The Bioavailability of CHF6563, an Ethanol-Free, Sublingual Neonatal Buprenorphine Formulation: A Bridging Study Conducted in Adults
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SUBMITTER: Kraft W
PROVIDER: S-EPMC10849686 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:ObjectiveNeonatal abstinence syndrome (NAS)--a clinical entity of infants from in utero exposure to psychoactive xenobiotic and buprenorphine--has been successfully used to treat NAS. However, nothing is known about the pharmacokinetics (PK) of buprenorphine in neonates with NAS. To our knowledge, this is the first study to investigate the population pharmacokinetic of sublingual buprenorphine in neonates with NAS.DesignA retrospective population PK analysis of: (1) neonates with NAS treated with sublingual buprenorphine in randomized, double blinded clinical study and (2) data from healthy adults from a previously published pharmacokinetic study.SettingNeonatal intensive care unit and general clinical research unit.PatientsTwenty-four neonates with NAS and five healthy adults.InterventionsAll participants received sublingual buprenorphine per study protocol.Measurements and main resultsA total of 303 PK data from 29 neonates and adults were used for model development. A population pharmacokinetic analysis was conducted using a first order conditional estimation with interaction in the NONMEM software program. A two-compartment linear PK model with first-order absorption process best described the pharmacokinetics of sublingual buprenorphine in neonates. The apparent clearance (CL) of buprenorphine was linearly related to body weight and matured with increasing age via two distinct saturated pathways. A typical neonate with NAS (body weight, 2.9 kg; postnatal age; 5.4 days) had a CL of 3.5 L/kg/hour and elimination half-life of 11 hours. Phenobarbital did not affect the clearance of buprenorphine compared to neonates of similar age and weight.ConclusionsThis is the first study to investigate the population PK of sublingual buprenorphine in neonatal NAS. To our knowledge, this is also the first report to describe the age-dependent changes of buprenorphine PK in this patient population. No buprenorphine dose adjustment is needed for neonates with NAS treated with buprenorphine and concurrent phenobarbital.
| S-EPMC5119858 | biostudies-literature
Project description:In utero exposure to drugs of abuse can lead to neonatal abstinence syndrome, a condition that is associated with prolonged hospitalization. Buprenorphine is a partial mu-opioid agonist used for treatment of adult detoxification and maintenance but has never been administered to neonates with opioid abstinence syndrome. The primary objective of this study was to demonstrate the feasibility and, to the extent possible in this size of study, the safety of sublingual buprenorphine in the treatment of neonatal abstinence syndrome. Secondary goals were to evaluate efficacy relative to standard therapy and to characterize buprenorphine pharmacokinetics when sublingually administered.We conducted a randomized, open-label, active-control study of sublingual buprenorphine for the treatment of opiate withdrawal. Thirteen term infants were allocated to receive sublingual buprenorphine 13.2 to 39.0 mug/kg per day administered in 3 divided doses and 13 to receive standard-of-care oral neonatal opium solution. Dose decisions were made by using a modified Finnegan scoring system.Sublingual buprenorphine was largely effective in controlling neonatal abstinence syndrome. Greater than 98% of plasma concentrations ranged from undetectable to approximately 0.60 ng/mL, which is less than needed to control abstinence symptoms in adults. The ratio of buprenorphine to norbuprenorphine was larger than that seen in adults, suggesting a relative impairment of N-dealkylation. Three infants who received buprenorphine and 1 infant who received standard of care reached protocol-specified maximum doses and required adjuvant therapy with phenobarbital. The mean length of treatment for those in the neonatal-opium-solution group was 32 compared with 22 days for the buprenorphine group. The mean length of stay for the neonatal-opium-solution group was 38 days compared with 27 days for those in the buprenorphine group. Treatment with buprenorphine was well tolerated.Buprenorphine administered via the sublingual route is feasible and apparently safe and may represent a novel treatment for neonatal abstinence syndrome.
| S-EPMC2574639 | biostudies-literature
Project description:More than half of infants exposed to opioids in utero develop neonatal abstinence syndrome (NAS) of severity to require pharmacological therapy. Current treatments are associated with prolonged hospitalization. We sought to optimize the dose of sublingual buprenorphine in the treatment of NAS.Randomized, Phase 1, open-label, active-control clinical trial comparing sublingual buprenorphine to oral morphine.Large, urban, tertiary care hospital.Twenty-four term infants requiring pharmacological treatment for NAS.Outcomes were neonatal safety, length of treatment and length of hospitalization.Sublingual buprenorphine was safe and effective. Infants treated with buprenorphine had a 23-day length of treatment compared to 38 days for those treated with morphine (P = 0.01), representing a 40% reduction. Length of hospital stay in the buprenorphine group was reduced 24%, from 42 to 32 days (P = 0.05).Sublingual buprenorphine was safe in NAS, with a substantial efficacy advantage over standard of care therapy with oral morphine.
