Pharmacokinetics of Sublingual Buprenorphine and Naloxone in Subjects with Mild to Severe Hepatic Impairment (Child-Pugh Classes A, B, and C), in Hepatitis C Virus-Seropositive Subjects, and in Healthy Volunteers (original) (raw)
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Intravenous buprenorphine and norbuprenorphine pharmacokinetics in humans
Drug and Alcohol Dependence, 2013
Background-Prescribed sublingual (SL) buprenorphine is sometimes diverted for intravenous (IV) abuse, but no human pharmacokinetic data are available following high-dose IV buprenorphine. Methods-Plasma was collected for 72 h after administration of placebo or 2, 4, 8, 12, or 16 mg IV buprenorphine in escalating order (single-blind, double-dummy) in 5 healthy male nondependent opioid users. Buprenorphine and its primary active metabolite, norbuprenorphine, were quantified by liquid chromatography tandem mass spectrometry with limits of quantitation of 0.1 μg/L. Results-Maximum buprenorphine concentrations (mean ± SE) were detected 10 min after 2, 4, 8, 12, 16 mg IV: 19.3±1.0, 44.5±4.8, 85.2±7.7, 124.6±16.6, and 137.7±18.8 μg/L, respectively. Maximum norbuprenorphine concentrations occurred 10-15 min (3.7±0.7 μg/L) after 16 mg IV administration. Conclusions-Buprenorphine concentrations increased in a significantly linear dose-dependent manner up to 12 mg IV buprenorphine. Thus, previously demonstrated pharmacodynamic ceiling effects (over 2-16 mg) are not due to pharmacokinetic adaptations within this range, although they may play a role at doses higher than 12 mg.
Human Pharmacokinetics of Intravenous, Sublingual, and Buccal Buprenorphine
Journal of Analytical Toxicology, 1996
Buprenorphine is a potent opioid analgesic used in the treatment of moderate to severe pain. At higher doses, it has demonstrated potential for treating heroin dependence. This study was undertaken to investigate buprenorphine pharmacokinetics by different routes of administration at dosages approximating those used in opioid-dependence studies. Six healthy men who were nondependent but who had a history of heroin use were administered buprenorphine in a crossover design study by intravenous (1.2 rag), sublingual (4.0 rag), and buccal (4.0 rag) routes of administration. Plasma samples were collected up to 96 h and assayed for buprenorphine and norbuprenorphine by negative chemical ionization tandem mass spectrometry. Plasma concentrations of buprenorphine and norbuprenorphine were analyzed by nonlinear regression analysis with standard noncompartmental methods. Buprenorphine bioavailability by the sublingual and buccal routes was estimated as 51.4% and 27.8%, respectively, although there was considerable interindividual variability by both routes of administration. The terminal elimination half-lives were longer for the sublingual and buccal routes than for the intravenous route. The extended elimination half-lives may be due to a shallow depot effect involving sequestration of buprenorphine in the oral mucosa. Norbuprenorphine mean peak plasma concentrations were less than 1 ng/mL and were highly variable among different routes of administration and individuals. The terminal elimination half-life of norbuprenorphine was longer than buprenorphine.
Pharmaceutics
Background: The aim of this analysis was to characterize the pharmacokinetics (PK) of sublingual buprenorphine (BUP) and its metabolites (buprenorphine glucuronide; BUP-g, norbuprenorphine; Nor-BUP, and norbuprenorphine glucuronide; Nor-BUP-g) in opioid use disorder (OUD) patients in Puerto Rico (PR) as a first step of evidence-based BUP dosing strategies in this population. Methods: BUP and metabolites concentrations were measured from 0 to 8 h after the administration of sublingual buprenorphine/naloxone films in 12 stable OUD subjects. Results: PK non-compartmental characteristics showed considerable variability in parameters between the subjects over the 8-h sampling time (tmax = 1.5 ± 0.7 h, Co = 1.6 ± 1.4 ng/mL, Cmax= 7.1 ± 6 ng/mL, and AUC0–8h = 26.8 ± 17.8 h·ng/mL). Subjects had a significantly higher tendency towards CYP-mediated N-demethylation, with the AUC0–8h ratios of the molar concentrations of [Nor-BUP + Nor-BUP-g] to BUP being (3.4 ± 1.9) significantly higher compar...
