Plasma Levels Of Buprenorphine Research Articles

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.

Pharmacokinetic Evaluation of a Topical Extended-release Analgesic in Mice.

Mice often undergo painful procedures and surgeries as part of biomedical research protocols. Buprenorphine, a partial μ-opioid receptor agonist and κ receptor antagonist, is commonly used to alleviate the pain associated with such procedures. Due to its pharmacokinetic profile, buprenorphine requires frequent dosing, resulting in handling stress that can impact animal welfare and study data. A long-acting transdermal buprenorphine formulation (LA-bup) was recently approved for use in cats to provide up to 4 d of postoperative analgesia. In this study, we characterized the pharmacokinetics of a single topical dosing of LA-bup in male and female CD-1 mice administered a 0.36-mg or 18-μL topical dose at select time points. Plasma buprenorphine concentrations were evaluated at 0.25, 0.5, 1, 1.5, 2, 4, 8, 24, 48, and 72 h (n = 3 mice/time point) and remained above the purported therapeutic threshold (1 ng/mL) from 1 to 24 h postadministration. Repeated daily dosing at 24 and 48 h demonstrated plasma levels above 1 ng/mL for up to 72 h with minimal accumulation or changes in maximal concentrations over time. Inadvertent transfer of the topical drug to nondosed mice in the same cage was evaluated by measuring plasma buprenorphine concentrations in nondosed mice cohoused with a single-dosed mouse. Male mice did not demonstrate transfer of drug via grooming or interactions, yet 2 out of 26 nondosed female mice had detectable buprenorphine plasma levels indicating a relatively low incidence of cross-ingestion in cohoused female mice. This study demonstrates that LA-bup is a promising analgesic in mice that could be used for tailored analgesia strategies, depending on the surgical model or duration of analgesic therapy.

A pharmacokinetic study of extended-release buprenorphine in cynomolgus monkeys (Macaca fasicularis).

A novel buprenorphine (BUP) extended-release formulation (BUP-XR) produced as a lipid-encapsulated, low viscosity BUP suspension for subcutaneous (SC) injection to control pain was evaluated for pharmacokinetics and safety in four adult male cynomolgus monkeys. Each animal was given 0.2 mg/kg reformulated BUP-XR SC. Clinical observations were made during the course of the study. Blood samples were obtained from each animal before BUP-XR administration, 6, 24, 48, 72, and 96 h post-BUP-XR injection. Plasma levels of buprenorphine were analyzed using HPLC-MS/MS. The PK values calculated included peak plasma concentration of the BUP analyte, time to peak plasma concentration, plasma half-life, area under the plasma concentration-time curve, clearance, apparent volume of distribution, and elimination rate constant (Cmax , Tmax , T½ , AUC0-t , CL, Vd, and Ke, respectively). Observable adverse clinical signs were not detected. BUP concentration peaked from 6 to 48 h, then declined in a linear fashion. Quantifiable plasma BUP was measured in all monkeys at all time points. Results indicate that a single BUP-XR dose at 0.2 mg/kg can reliably provide plasma levels of BUP reported in the literature to be therapeutically relevant for up to 96 h. Because of the lack of any clinical observations or adverse effects at the injection site or absence of observable abnormal behaviors, it may be concluded that the use of BUP-XR is safe and efficacious in this species of non-human primate at the dose regimen described in this study for up to 96 h post-administration.

Comparative Pharmacokinetics and Injection Site Histopathology in Nude Mice Treated with Long-acting Buprenorphine Formulations.

