Chemical formula: C₂₉H₄₁NO₄ Molecular mass: 467.64 g/mol PubChem compound: 644073
Buprenorphine is an opioid partial agonist/antagonist which binds to the μ (mu) and κ (kappa) receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible properties at the µ receptors which, over a prolonged period, minimises the need for use of other opioids.
During clinical pharmacologic studies in opioid-dependent patients, buprenorphine shows ceiling effects on a number of PD and safety parameters. It has a relatively wide therapeutic window as a consequence of its partial agonist/antagonist properties, which attenuates suppression of cardiovascular and respiratory function.
During clinical pharmacologic studies in opiate-dependent subjects, buprenorphine demonstrated a ceiling effect on a number of parameters, including positive mood, “good effect” and respiratory depression.
When taken orally, buprenorphine undergoes first-pass hepatic metabolism with N-dealkylation and glucuroconjugation in the small intestine. N-dealkylation and glucuroconjugation also take place in the liver. The use of this medicinal product by the oral route is therefore inappropriate.
Peak plasma concentrations are achieved 90 minutes after sublingual administration and the maximal dose-concentration relationship is linear, between 2mg and 16mg.
After injection, the buprenorphine plasma concentration increases with a median time to maximum plasma concentration (tmax) of about 24 hours. Buprenorphine has complete absolute bioavailability. Steady-state exposure is reached at the fourth weekly dose. Dose-proportional increases in exposure are observed in the dose interval 8 mg to 32 mg.
After buprenorphine implant insertion, an initial buprenorphine peak was observed and the median Tmax occurred at 12 hours after insertion. After the initial buprenorphine peak, the plasma buprenorphine concentrations decreased slowly and steady-state plasma buprenorphine concentrations were reached by approximately week 4. Mean steady-state plasma buprenorphine concentrations were consistent across all clinical studies, at approximately 0.5 to 1 ng/mL (with the 4-implant dose), and were maintained for approximately 20 weeks (week 4 through week 24) in a 24-week treatment period. At steady state, a small decrease in buprenorphine concentrations was also recorded between week 4 and week 24. Generally, concentrations were comparable to the trough buprenorphine concentration of 8 mg per day sublingual buprenorphine.
The absorption of buprenorphine is followed by a rapid distribution phase and a half-life of 2 to 5 hours.
After injection, the apparent volume of distribution for buprenorphine is approximately 1900 L.
Buprenorphine is approximately 96% protein-bound, primarily to alpha and beta globulin.
Buprenorphine is oxidatively metabolised by 14-N-dealkylation to N-desalkyl-buprenorphine (also known as norbuprenorphine) via cytochrome P450 CYP3A4 and by glucuroconjungation of the parent molecule and the dealkylated metabolite. Norbuprenorphine is a µ-opioid agonist with weak intrinsic activity.
Subcutaneous administration of buprenorphine results in significantly lower plasma concentrations of norbuprenorphine metabolite compared to administration of sublingual buprenorphine, due to avoidance of first-pass metabolism.
Elimination of buprenorphine is bi- or tri- exponential, with a long terminal elimination phase of 20 to 25 hours, due in part to reabsorption of buprenorphine after intestinal hydrolysis of the conjugated derivative, and in part to the highly lipophilic nature of the molecule.
Elimination of buprenorphine is release-rate limited with a terminal half-life ranging from 3 to 5 days.
Buprenorphine is primarily eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites (70%), the remainder being eliminated in the urine. Total clearance of buprenorphine is approximately 68 L/h.
Clinical studies of buprenorphine did not include patients over 65 years; therefore, the use of the product in this population is not recommended. The efficacy and safety of buprenorphine in elderly patients >65 years has not been established.
Renal elimination plays a relatively small role (approximately 30%) in the overall clearance of buprenorphine and buprenorphine plasma concentrations were not increased in patients with renal impairment. No buprenorphine dose adjustment is therefore considered necessary for patients with renal impairment.
The effect of hepatic impairment on the pharmacokinetics of buprenorphine has not been studied. Buprenorphine is extensively metabolized in the liver and increased plasma levels were found to be increased in patients with moderate and severe hepatic impairment. Buprenorphine is contraindicated in patients with severe hepatic impairment.
Overall, buprenorphine plasma exposure increased approximately 3-fold in subjects with severely impaired hepatic function.
No pharmacokinetic data in paediatrics (less than 18 years) are available. Simulated buprenorphine exposure data in adolescents aged 16 years show lower Cmax and AUC compared to observed values in adults for weekly and monthly buprenorphine administration.
No effect on fertility or general reproductive performance was observed in rats treated with buprenorphine. In embryofoetal developmental toxicity studies conducted in rats and rabbits using buprenorphine, no embryofoetal toxicity effects were observed. In a rat pre- and post-natal developmental toxicity study with buprenorphine there was pup mortality, decreased pup body weight and concomitant maternal reduced food consumption and clinical signs.
A standard battery of genotoxicity tests indicated that buprenorphine is non-genotoxic.
In long-term studies in rats and mice there was no evidence of any carcinogenic potential relevant for humans.
In single- and repeat-dose toxicity studies in rats, rabbits, guinea pigs, dogs and minipigs, buprenorphine transdermal patch caused minimal or no adverse systemic events, whereas skin irritation was observed in all species examined. Toxicological data available did not indicate a sensitising potential of the additives of the transdermal patches.
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