Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacodynamic group
Drugs used in opioid dependence ATC-code: N07BC01

Mechanism of action
Buprenorphine is an opioid partial agonist/antagonist which attaches itself to the µ (mu) k (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 opioid-dependent patient.

Clinical efficacy and safety
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.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Absorption
When taken orally, buprenorphine undergoes first-pass hepatic metabolism with N-dealkylation and glucuroconjungation in the small intestine. The use of this medication by oral route is therefore inappropriate.

Peak plasma concentrations are achieved 90 minutes after sublingual administration and the maximal dose- concentration relationship is linear, between 2 mg and 16 mg.

Distribution

The absorption of buprenorphine is followed by a rapid distribution phase and a half - life of 2 to 5 hours.

Biotransformation and elimination
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 µ (mu) agonist with weak intrinsic activity.

Elimination of buprenorphine is bi- or tri- exponential, with long terminal elimination phase of 20-25 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.

Hepatic Impairment

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 Suboxone 2.0/0.5mg (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)
Moderate
Mild Hepatic                           Severe Hepatic
Hepatic
Impairment                             Impairment
Impairment
PK Parameter     (Child-Pugh                            (Child-Pugh Class (Child-Pugh
Class A)                               C)
Class B)
(n=9)                                  (n=8)
(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.