Two long-acting formulations of buprenorphine are commercially available as analgesics for rodents. However, these drugs have not yet been studied in nude mice. We sought to investigate whether the manufacturer-recommended or labeled mouse doses of either drug would provide and sustain the purported therapeutic plasma concentration of buprenorphine (1 ng/mL) over 72 h in nude mice and to characterize the injection site histopathology. NU/NU nude and NU/+ heterozygous mice were subcutaneously injected with extended-release buprenorphine polymeric formulation (ER; 1 mg/kg), extendedrelease buprenorphine suspension (XR; 3.25 mg/kg), or saline (2.5 mL/kg). Plasma concentrations of buprenorphine were measured 6, 24, 48, and 72 h after injection. The injection site was examined histologically at 96 h after administration. XR dosing yielded significantly higher plasma buprenorphine concentrations than did ER dosing at every time point in both nude and heterozygous mice. No significant difference in plasma buprenorphine concentrations were detected between nude and heterozygous mice. Both formulations yielded plasma levels of buprenorphine of over 1 ng/mL at 6 h; XR sustained buprenorphine plasma levels above 1 ng/mL for over 48 h, whereas ER sustained this level for over 6 h. Injections sites of both formulations were characterized by a cystic lesion with a fibrous/fibroblastic capsule. ER induced more inflammatory infiltrates than did XR. This study indicates that while both XR and ER are suitable for use in nude mice, XR has a longer duration of likely therapeutic plasma levels and induces less subcutaneous inflammation at the injection site.

Buprenorphine exposure levels to optimize treatment outcomes in opioid use disorder.

The severity of the ongoing opioid crisis, recently exacerbated by the COVID-19 pandemic, emphasizes the importance for individuals suffering from opioid use disorder (OUD) to have access to and receive efficacious, evidence-based treatments. Optimal treatment of OUD should aim at blocking the effects of illicit opioids while controlling opioid craving and withdrawal to facilitate abstinence from opioid use and promote recovery. The present work analyses the relationship between buprenorphine plasma exposure and clinical efficacy in participants with moderate to severe OUD using data from two clinical studies (39 and 504 participants). Leveraging data from placebo-controlled measures assessing opioid blockade, craving, withdrawal and abstinence, we found that buprenorphine plasma concentrations sustained at 2-3ng/ml (corresponding to ≥70% brain mu-opioid receptor occupancy) optimized treatment outcomes in the majority of participants, while some individuals (e.g., injecting opioid users) needed higher concentrations. Our work also included non-linear mixed effects modeling and survival analysis, which identified a number of demographic, genetic and social factors modulating treatment response and retention. Altogether, these findings provide key information on buprenorphine plasma levels that optimize clinical outcomes and increase the likelihood of individual treatment success. NLM identifiers: NCT02044094, NCT02357901.

Differentiating the Effect of an Opioid Agonist on Cardiac Repolarization From µ-Receptor–mediated, Indirect Effects on the QT Interval: A Randomized, 3-way Crossover Study in Healthy Subjects

PurposeA thorough QT study was conducted in healthy subjects to evaluate the effect of buprenorphine hydrochloride administered through a buccal soluble film under coverage of naltrexone to block confounding, secondary QT effects. MethodsHealthy subjects were enrolled in a randomized, partially blinded, 4-way crossover designed study. Subjects received buprenorphine 3 mg with naltrexone, naltrexone alone (with placebo films), placebo (placebo films and placebo naltrexone), and open-label moxifloxacin 400 mg with placebo naltrexone in separate in-house treatment periods. Naltrexone treatment (50 mg) was initiated 12 hours before buprenorphine and was given every 12 hours for a total of 4 doses. ECG data were extracted from a continuous recording predose and serially after dosing on the treatment day. ECG intervals were measured at a central ECG laboratory by using the high-precision QT technique. The QT interval was corrected for heart rate with Fridericia’s formula (QTcF), and change-from-predose baseline QTcF (∆QTcF) was analyzed by using a mixed effect model. FindingsFifty-eight subjects (35 males) with a mean age of 32 were enrolled into the study. Treatment with buprenorphine 3 mg resulted in a small QT effect with the largest mean naltrexone-corrected ∆QTcF reaching 5.8 msec at 8 hours’ postdosing (upper bound of the 90% CI below 10 msec). Exposure response analysis with a linear model demonstrated a significant linear relationship between plasma levels and naltrexone-corrected ∆QTcF, with an estimated mean slope of 0.65 msec per nanogram/milliliter (90% CI, 0.22 to 1.08). Using the exposure response model, an effect on ∆QTcF of 4.5 msec (2.80 to 6.12) can be predicted at the observed geometric peak plasma level after administration of the 3-mg buprenorphine dose in this study (3.6 ng/mL [3.33 to 3.98]). Naltrexone alone did not have a relevant effect on the QTcF interval. ImplicationsThe present study showed that buprenorphine plasma levels up to 5 ng/mL had no effect on the QTc above the level of clinical concern.

