Simplified processing and rapid quantification of buprenorphine, norbuprenorphine, and their conjugated metabolites in human plasma using UPLC-MS/MS: Assessment of buprenorphine exposure during opioid use disorder treatment.

Opioid use disorder (OUD) is a chronic neurobehavioral ailment and is prevalent in pregnancy. OUD is commonly treated with methadone or buprenorphine (BUP). Pregnancy is known to alter the pharmacokinetics of drugs and may lead to changes in drug exposure and response. A simple, specific, and sensitive analytical method for measuring the parent drug and its metabolites is valuable for assessing the impact of pregnancy on drug exposure. A new liquid chromatography-tandem mass spectrometric method that utilized a simple protein precipitation procedure for sample preparation and four deuterated internal standards for quantification was developed and validated for BUP and its major metabolites (norbuprenorphine [NBUP], buprenorphine-glucuronide [BUP-G], and norbuprenorphine-glucuronide [NBUP-G]) in human plasma. The standard curve was linear over the concentration range of 0.05-100 ng/mL for BUP and NBUP, and 0.1-200 ng/mL for BUP-G and NBUP-G. Intra- and inter-day bias and precision were within ±15% of nominal values for all the analytes. Quality controls assessed at four levels showed high recovery consistently for all the analytes with minimal matrix effect. Adequate analyte stability was observed at various laboratory conditions tested. Overall, the developed method is simple, sensitive, accurate and reproducible, and was successfully applied for the quantification of BUP and its metabolites in plasma samples collected from pregnant women in a clinical study assessing BUP exposure during OUD treatment.

Assessment of drug-drug interactions between daclatasvir and methadone or buprenorphine-naloxone.

Hepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in non-HCV-infected subjects receiving methadone (40 to 120 mg; n = 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg; n = 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCτ) or maximum concentration in plasma (C max) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R- and S-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCτ for R-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24), S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUCτ was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized C max for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments.

[The financial impact of maintenance treatment in heroin addictive behavior: the case of Subutex]. / Les enjeux financiers des traitements de substitution dans l'héroïnomanie: le cas de Subutex.

BACKGROUND: The development of maintenance treatment for subjects with addictive behavior is an important public health issue. As such, the social effectiveness of maintenance products must be examined from an economical and social point of view. This paper aims at presenting the financial costs involved in the use of Subutex, a product commercialized since 1996. METHODS: A complete typology of costs related to drug addiction and its consequences was set up. Some of these costs were estimated on the basis of data drawn from the literature. The cost of Subutex use for maintenance treatment was assessed and compared with the financial stakes including the potential reduction of the economic and social cost of drug addiction. RESULTS: Monthly treatment cost of Subutex was 1252 FrF per drug abuser on maintenance treatment. By extrapolation, for a population of 40,000 drug abusers, the direct medical cost of Subutex during a course of maintenance treatment with general practitioner follow-up was estimated at 600 millions FrF. US data sources were applied to France to assess the cost of illnesses attributable to drug addiction. The cost reached 4.8 billions FrF. The cost of delinquency associated with drug addiction, which mostly concerns money laundered to purchase substances was an estimated 6.4 billions FrF. Finally, the cost of public anti-drug abuse programs was nearly 4.7 billions FrF. Thus, the direct cost of drug addiction consequences reached 15.6 billions FrF. This cost should be compared with the annual cost of Subutex for public organizations which was an estimated 600 millions FrF. CONCLUSIONS: The "profit" threshold of maintenance treatment with Subutex in terms of direct costs is very low. A decrease of only 4% of the costs associated with drug addiction would make it possible to balance the financial budget for the community. Our analysis does not take into acount absolutely all the public health and safety aspects involved in the use of Subutex. It does however provide a useful assessment of the financial aspects of the question and justification for this therapeutic strategy from a budgetary point of view.