Boceprevir and Ucalm (St John's Wort)
The purpose of the study is to look at whether taking a new medication for hepatitis C (boceprevir) together with a herbal remedy commonly used for the treatment of depression (SJW) has any effect on the levels of boceprevir in the blood, compared to when boceprevir is taken on its own.
Treatment of hepatitis C genotype one, a specific common type of hepatitis C, has recently been revolutionised with the addition of a new class of drugs called protease inhibitors (PIs). Boceprevir belongs to this class of antiviral drugs and it is administered in combinations with other drugs to treat hepatitis C. One of the common side effects of treatment for hepatitis C is low mood (depression).
SJW is known to cause drug interactions, so taking SJW at the same time as boceprevir may result in a change in how both of these drugs usually work. It is therefore important to find out if the levels of boceprevir in the blood are significantly affected by taking SJW.
The study aims to help us understand whether it will be safe to take SJW whilst being simultaneously treated for hepatitis C with boceprevir.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Primary Purpose: Prevention
|Official Title:||Phase I Evaluation of the Pharmacokinetics and Safety of Boceprevir and Ucalm (St John's Wort) When Co-administered to Male and Female Healthy Volunteers.|
- Pharmacokinetics of boceprevir in the presence of Ucalm (St John's Wort) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
Pharmacokinetic parameters of boceprevir and SJW will be evaluated when given in combination at steady-state to evaluate possible differences in concentrations during co-administration versus drug given alone.
The pharmacokinetic parameters calculated for boceprevir and SJW will be Ctrough,the maximum observed plasma concentration (Cmax), time point at Cmax (Tmax), and total drug exposure, expressed as the area under the plasma concentration-time curve All pharmacokinetic parameters will be calculated using non-compartmental modelling techniques (WinNonlin®) and all statistical calculations performed Within-participant changes in the assessed pharmacokinetic parameters (drug alone vs drug combination) will be evaluated by calculating geometric
- Safety and tolerability of the co-administration of Ucalm (St John's Wort) and boceprevir [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
Safety and tolerability of medications will also be assessed by questions, physical examination and laboratory parameters. These will be performed at regular intervals during the drug study.
All safety data and adverse events will be summarised
- Genetic polymorphisms [ Time Frame: 6 months ] [ Designated as safety issue: No ]To investigate the association between genetic polymorphisms in drug disposition genes and drug exposure
|Study Start Date:||August 2012|
|Study Completion Date:||December 2012|
|Primary Completion Date:||December 2012 (Final data collection date for primary outcome measure)|
|Experimental: Group A||Drug: St John's Wort first|
|Experimental: Group B||Drug: Boceprevir first|
Boceprevir is a strong inhibitor of CYP3A4/5. Medicines metabolized primarily by CYP3A4/5 may have increased exposure when administered with boceprevir, which could increase or prolong their therapeutic and adverse reactions. Boceprevir does not inhibit or induce the other enzymes of the CYP450 family.
Boceprevir has been shown to be a P-glycoprotein and breast cancer resistant protein (BCRP) substrate in vitro. There is potential for inhibitors/inducers of these transporters to alter the concentrations of boceprevir; the clinical implications of these interactions are not known.Boceprevir is partly metabolized by CYP3A4/5. Co-administration of boceprevir with medicines that induce or inhibit CYP3A4/5 could increase or decrease exposure to boceprevir and affect its efficacy.Boceprevir, in combination with peginterferon and ribavirin, is contraindicated when coadministered with medicines that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma concentrations are associated with serious and/or lifethreatening events such as orally administered midazolam and triazolam, bepridil, pimozide, lumefantrine, halofantrine, and tyrosine kinase inhibitors, and ergot derivatives(dihydroergotamine, ergonovine, ergotamine, methylergonovine).
Boceprevir is primarily metabolized by aldoketo reductase (AKR). In medicine interaction trials conducted with AKR inhibitors diflunisal and ibuprofen, boceprevir exposure did notincrease to a clinically significant extent. Boceprevir may be co-administered with AKR inhibitors. The concomitant use of boceprevir with stong CYP3A4 inducers such as rifampicin or anticonvulsants (such as phenytoin, phenobarbital or carbamazepine) may significantly reduce the plasma exposure of boceprevir. As no data is available, the combination of boceprevir with these medicines is not recommended.
The metabolism of St John's Wort is not currently known. Treatment with St John's wort for 14 days resulted in significant increases in the urinary 6-beta-hydroxycortisol/cortisol ratio, suggesting that St John's wort is an inducer of CYP3A4. For this reason, it is notrecommended to administer SJW with CYP3A4 metabolized drugs. Furthermore,interactions may occur with P-glycoprotein substrates, as St. John's wort can induce the activity of transmembrane transporters. This might decrease the effectiveness of some medications.
For the reasons illustrated above, the potential for a drug interaction between SJW and boceprevir is high and the co-administration must be studied in order to gain information on whether: i) SJW leads to a decrease in boceprevir concentrations and therefore efficacy; ii) boceprevir leads to an increase in SJW (hyperacin) exposure with risk of toxicity.
The safety and PK of the combination should be known especially in view of the common side effects caused by interferon, which is co-administered with boceprevir for the treatment of hepatitis C: as interferon causes depression, patients may chose to take SJW rather than prescribed anti-depressants to manage their mood changes during antihepatitis treatment.