetics and receptor occupancy in the human brain, was crucial for dose selection in future clinical studies. GSK1144814 occupancy data were acquired in parallel with the first-time-in-human safety and tolerability study. [¹¹C]GR-205171 a selective NK1 receptor PET ligand was used to estimate NK1 occupancy at several time-points following single dose administration of GSK1144814. The time-plasma concentration-occupancy relationship post-single dose administration was assessed, and used to predict the plasma concentration-occupancy relationship following repeat dose administration. Repeat dose predictions were tested in a subsequent cohort of subjects examined following approximately 7 and 14 days dosing with GSK1144814. GSK1144814 was shown to demonstrate a dose-dependent occupancy of the NK1 receptor with an estimated in vivo EC50~0.9 ng/mL in the human brain. A direct relationship was seen between the GSK1144814 plasma concentration and its occupancy of the brain NK1 receptor, indicating that in future clinical trials the occupancy of brain receptors can be accurately inferred from the measured plasma concentration. Our data provided support for the further progression of this compound and have optimised the likely therapeutic dose range.

Contribution of SPECT measurements of D2 and 5-HT2A occupancy to the clinical development of the antipsychotic SB-773812.

UNLABELLED: The aim of this study was to assess human striatal dopamine receptor 2 (D(2)) and cortical 5-hydroxytryptamine receptor 2A (5-HT(2A)) occupancy of SB-773812 to demonstrate brain penetration and binding to the target receptors and assess the pharmacokinetics-receptor occupancy relationship over time to aid dose selection and dosage regimen, in preparation for the phase II trials. METHODS: D(2) and 5-HT(2A) occupancy were measured over time (both at the time of maximum [T(max); 6 ± 2 h] and at the time of minimum [T(trough); 24 ± 4 h] plasma concentration after dosing) by means of (123)I-iodobenzamide and (123)I-4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]5-iodo-2-methoxybenzamide ((123)I-R91150) SPECT in 3 studies. Study A consisted of SB-773812 single doses in healthy volunteers-D(2) occupancy measured at 48 (n = 9) and 56 mg (n = 9) and 5-HT(2A) occupancy at 56 mg (n = 9); study B consisted of D(2) and 5-HT(2A) occupancy measured in 12 stabilized-schizophrenia patients on stable doses (16-18 d of 56 mg/d) after washout of previous medication; and study C included D(2) occupancy measured in a double-blind study of patients with acutely exacerbated schizophrenia (n = 10) on stable doses (18-21 d) of SB-773812 (100 mg/d; n = 7) or risperidone (6 mg/d; n = 3). RESULTS: Study A showed less than 30% D(2) occupancy at T(max), maintained at T(trough). 5-HT(2A) occupancy was 74%-97% and also maintained over time. Study B revealed that 8 of the 12 schizophrenia patients showed more than 40% D(2) occupancy. 5-HT(2A) occupancy ranged from 91% to 100%. In study C, SB-773812-induced D(2) occupancy was 60.3% ± 13.3% at T(max) and 55.1% ± 4.9% at T(trough). The pharmacokinetics-receptor occupancy relationship was assessed in each study and strengthened, combining all data to yield a concentration associated with 50% occupancy (EC(50)) of 92.7 ± 13.5 ng/mL for D(2) and 2.11 ± 0.50 ng/mL for 5-HT(2A). CONCLUSION: In all subjects, SB-773812 showed penetration into the brain, reaching its target receptors. In patients with schizophrenia, D(2) occupancy levels induced by a single dose were maintained over time, indicating that once-daily dosing regimens are appropriate. Pharmacokinetics-receptor occupancy analysis provided guidance for the selection of a clinically effective dose, supporting progression in phase II.