| S-EPMC3022999 | biostudies-literature
Project description:Background and objectiveIn 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.MethodsPharmacokinetic 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.ResultsThe 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.ConclusionsThis 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 registrationsISRCTN41550730 (05/19/2014), ISRCTN24987553 (07/29/2014), NCT02611752 (11/23/2015), NCT02710526 (03/16/2016).
| S-EPMC10520114 | biostudies-literature
Project description:BackgroundBisphenol A (BPA) risk assessment is currently hindered by the rejection of reported higher-than-expected plasma BPA concentrations in humans after oral ingestion. These are deemed incompatible with the almost complete hepatic first-pass metabolism of BPA into its inactive glucurono-conjugated form, BPA glucuronide (BPAG).ObjectivesUsing dogs as a valid model, we compared plasma concentrations of BPA over a 24-hr period after intravenous, orogastric, and sublingual administration in order to establish the absolute bioavailability of BPA administered sublingually and to compare it with oral bioavailability.MethodsSix dogs were sublingually administered BPA at 0.05 mg/kg and 5 mg/kg. We compared the time course of plasma BPA concentrations with that obtained in the same dogs after intravenous administration of the same BPA doses and after a 20-mg/kg BPA dose administrated by orogastric gavage.ResultsThe data indicated that the systemic bioavailability of BPA deposited sublingually was high (70-90%) and that BPA transmucosal absorption from the oral cavity led to much higher BPA internal exposure than obtained for BPA absorption from the gastrointestinal tract. The concentration ratio of BPAG to BPA in plasma was approximately 100-fold lower following sublingual administration than after orogastric dosing, distinguishing the two pathways of absorption.ConclusionsOur findings demonstrate that BPA can be efficiently and very rapidly absorbed through the oral mucosa after sublingual exposure. This efficient systemic entry route of BPA may lead to far higher BPA internal exposures than known for BPA absorption from the gastrointestinal tract.
| S-EPMC3734497 | biostudies-literature
Project description:AimsTo evaluate the safety and efficacy of buprenorphine implants (BI) versus placebo implants (PI) for the treatment of opioid dependence. A secondary aim compared BI to open-label sublingual buprenorphine/naloxone tablets (BNX).DesignRandomized, double-blind, placebo-controlled trial. Subjects received either four buprenorphine implants (80 mg/implant) (n = 114), four placebo implants (n = 54) or open-label BNX (12-16 mg/day) (n = 119).SettingTwenty addiction treatment centers.ParticipantsAdult out-patients (ages 18-65) with DSM-IV-TR opioid dependence.MeasurementsThe primary efficacy end-point was the percentage of urine samples negative for opioids collected from weeks 1 to 24, examined as a cumulative distribution function (CDF).FindingsThe BI CDF was significantly different from placebo (P < 0.0001). Mean [95% confidence interval (CI)] proportions of urines negative for opioids were: BI = 31.2% (25.3, 37.1) and PI = 13.4% (8.3, 18.6). BI subjects had a higher study completion rate relative to placebo (64 versus 26%, P < 0.0001), lower clinician-rated (P < 0.0001) and patient-rated (P < 0.0001) withdrawal, lower patient-ratings of craving (P < 0.0001) and better subjects' (P = 0.031) and clinicians' (P = 0.022) global ratings of improvement. BI also resulted in significantly lower cocaine use (P = 0.0016). Minor implant-site reactions were comparable in the buprenorphine [27.2% (31 of 114)] and placebo groups [25.9% (14 of 54)]. BI were non-inferior to BNX on percentage of urines negative for opioids [mean (95% CI) = 33.5 (27.3, 39.6); 95% CI for the difference of proportions = (-10.7, 6.2)].ConclusionsCompared with placebo, buprenorphine implants result in significantly less frequent opioid use and are non-inferior to sublingual buprenorphine/naloxone tablets.
| S-EPMC4669043 | biostudies-literature
Project description:ObjectivesThe aim of the study was to evaluate treatment retention, efficacy, and preference ratings among opioid-dependent patients transitioning between a buprenorphine/naloxone rapidly dissolving sublingual tablet formulation (BNX-RDT) and BNX film.MethodsAfter a 2-day, blinded, fixed-dose induction with BNX-RDT (5.7/1.4 mg and 5.7/1.4 or 11.4/2.8 mg, respectively) or buprenorphine (8 mg and 8 or 16 mg, respectively), patients received open-label titrated doses of BNX-RDT or BNX film (generic buprenorphine induction group) during days 3 to 14. On day 15, patients switched treatment (using a conversion ratio of 5.7-8 mg) and continued switched treatment through day 22. Assessments included treatment retention, opioid withdrawal (Clinical and Subjective Opiate Withdrawal scales), opioid cravings (0-100 visual analog scale [VAS]), and preference ratings.ResultsOf the 287 patients who switched from BNX-RDT to BNX film and 279 patients who switched from BNX film to BNX-RDT at day 15, 8.7% and 6.1% withdrew, respectively. Reductions in opioid withdrawal and cravings were similar with both formulations through day 15; after switching treatment, reductions were maintained through day 22 in both groups. Preference ratings at day 22 (patients had received both formulations) favored BNX-RDT for taste, mouthfeel, ease of administration, and overall preference (all P < 0.0001).ConclusionsIn both patient groups who switched treatment at day 15, more than 90% were retained in treatment, and reductions in opioid withdrawal and cravings were sustained. A significant majority of patients preferred BNX-RDT over BNX film, the clinical impact of which requires further study.