Opioid detoxification via single 7-day application of a buprenorphine transdermal patch: an open-label evaluation

Managed withdrawal (i.e., detoxification) from opioid dependence is a widespread clinical procedure that is a necessary step for those pursuing abstinence. Buprenorphine is one effective detoxification treatment, however, consensus regarding effective detoxification procedures is lacking. This study evaluated the efficacy of a buprenorphine transdermal formulation (i.e., patch) in suppressing opioid withdrawal, its safety and tolerability, and its biodelivery when applied for 7 days. Physically dependent opioid (heroin) users (n = 12) completed a 10-day opioid detoxification in a residential research unit. Each received a single patch application that remained in place for 7 days. Blood samples were drawn prior to patch application and once daily thereafter. Assessments, four times daily, included: the amount of rescue medications ordered to treat withdrawal discomfort; self-report and observer ratings of opioid withdrawal and agonist effects; and vital sign measures. Overall, the patch appeared safe and well-tolerated. Buprenorphine plasma levels peaked 48 h after patch application at 0.59 ng/ml. Indices of withdrawal (self-reports, observer ratings, rescue medication) were significantly reduced within 24 h of patch application, continued to decline thereafter, and did not reappear following patch removal. This study confirms that transdermal buprenorphine is safe and clinically effective, and suggests that a 7-day application may provide an effective and comfortable means of detoxification. This patch formulation would appear to be a useful opioid detoxification treatment by reducing compliance concerns, and administering buprenorphine in a formulation less likely to be diverted to illicit use.

Pharmacokinetics of Buprenorphine: A Comparison of Sublingual Tablet Versus Liquid after Chronic Dosing

Although buprenorphine is approved for use in the outpatient treatment of opioid addiction in 2 tablet formulations, a monoproduct containing buprenorphine only (Subutex) and a buprenorphine/naloxone combination product (Suboxone), much of the clinical data that support the approval by the U.S. Food and Drug Administration were generated by using a sublingual liquid. To interpret the literature in prescribing parameters for tablet buprenorphine, this study was designed to determine steady state buprenorphine plasma levels for the 2 formulations and to assess the relative bioavailability of each. A randomized, double-blind, crossover study with dose increases was conducted during a 12-week period at an outpatient treatment clinic. Of the 184 subjects initially randomized to treatment, 133 (72.3%) were evaluated for the steady-state trough plasma concentration, 16 (8.7%) for relative bioavailability, and 31 (16.8%) for dose proportionality. At steady state, differences in the trough plasma concentrations of buprenorphine between the 2 formulations were found across all the dose levels. Average plasma concentration (Cavg) of the tablet at twice the milligram dose of the liquid was twice that of the liquid; intersubject variability was greater for the tablet. At double the dose of tablet, there is no difference in steady state plasma concentrations. The bioavailability seems equivalent for the 2 formulations across all the dose levels.

The effects of chronic buprenorphine on intake of heroin and cocaine in rats and its effects on nucleus accumbens dopamine levels during self-administration

Buprenorphine reduces both heroin and cocaine intake in opioid addicts, but the mechanisms remain unclear. To determine the effects of chronic buprenorphine treatment on intake of heroin and/or cocaine and measure nucleus accumbens (NAc) dopamine (DA) levels during self-administration. In experiment 1, plasma levels of buprenorphine were determined in rats with buprenorphine osmotic minipumps (3.0 mg/kg/day) using an ELISA. In experiment 2, rats self-administered (FR1) one dose of heroin [(0.025, 0.05, or 0.1 mg/kg/infusion (inf)] and one dose of cocaine (0.25, 0.5, or 1.0 mg/kg/inf) before and under sham or chronic buprenorphine treatment (1.5 or 3.0 mg/kg/day). In experiment 3, the effect of sham or chronic buprenorphine treatment (3.0) on heroin (0.05 mg/kg/inf) or cocaine (0.5 mg/kg/inf) self-administration under FR5 and progressive ratio (PR) schedules was evaluated. In experiment 4, in vivo microdialysis sampling from the NAc was carried out during heroin (0.05 mg/kg/inf) or cocaine (0.5 mg/kg/inf) self-administration (FR1) under sham or buprenorphine treatment (3.0). Buprenorphine levels in plasma were stable over time. Buprenorphine treatment had no effect on total heroin intake at any dose or under any schedule, whereas it suppressed cocaine intake at all doses and under all schedules. Buprenorphine enhanced basal levels of DA, attenuated the NAc DA response to heroin, and enhanced the DA response to cocaine. It is interesting to note that buprenorphine increased the latency to respond to drug-associated cues at the start of self-administration sessions. Chronic buprenorphine reduces cocaine, but not heroin, intake and possibly reduces drug seeking by reducing the salience of the drug-associated cues.

Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine

The present study was designed to study the impact of intermittent hemodialysis on the disposition of the partial agonist buprenorphine and its metabolite norbuprenorphine during therapy with transdermal buprenorphine in chronic pain patients with end-stage kidney disease. Ten patients (mean age 63 years) who had received transdermal buprenorphine for at least 1 week, were asked to provide blood samples immediately before and after hemodialysis. Blood samples were analysed for buprenorphine and its metabolite norbuprenorphine. The median buprenorphine plasma concentrations were found to be 0.16 ng/ml before and 0.23 ng/ml after hemodialysis. A significant correlation between plasma levels and administered doses was observed (Spearman R = 0.74; P < 0.05). In three patients norbuprenorphine plasma levels were detected. No differences in pain relief before and after hemodialysis were observed. This investigation shows no elevated buprenorphine and norbuprenorphine plasma levels in patients with renal insufficiency receiving transdermal buprenorphine up to 70 μg/h. Furthermore, hemodialysis did not affect buprenorphine plasma levels, leading to stable analgesic effects during the therapy.

Opioids: clinical pharmacology: Evaluation of a novel intranasal formulation of buprenorphine in healthy volunteers

Intranasal delivery of opioid drugs is a convenient way to provide fast onset analgesia. The aim of the current study was to determine the pharmacokinetic and tolerability profile of a novel, pectin-based, intranasal formulation of buprenorphine in healthy volunteers. The study comprised a randomised, double-blind, placebo-controlled, alternating panel, rising single dose design. A total of 20 subjects (male and female) were used. Three doses (0.1mg, 0.2mg and 0.4mg) of the novel pectin-based formulation of buprenorphine were delivered intranasally using a standard Pfeiffer single-dose (100μL) spray device. Placebo devices delivered 100μL of normal saline solution. The pharmacokinetic profile was determined from 0-8h and buprenorphine content in plasma was measured using LC-MS/MS. Pharmacodynamic measures comprised: saccadic eye movements, incidence of nausea and vomiting, and taste disturbance. Nasal irritancy was also assessed. The results show that intranasal administration of buprenorphine produced a dose-related increase in plasma exposure. Cmax values (mean±SD) were: 0.37±0.13 ng/ml; 1.04±0.34 ng/ml; 1.37±0.43 ng/ml for 0.1, 0.2 and 0.4 mg, respectively. These plasma levels are within the accepted therapeutic range for buprenorphine. Tmax values indicate rapid delivery of drug to the systemic circulation (0.25-0.625h). There was an increase in opioid-like side effects as the dose was escalated from 0.1 to 0.4mg, the systemic tolerability profile being representative of the expected pharmacology of buprenorphine. At 0.1 and 0.2 mg there were no significant reports of nasal irritancy or taste disturbance. This study demonstrates rapid attainment of buprenorphine plasma levels and an acceptable tolerability profile following intranasal delivery of a novel pectin-based formulation.

