Effects of Rifampicin on the Pharmacokinetics and Pharmacodynamics of Sublingual and Intravenous Buprenorphine
Effects of Rifampicin on the Pharmacokinetics and Pharmacodynamics of Sublingual and Intravenous Buprenorphine: A Four-phase Cross-over Study in Healthy Subjects.
調査の概要
詳細な説明
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.
研究の種類
入学 (実際)
段階
- フェーズ 4
連絡先と場所
研究場所
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Turku、フィンランド、20500
- Turku University Hospital
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria:
- non-smoking
- aged 18-40 years
- body weights within ±15% of the ideal weight for height
Exclusion Criteria
- A previous history of intolerance to the study drugs or to related compounds and additives.
- Concomitant drug therapy of any kind for at least 14 days prior to the study.
- Subjects younger than 18 years and older than 40 years.
- Existing or recent significant disease.
- History of hematological, endocrine, metabolic or gastrointestinal disease, including gut motility disorders.
- History of asthma or any kind of drug allergy.
- Previous or present alcoholism, drug abuse, psychological or other emotional problems that are likely to invalidate informed consent, or limit the ability of the subject to comply with the protocol requirements.
- A positive test result for urine toxicology.
- A "yes" answer to any one of the Abuse Questions.
- Pregnancy or nursing.
- Donation of blood for 4 weeks prior and during the study.
- Special diet or life style conditions which would compromise the conditions of the study or interpretation of the results.
- Participation in any other studies involving investigational or marketed drug products concomitantly or within one month prior to the entry into this study.
- Smoking for one month before the start of the study and during the whole study period.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：基礎科学
- 割り当て：ランダム化
- 介入モデル：クロスオーバー割り当て
- マスキング：独身
武器と介入
参加者グループ / アーム |
介入・治療 |
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アクティブコンパレータ：Rifampicin
The volunteers will be given oral rifampicin (Rimapen, Orion, Finland) 600 mg as a single daily dose at 20.00 for 7 days
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The volunteers will be given oral rifampicin (Rimapen, Orion, Finland) 600 mg as a single daily dose at 20.00 for 7 days
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プラセボコンパレーター：Placebo
The volunteers will be given oral placebo at 20.00 for 7 days
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The volunteers will be given Oral placebo at 20.00 for 7 days [Phase 1 ]
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アクティブコンパレータ：Buprenorphine
The volunteers will be given single dose of 0,4 mg intra venous buprenorphine or 0,6 mg sublingual buprenorphine on day 5.
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The volunteers will be given single dose of 0,4 mg intra venous buprenorphine or 0,6 mg sublingual buprenorphine on day 5.
他の名前：
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
時間枠 |
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Concentration of buprenorphine and its metabolites in plasma and urine concebtration of buprenorphine
時間枠：0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 and 20 hours after administration of buprenorphine
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0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 and 20 hours after administration of buprenorphine
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Pharmacodynamic effects
時間枠：1, 2,3, 4, 5, 6, 8, 10, 12, 20 hours after administration of buprenorphine
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The psychomotor effects on bubrenorphine will be assessed with the measurement of pupil size, Maddox wing test and symbol substitution test.
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1, 2,3, 4, 5, 6, 8, 10, 12, 20 hours after administration of buprenorphine
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Analgesia
時間枠：1, 2, 3, 4, 5, 6, 8, 10, 12 hours after the administration of buprenorphine
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The analgesic effect of buprenorphine will be evaluated using the cold pressor test.
The cold pain test has been shown to be sensitive to opioid analgesia, and it enables repeated assessments of cold pain threshold, tolerance, intensity and unpleasantness
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1, 2, 3, 4, 5, 6, 8, 10, 12 hours after the administration of buprenorphine
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協力者と研究者
研究記録日
主要日程の研究
研究開始
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (見積もり)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
キーワード
追加の関連 MeSH 用語
その他の研究ID番号
- Rifabupre
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