| S-EPMC4888929 | biostudies-literature
Project description:ImportanceExtended-release buprenorphine (XRB), a monthly injectable long-acting opioid use disorder (OUD) treatment, has not been studied for use in corrections facilities.ObjectiveTo compare treatment retention following release from jail among adults receiving daily sublingual buprenorphine-naloxone (SLB) vs those receiving XRB.Design, setting, and participantsThis open-label, randomized comparative effectiveness study included 52 incarcerated adults in New York City observed for 8 weeks postrelease between June 2019 and May 2020. Participants were soon-to-be-released volunteers from 1 men's and 1 women's jail facility who had OUDs already treated with SLB. Follow-up treatment was received at a primary care clinic in Manhattan. Data were analyzed between June 2020 and December 2020.InterventionsXRB treatment was offered prior to release and continued monthly through 8 weeks after release. SLB participants continued to receive daily directly observed in-jail SLB administration, were provided a 7-day SLB supply at jail release, and followed up at a designated clinic (or other preferred clinics).Main outcomes and measuresBuprenorphine treatment retention at 8 weeks postrelease.ResultsA total of 52 participants were randomized 1:1 to XRB (26 participants) and SLB (26 participants). Participants had a mean (SD) age of 42.6 (10.0) years; 45 participants (87%) were men; and 40 (77%) primarily used heroin prior to incarceration. Most participants (30 [58%]) reported prior buprenorphine use; 18 (35%) reported active community buprenorphine treatment prior to jail admission. Twenty-one of 26 assigned to XRB received 1 or more XRB injection prior to release; 3 initiated XRB postrelease; and 2 did not receive XRB. Patients in the XRB arm had fewer jail medical visits compared with daily SLB medication administration (mean [SD] visits per day: XRB, 0.11 [0.03] vs SLB, 1.06 [0.08]). Community buprenorphine treatment retention at week 8 postrelease was 18 participants in the XRB group (69.2%) vs 9 in the SLB group (34.6%), and rates of opioid-negative urine tests were 72 of 130 tests in the XRB group (55.3%) and 50 of 130 tests in the SLB group (38.4%). There were no differences in rates of serious adverse events, no overdoses, and no deaths.Conclusions and relevanceXRB was acceptable among patients currently receiving SLB, and patients had fewer in-jail clinic visits and increased community buprenorphine treatment retention when compared with standard daily SLB treatment. These results support wider use and further study of XRB as correctional and reentry OUD treatment.Trial registrationClinicalTrials.gov Identifier: NCT03604159.
| S-EPMC8427378 | biostudies-literature
Project description:Glaucoma is a wide-spread eye disease caused by elevated intraocular pressure. Uncontrolled, this pressure may lead to damages to the optic nerve. Prostaglandin analogues, such as latanoprost and travoprost (which are water-insoluble active substances), are the most used class of active pharmaceutical ingredient. To administer them as eye drops, preservatives, such as benzalkonium chloride, are used as solubilizers. The latter is known to cause a local inflammation when used chronically and is not recommended for patients with ocular surface disorders. In this work, we sought to use polysorbate 80 (PS80) as a solubilizing agent simultaneously with sodium hyaluronate (NaHA) as a thickener and cytoprotective agent for the corneal surface. The first part of this study assessed the compatibility of the excipients with the active substance, using physicochemical methods such as spectra fluorescence and differential scanning calorimetry (DSC), as well as the solubilization mechanism of PS80 regarding prostaglandin analogues using nuclear magnetic resonance (NMR). The second part evaluated the stability of a formula candidate, its viscosity upon instillation, and its pharmacokinetic profile in rabbits as compared to the commercially approved medicine Travatan®. The results show that sodium hyaluronate is inert with respect to travoprost, while PS80 successfully solubilizes it, meaning that benzalkonium chloride is no longer required. Moreover, the pharmacokinetic profiles of the rabbits showed that the original formula described in the present study enhanced the ocular bioavailability of the drug, making it a promising product to control intraocular pressure with a potential reduced dosage of travoprost, therefore minimizing its related side effects.
| S-EPMC8877962 | biostudies-literature
Project description:Infants exposed in utero to opioids will demonstrate a withdrawal syndrome known as neonatal abstinence syndrome (NAS). Buprenorphine is a long-acting opioid with therapeutic use in medication-assisted treatment of opioid dependency in adults and adolescents. Emerging data from clinical trials and treatment cohorts demonstrate the efficacy and safety of sublingual buprenorphine for those infants with NAS who require pharmacologic treatment. Pharmacometric modeling will assist in defining the exposure-response relationships and facilitate dose optimization.
| S-EPMC5739935 | biostudies-literature