Pharmacokinetic evaluation of transdermal buprenorphine in man

Abstract Transdermal delivery of the synthetic opiate analgesic, buprenorphine, was studied in healthy volunteers. Pharmacokinetic, safety and tolerability data were obtained in a group of 12 healthy subjects following administration of a short intravenous infusion and the application of both aqueous- and ethanol-based fillable transdermal therapeutic systems (FTTS), containing 8 and 37.5 mg of drug, respectively. The total amount delivered by the 10 cm 2 aqueous reservoir system ranged from 0.11 to 0.67 mg over the 24 h application period and the steady state in vivo flux rates were 0.56–1.91 μg/cm 2 /h. The total amount delivered by the 5 cm 2 ethanol-based FTTS ranged from 0.33 to 0.96 mg and the steady state in vivo flux values were 2.14–5.62 μg/cm 2 /h. The results of the feasibility investigation demonstrated that transdermal delivery of buprenorphine produced sustained plasma levels of drug within the range observed after intravenous dosing and that an ethanolic formulation produced approximately a four-fold increase in transdermal flux. The in vivo investigation suggests that transdermal delivery could provide appropriate plasma levels of buprenorphine for sustained analgesic effect.

Investigation of the antinociceptive activity of buprenorphine in sheep.

1. Buprenorphine given intravenously (6 micrograms kg-1) was examined for its antinociceptive activity in unrestrained sheep using devices to measure thermal and mechanical thresholds. 2. The plasma levels of buprenorphine following intravenous injection over the time period of the antinociceptive testing were measured using a radioimmunoassay. 3. Buprenorphine produced a clear antinociceptive effect lasting for up to three and a half hours when measured by the thermal threshold test, but no detectable antinociception in the mechanical test. 4. The plasma levels of buprenorphine indicated that the drug was rapidly distributed in a manner not dissimilar to that reported in man, although individual animals showed a wide variation in some parameters. 5. When plasma levels of the drug were high (less than 700 pg ml-1) during the first sixty minutes, no antinociceptive activity in the thermal test could be detected, which may be due to the slow receptor kinetics shown by this drug.

Analysis of buprenorphine and its n-dealkylated metabolite in plasma and urine by selected-ion monitoring

A selected-ion monitoring method as developed for determination of buprenorphine and its N-dealkylated metabolite (norbuprenorphine) in human plasma and urine. N-Propylnorbuprenorphine was added as internal standard to 2–3 ml of sample and the alkaloids were extracted with toluene—2-butanol at pH 9.4. After back-extraction in dilute sulphuric acid, the compounds were heated at 110°C. This procedure led to quantitative loss of methanol followed by ring formation between the 6-methoxy group and the branched side- chain of all compounds. The derivatives were extracted into dichloromethane—2-butanol and treated with pentafluoropropionic anhydride. The resulting derivatives were suitable for selected-ion monitoring analysis. The coefficient of variation was found to be 4.5% at 5 ng/ml and 8.9% at 50 ng/ml in urine. The corresponding values for plasma were 6.2% and 5.3%, respectively. The lower limit of detection in plasma was 150 pg/ml, permitting analysis of plasma levels of buprenorphine for 24 h and urine levels of buprenorphine and norbuprenorphine for more than seven days after a therapeutic dose of buprenorphine. This method is the first with sufficient specificity and sensitivity for characterization of the clinical pharmacokinetics of buprenorphine.

Sublingual buprenorphine used postoperatively: clinical observations and preliminary pharmacokinetic analysis.

1 Buprenorphine is a long-acting opiate analgesic. This study was designed to investigate the pharmacokinetics of this drug when given by the sublingual route to ten postoperative patients. Plasma levels of buprenorphine were measured by a specific radioimmunoassay. 2 Plasma levels of the drug following sublingual administration of 0.4 mg showed an apparent delay in absorption and then rose slowly to reach low but significant levels by 3 h. There was considerable variation in the time at which peak levels were achieved. The average systemic availability of the drug by this route was estimated to be 30% by 3 h. 3 Analgesic efficacy and duration of sublingual buprenorphine were assessed using demand analgesia. The analgesia was of about 9 h duration, similar to that achieved by parenteral administration of 0.3 mg of the drug to an equivalent group of patients. The sublingual dose caused a significant fall in the postoperatively elevated group of patients. The sublingual dose caused a significant fall in the postoperatively elevated plasma glucose, and prevented any further rise in plasma cortisol. 4 Reasons for the efficacy of the sublingual route are discussed and it is suggested that this route may be particularly appropriate for highly lipophilic drugs like buprenorphine.