Buprenorphine is protective against the depressive effects of norbuprenorphine on ventilation

Mégarbane, Bruno; Marie, Nicolas; Pirnay, Stéphane; Borron, Stephen W.; Guèye, Papa; Risède, Patricia; Monier, Claire; Noble, Florence; Baud, Frédéric J.

doi:10.1016/j.taap.2005.08.002

Cited by 57 publications

(54 citation statements)

References 33 publications

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“…Evidently, buprenorphine and norbuprenorphine differ in their in vivo -opioid receptor association-dissociation kinetics. This is consistent with results from in vitro binding studies, which show that norbuprenorphine binding to the -opioid receptor is more rapid and reversible compared with buprenorphine (Megarbane et al, 2006).…”

Section: Discussionsupporting

confidence: 90%

Pharmacokinetic-Pharmacodynamic Modeling of the Respiratory Depressant Effect of Norbuprenorphine in Rats

Yassen¹,

Kan²,

Olofsen³

et al. 2007

J Pharmacol Exp Ther

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The objective of this investigation was to characterize the pharmacokinetic-pharmacodynamic (PK-PD) correlation of buprenorphine's active metabolite norbuprenorphine for the effect on respiration in rats. Following i.v. administration in rats (dose range 0.32-1.848 mg), the time course of the concentration in plasma was determined in conjunction with the effect in ventilation as determined with a novel whole-body plethysmography technique. The PK of norbuprenorphine was best described by a three-compartment PK model with nonlinear elimination. A saturable biophase distribution model with a power PD model described the PK-PD relationship best. No saturation of the effect at high concentrations was observed, indicating that norbuprenorphine acts as a full agonist with regard to respiratory depression. Moreover, analysis of the hysteresis based on the combined receptor association-dissociation biophase distribution model yielded high values of the rate constants for receptor association and dissociation, indicating that these processes are not rate-limiting. In a separate analysis, the time course of the plasma concentrations of buprenorphine and norbuprenorphine following administration of both the parent drug and the metabolite were simultaneously analyzed based on a six-compartment PK model with nonlinear elimination of norbuprenorphine. This analysis showed that following i.v. administration, 10% of the administered dose of buprenorphine is converted into norbuprenorphine. By simulation it is shown that following i.v. administration of buprenorphine, the concentrations of norbuprenorphine reach values that are well below the values causing an effect on respiration.Recently, the pharmacokinetic-pharmacodynamic (PK-PD) relationship of buprenorphine for the effect on the respiratory response has been studied in rats and humans (Yassen et al., 2007). In these investigations, buprenorphine has been shown to display ceiling of the respiratory depressant effect, indicating that buprenorphine acts functionally as a partial agonist at the -opioid receptor. The in vivo behavior correlates well with data obtained from in vitro receptor binding assays (Martin et al., 1976;Lee et al., 1999;Lutfy et al., 2003). Clearly, partial agonistic activity for respiratory depression contributes to the safety profile on buprenorphine administration even at high doses .In the previous investigations, the observed hysteresis between plasma concentration and effect has in part been explained by slow receptor association and dissociation kinetics at the -opioid receptor. This pharmacological characteristic is unique for buprenorphine and is not shared by other opiates like morphine and fentanyl (Cowan et al., 1977;Boas and Villiger, 1985). The slow receptor association-dissociation kinetics may be a complicating factor in the reversal of buprenorphine-induced respiratory depression with naloxone. Furthermore, buprenorphine was shown to bind with high affinity to the -opioid receptor. Specifically, the estimate of the equilibrium d...

