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.
Panoramica dello studio
Stato
Condizioni
Intervento / Trattamento
Descrizione dettagliata
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.
Tipo di studio
Iscrizione (Effettivo)
Fase
- Fase 4
Contatti e Sedi
Luoghi di studio
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Turku, Finlandia, 20500
- Turku University Hospital
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Criteri di partecipazione
Criteri di ammissibilità
Età idonea allo studio
Accetta volontari sani
Sessi ammissibili allo studio
Descrizione
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.
Piano di studio
Come è strutturato lo studio?
Dettagli di progettazione
- Scopo principale: Scienza basilare
- Assegnazione: Randomizzato
- Modello interventistico: Assegnazione incrociata
- Mascheramento: Separare
Armi e interventi
Gruppo di partecipanti / Arm |
Intervento / Trattamento |
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Comparatore attivo: 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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Comparatore placebo: 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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Comparatore attivo: 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.
Altri nomi:
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Cosa sta misurando lo studio?
Misure di risultato primarie
Misura del risultato |
Lasso di tempo |
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Concentration of buprenorphine and its metabolites in plasma and urine concebtration of buprenorphine
Lasso di tempo: 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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Misure di risultato secondarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
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Pharmacodynamic effects
Lasso di tempo: 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
Lasso di tempo: 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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Collaboratori e investigatori
Sponsor
Studiare le date dei record
Studia le date principali
Inizio studio
Completamento primario (Effettivo)
Completamento dello studio (Effettivo)
Date di iscrizione allo studio
Primo inviato
Primo inviato che soddisfa i criteri di controllo qualità
Primo Inserito (Stima)
Aggiornamenti dei record di studio
Ultimo aggiornamento pubblicato (Stima)
Ultimo aggiornamento inviato che soddisfa i criteri QC
Ultimo verificato
Maggiori informazioni
Termini relativi a questo studio
Parole chiave
Termini MeSH pertinenti aggiuntivi
- Effetti fisiologici delle droghe
- Meccanismi molecolari dell'azione farmacologica
- Agenti antinfettivi
- Depressori del sistema nervoso centrale
- Agenti del sistema nervoso periferico
- Inibitori della sintesi degli acidi nucleici
- Inibitori enzimatici
- Analgesici
- Agenti del sistema sensoriale
- Agenti antibatterici
- Analgesici, oppioidi
- Narcotici
- Antagonisti narcotici
- Agenti leprostatici
- Induttori enzimatici del citocromo P-450
- Induttori del citocromo P-450 CYP3A
- Agenti antitubercolari
- Antibiotici, Antitubercolari
- Induttori del citocromo P-450 CYP2B6
- Induttori del citocromo P-450 CYP2C8
- Induttori del citocromo P-450 CYP2C19
- Induttori del citocromo P-450 CYP2C9
- Buprenorfina
- Rifampicina
Altri numeri di identificazione dello studio
- Rifabupre
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