Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Sun Pharmaceutical Industries Europe B.V., Polarisavenue 87, 2132 JH, Hoofddorp, The Netherlands
Pharmacotherapeutic group: Other nervous system drugs; drugs used in addictive disorders; drugs used in opioid dependence
ATC code: N07BC01
Buprenorphine is an opioid partial agonist/antagonist which attaches itself to the μ (mu) and κ (kappa) receptors of the brain. Its activity in opioid maintenance treatment is attributed to its slowly reversible link with the μ receptors which, over a prolonged period, minimises the need of the addicted patient for drugs.
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.
The absorption of buprenorphine is followed by a rapid distribution phase and a half-life of 2 to 5 hours.
Buprenorphine is oxidatively metabolised by 14-N-dealkylation to N-desalkyl-buprenorphine (also known as norbuprenorphine) via cytochrome P450 CYP3A4 and by glucuroconjugation of the parent molecule and the dealkylated metabolite. Norbuprenorphine is a μ (mu) agonist with weak intrinsic activity.
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.
Buprenorphine is essentially eliminated in the faeces by biliary excretion of the glucuroconjugated metabolites (70%), the rest being eliminated in the urine.
The effect of hepatic impairment on the pharmacokinetics of buprenorphine and naloxone were evaluated in a postmarketing study.
Table 2 summarizes the results from a clinical trial in which the exposure of buprenorphine was determined after administering a buprenorphine/naloxone sublingual tablet in healthy subjects, and in subjects with varied degrees of hepatic impairment.
Table 2. Effect of hepatic impairment on pharmacokinetic parameters of buprenorphine following buprenorphine/naloxone administration (change relative to healthy subjects):
| PK Parameter | Mild Hepatic Impairment (Child-Pugh Class A) (n=9) | Moderate Hepatic Impairment (Child-Pugh Class B) (n=8) | Severe Hepatic Impairment (Child-Pugh Class C) (n=8) |
|---|---|---|---|
| Buprenorphine | |||
| Cmax | 1.2-fold increase | 1.1-fold increase | 1.7-fold increase |
| AUClast | Similar to control | 1.6-fold increase | 2.8-fold increase |
Overall, buprenorphine plasma exposure increased approximately 3-fold in patients with severely impaired hepatic function.
Acute toxicity of buprenorphine was determined in the mouse and rat following oral and parenteral administration. The median lethal doses (LD50) in the mouse were 26, 94 and 261 mg/kg for intravenous, intraperitoneal and oral administration, respectively. The LD50 values in a rat were 35, 243 and 600 mg/kg for intravenous, intraperitoneal and oral administration, respectively.
When beagles were dosed continuously subcutaneously for one month, rhesus monkeys orally for one month and rats and baboons intramuscularly for six months, buprenorphine showed remarkably low tissue and biochemical toxicities.
From teratology studies in rats and rabbits, it was concluded that buprenorphine is not embryotoxic or teratogenic, and it does not have any marked effects on weaning potential. There were no adverse effects on fertility or general reproductive function in rats, although at the highest intramuscular dose (5mg/kg/day) the mothers experienced some difficulty in parturition and there was a high neonatal mortality.
Minimal to moderate hyperplasia of the bile duct with associated peribiliary fibrosis occurred in dogs following 52 weeks of oral dosing of 75mg/kg/day.
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