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Section: Discussionsupporting

confidence: 90%

Pharmacokinetic-Pharmacodynamic Modeling of the Respiratory Depressant Effect of Norbuprenorphine in Rats

Yassen¹,

Kan²,

Olofsen³

et al. 2007

J Pharmacol Exp Ther

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“…This increase does not appear to be clinically significant. Both BUP and norBUP are pharmacologically active but possess a number of differing receptor specificities and pharmacological properties in cell culture and animal models that are not well studied at the clinical level and that render it difficult to establish their relative contributions to stable maintenance (36)(37)(38)(39)(40). MET, BUP, and NLX are not potent inhibitors or inducers of CYP3A4, and as would be anticipated, DCV exposure parameters in both parts of the study were similar to historical values for healthy volunteers.…”

Section: Discussionmentioning

confidence: 99%

Assessment of Drug-Drug Interactions between Daclatasvir and Methadone or Buprenorphine-Naloxone

Garimella

Wang

Luo

et al. 2015

Antimicrob Agents Chemother

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cHepatitis 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 (AUC) 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 AUC 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 AUC 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.

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“…This is potentially interesting as norbuprenorphine is a more potent respiratory depressant (compared with buprenorphine itself). Indeed buprenorphine is, in animal studies at least, actually protective against the respiratory depressant effect of norbuprenorphine [27]. Will high plasma buprenorphine levels in conjunction with low norbuprenorphine levels be the desired relationship?…”

Section: Discussionmentioning

confidence: 99%

Randomised Comparison of a Novel Buprenorphine Oral Lyophilisate versus Existing Buprenorphine Sublingual Tablets in Opioid-Dependent Patients: A First-in-Patient Phase II Randomised Open Label Safety Study

et al. 2017

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Aims: To test the safety of new buprenorphine oral lyophilisate wafer (“bup-lyo”) versus standard sub-lingual buprenorphine (“bup-SL”). Design: Randomised (2:1) open-label study; opioid-dependent subjects; subsequent partial cross-over. Settings: Specialised clinical trials facility and addictions treatment facility. Participants: Opioid-dependent subjects (n = 36) commencing buprenorphine maintenance (personalised dose-titration) including patients co-using alcohol, cocaine and benzodiazepines (below thresholds). Measurements: Respiratory function (respiratory rate, pulse-oximetry); medication hold and dose adequacy; opiate withdrawal signs and symptoms; tablet disintegration times; treatment retention. Pharmacokinetics (PK) for plasma buprenorphine and norbuprenorphine (n = 11). Findings: Oral lyophilised buprenorphine (“bup-lyo”) completely dissolved within 2 min for 58 vs. 5% for “bup-SL.” Dose titration resulted in similar maintenance dosing (10.8 vs. 9.6 mg). There were no significant between-group differences in opiate-withdrawal phenomena, craving, adequacy of “hold,” respiratory function. No serious adverse events (AEs), nor “severe” AEs, although more AEs and Treatment-Emergent AEs with “bup-lyo” (mostly “mild”). PK found greater bioavailability of buprenorphine with “bup-lyo” (but not norbuprenorphine). Conclusions: Orally disintegrating buprenorphine oral lyophilisate wafer disintegrated rapidly. No increased respiratory depression was found and clinically no difference between medications was observed. PK found substantially increased bioavailability of buprenorphine (but not of nor-buprenorphine) with “bup-lyo” relative to “bup-SL.” In supervised dosing contexts, rapidly disintegrating formulations may enable wider buprenorphine prescribing.

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Buprenorphine is protective against the depressive effects of norbuprenorphine on ventilation

Cited by 57 publications

References 33 publications

Pharmacokinetic-Pharmacodynamic Modeling of the Respiratory Depressant Effect of Norbuprenorphine in Rats

Pharmacokinetic-Pharmacodynamic Modeling of the Respiratory Depressant Effect of Norbuprenorphine in Rats

Assessment of Drug-Drug Interactions between Daclatasvir and Methadone or Buprenorphine-Naloxone

Randomised Comparison of a Novel Buprenorphine Oral Lyophilisate versus Existing Buprenorphine Sublingual Tablets in Opioid-Dependent Patients: A First-in-Patient Phase II Randomised Open Label Safety Study

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