Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1. Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics, opioids; ATC code: N02 AE01

Buprenorphine is an agonist opioid, acting at the mu opioid receptor. It also has antagonistic activity at the kappa opioid receptor.
Efficacy has been demonstrated in seven pivotal phase III studies of up to 12 weeks duration in patients with non-malignant pain of various aetiologies. These included patients with moderate and severe OA and back pain. BuTrans demonstrated clinically significant reductions in pain scores (approximately 3 points on the BS-11 scale) and significantly greater pain control compared with placebo.

A long term, open-label extension study (n=384) has also been performed in patients with non-malignant pain. With chronic dosing, 63% of patients were maintained in pain control for 6 months, 39% of patients for 12 months, 13% of patients for 18 months and 6% for 21 months. Approximately 17% were stabilised on the 5 mg dose, 35% on the 10 mg dose and 48% on the 20 mg dose.

Pharmacokinetic Properties

5.2. Pharmacokinetic properties
There is evidence of enterohepatic recirculation.

Studies in non-pregnant and pregnant rats have shown that buprenorphine passes the blood-brain and placental barriers. Concentrations in the brain (which contained only unchanged buprenorphine) after parenteral administration were 2-3 times higher than after oral administration. After intramuscular or oral administration buprenorphine apparently accumulates in the foetal gastrointestinal lumen – presumably due to biliary excretion, as enterohepatic circulation has not fully developed.

Each patch provides a steady delivery of buprenorphine for up to seven days. Steady state is achieved during the first application. After removal of BuTrans, buprenorphine concentrations initially decline at a rate of approximately 50% in 12 hours. Thereafter, mean elimination half-lives have been reported to be between 30 and 45 hours.

Absorption:
Following BuTrans application, buprenorphine diffuses from the patch through the skin. In clinical pharmacology studies, the median time for BuTrans 10 μg/h to deliver detectable buprenorphine concentrations (25 picograms/ml) was approximately 17 hours. Analysis of residual buprenorphine in patches after 7-day use shows 15% of the original load delivered. A study of bioavailability, relative to intravenous administration, confirms that this amount is systemically absorbed. Buprenorphine concentrations remain relatively constant during the 7-day patch application.

Application site:
A study in healthy subjects demonstrated that the pharmacokinetic profile of buprenorphine delivered by BuTrans is similar when applied to upper outer arm, upper chest, upper back or the side of the chest (midaxillary line, 5th intercostal space). The absorption varies to some extent depending on the application site and the exposure is at the most approximately 26 % higher when applied to the upper back compared to the side of the chest.

In a study of healthy subjects receiving BuTrans repeatedly to the same site, an almost doubled exposure was seen with a 14 day rest period. For this reason, rotation of application sites is recommended, and a new patch should not be applied to the same skin site for 3-4 weeks.

In a study of healthy subjects, application of a heating pad directly on the transdermal patch caused a transient 26 - 55% increase in blood concentrations of buprenorphine. Concentrations returned to normal within 5 hours after the heat was removed. For this reason, applying direct heat sources such as hot water bottles, heat pads or electric blankets directly to the patch is not recommended. A heating pad applied to a BuTrans site immediately after patch removal did not alter absorption from the skin depot.

Distribution:
Buprenorphine is approximately 96% bound to plasma proteins.
Studies of intravenous buprenorphine have shown a large volume of distribution, implying extensive distribution of buprenorphine. In a study of intravenous buprenorphine in healthy subjects, the volume of distribution at steady state was 430 L, reflecting the large volume of distribution and lipophilicity of the active substance.
Following intravenous administration, buprenorphine and its metabolites are secreted into bile, and within several minutes, distributed into the cerebrospinal fluid. Buprenorphine concentrations in the cerebrospinal fluid appear to be approximately 15% to 25% of concurrent plasma concentrations.

Biotransformation and elimination:
Buprenorphine metabolism in the skin following BuTrans application is negligible. Following transdermal application, buprenorphine is eliminated via hepatic metabolism, with subsequent biliary excretion and renal excretion of soluble metabolites. Hepatic metabolism, through CYP3A4 and UGT1A1/1A3 enzymes, results in two primary metabolites, norbuprenorphine and buprenorphine 3-O-glucuronide, respectively.
Norbuprenorphine is glucuronidated before elimination. Buprenorphine is also eliminated in the faeces. In a study in post-operative patients, the total elimination of buprenorphine was shown to be approximately 55L /h.

Norbuprenorphine is the only known active metabolite of buprenorphine.

Effect of buprenorphine on the pharmacokinetics of other active substances: Based on in vitro studies in human microsomes and hepatocytes, buprenorphine does not have the potential to inhibit metabolism catalysed by the CYP450 enzymes CYP1A2, CYP2A6 and CYP3A4 at concentrations obtained with use of BuTrans 20 µg/h transdermal patch. The effect on metabolism catalysed by CYP2C8, CYP2C9 and CYP2C19 has not been studied.