Drug and Alcohol Dependence, 2003
Although only a partial m-opiate agonist, buprenorphine can be abused and diverted from medical therapy to the illicit drug market. A combination of buprenorphine and naloxone for sublingual administration may discourage diversion and abuse by precipitating opiate withdrawal when taken parenterally. Because opiate-abusing populations are not homogeneous and have varying levels of opiate dependence, the efficacy of buprenorphine and naloxone in precipitating opiate withdrawal or in attenuating the pleasurable effects of buprenorphine may vary. This chapter describes the effects of sublingual and parenteral buprenorphine and naloxone combinations in several populations of opiate-dependent people. We conclude that buprenorphine and naloxone combinations should not diminish the efficacy of sublingual buprenorphine, but should have lower abuse liability than buprenorphine alone. #
Effects of buprenorphine/naloxone in opioid-dependent humans
Psychopharmacology, 2001
Rationale: Buprenorphine is a partial mu opioid agonist under development as a sublingual (SL) medication for opioid dependence treatment in the United States. Because buprenorphine may be abused, tablets combining buprenorphine with naloxone in a 4:1 ratio have been developed to reduce that risk. Low doses of injected buprenorphine/naloxone have been tested in opioid-dependent subjects, but higher doses (more than 2 mg of either medication) and direct comparisons to SL buprenorphine/naloxone have not been examined. Objectives: To assess and compare the effects of intramuscular (IM) versus SL buprenorphine/naloxone in opioid-dependent volunteers. Methods: Opioid-dependent volunteers were maintained on 40 mg per day of oral hydromorphone while on a residential research ward. After safety testing in two pilot subjects, participants (n=8) were tested with both IM and SL buprenorphine/naloxone (1/0.25, 2/0.5, 4/1, 8/2, 16/4 mg); IM hydromorphone (10 mg) and naloxone (0.25 mg); both IM and SL buprenorphine alone (8 mg); and placebo. Test sessions were twice per week; dosing was doubleblind. Results: Intramuscular buprenorphine/naloxone produced dose-related increases on indices of opioid antagonist effects. Effects were consistent with naloxoneprecipitated withdrawal, and were short-lived. As withdrawal effects dissipated, euphoric opioid agonist effects from buprenorphine did not appear. Sublingual bupre-norphine/naloxone produced neither opioid agonist nor antagonist effects. Conclusions: Intramuscular injection of buprenorphine/naloxone precipitates withdrawal in opioid dependent persons; therefore, the combination has a low abuse potential by the injection route in this population. Sublingual buprenorphine/naloxone by tablet is well tolerated in opioid dependent subjects, and shows neither adverse effects (i.e., precipitated withdrawal) nor a high abuse potential (i.e., opioid agonist effects).
Relative bioavailability of different buprenorphine formulations under chronic dosing conditions
Drug and Alcohol Dependence, 2004
Background: Buprenorphine is an approved medication for the treatment of opioid dependence. Three sublingual formulations have been used at various times during its development-a solution containing alcohol, tablets containing buprenorphine alone, and tablets containing buprenorphine plus naloxone. This study compared the relative buprenorphine bioavailability of these different formulations. Methods: Outpatient volunteers (N = 10) were maintained for 14 days of daily administration on each formulation; the dose of buprenorphine (8 mg) was constant across formulations. Blood samples were collected and tested for buprenorphine and norbuprenorphine concentrations after 7 and 14 days maintenance on each formulation. Serial samples were collected before and for 6 h after a daily dose of each formulation. Results: Peak buprenorphine concentrations (C max ) and area under the curve (AUC) for the 6 h interval (AUC 0-6 ) were highest for the solution and lowest for buprenorphine alone tablets; values for combination tablets were more similar to those for solution. Differences between formulations were less pronounced at day 14 than day 7. There was considerable between-subject variability in concentrations produced. Conclusions: These results suggest there may be greater bioavailability of buprenorphine/naloxone versus buprenorphine alone tablets, and that the bioavailability of buprenorphine from the former is very similar to that seen with solution after 2 weeks of stabilization on each formulation.
Biological Psychiatry, 2007
Background: Buprenorphine (BUP) is effective in the treatment of opioid dependence when given on alternating days, probably as a result of long-lasting occupation of opioid receptors (ORs). This study examined the duration of action of BUP at ORs and correlations with pharmacokinetic and pharmacodynamic outcomes in 10 heroin-dependent volunteers. Methods: Availability of OR (measured with positron emission tomography and [ 11 C]-carfentanil), plasma BUP concentration, opioid withdrawal symptoms, and blockade of hydromorphone (HYD; heroin-like agonist) effects were measured at 4, 28, 52, and 76 hours after omitting the 16 mg/d dose of BUP in a study reported elsewhere. Results: Relative to heroin-dependent volunteers maintained on BUP placebo, whole-brain OR availability was 30%, 54%, 67%, and 82% at 4, 28, 52, and 76 hours after BUP. Regions of interest showed similar effects. Plasma concentrations of BUP were time dependent, as were withdrawal symptoms, carbon dioxide sensitivity and extent of HYD blockade. Availability of OR was also correlated with BUP plasma concentration, withdrawal symptoms, and HYD blockade. Conclusions: Together with our previous findings, it appears that OR availability predicts changes in pharmacokinetic and pharmacodynamic measures and that about 50%-60% BUP occupancy is required for adequate withdrawal symptom suppression (in the absence of other opioids) and HYD blockade.
Sublingual versus subcutaneous buprenorphine in opiate abusers
Clinical pharmacology and therapeutics, 1989
To compare the pharmacologic profiles of sublingually and subcutaneously administered buprenorphine, 10 healthy male subjects with histories of opiate abuse were given sublingually administered buprenorphine (1, 2, and 4 mg), subcutaneously administered buprenorphine (1 and 2 mg), and placebo in a double-blind, double-dummy, placebo-controlled study. All active buprenorphine dosages produced a significant degree of miosis but no significant changes in body temperature, blood pressure, or respiratory or heart rate. Buprenorphine produced varying degrees of euphoria related to dose and route of administration but little dysphoria and sedation, as assessed by subscales of the Addiction Research Center Inventory. Subject "liking" for buprenorphine was reported by both observers and subjects. The relative potency of sublingually to subcutaneously administered buprenorphine was calculated for both physiologic and behavioral parameters and found to be approximately two thirds. Th...