Healthy Clinical Trial
Official title:
Effects of Rifampicin on the Pharmacokinetics and Pharmacodynamics of Sublingual and Intravenous Buprenorphine: A Four-phase Cross-over Study in Healthy Subjects.
This study is aimed to examine the possible interactions of sublingual and intravenous buprenorphine with rifampicin.
Variability in drug response can be due to either pharmacokinetic or pharmacodynamic
factors. The reasons why people differ in pharmacokinetics or pharmacodynamics are manifold
and include, e.g., genetic factors, diseases, age and concomitantly administered drugs.
Oxidation reactions are dominant in the metabolism of drugs and cytochrome P-450 enzymes
(CYP) have been recognized as chief contributors. We have previously shown that drug
interactions mediated by the inhibition of CYP enzymes may be of major clinical
significance.Buprenorphine is a semisynthetic partial µ-opioid receptor agonist. In low
doses, it is used in the treatment of moderate acute and chronic pain whereas in high doses,
it is used in the management of opioid withdrawal symptoms and opioid addiction. It has high
affinity for the µ-opioid receptor and its analgesic efficacy is 20-40 times that of
morphine. It acts as an antagonist at the myy-opioid receptor and as an agonist at the
myy-opioid receptor and opioid-like receptor (ORL-1).
Buprenorphine undergoes extensive first-pass metabolism and has low oral bioavailability of
15 %. Bioavailability following sublingual administration of buprenorphine is higher, 50-60
%. After high sublingual doses of buprenorphine (8-24 mg), peak plasma concentrations are
reached in 1 hour and after low sublingual doses (0.4 mg) they are reached in approximately
3 h. Approximately two-thirds of a buprenorphine dose is excreted unchanged, and the rest is
metabolized in the liver and intestinal wall. N-dealkylation of buprenorphine mainly via
CYP3A but also CYP2C8 yields norbuprenorphine, and glucuronidation yields
buprenorphine-3-glucuronide. Norbuprenorphine is excreted in the urine after subsequent
conjugation. 80-90 % of buprenorphine is excreted by the biliary system and enterohepatic
circulation.Although few interaction studies of high-dose buprenorphine and antiretrovirals
have been conducted, the effect of CYP3A inducers on the pharmacokinetics of low-dose
buprenorphine is unknown. Because the use of buprenorphine in pain management is increasing
after the introduction of transdermal buprenorphin patches to the market, it is clinically
relevant to study and quantify possible interactions of buprenorphine with inducers of its
CYP3A-mediated metabolism such as rifampicin.
;
Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Basic Science
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