Interaction Between Paroxetine and Telaprevir

Study Overview
=================
Brief Summary
-----------------
Hepatitis C (HCV) infected patients are often in need for an antidepressant. The introduction of Direct Acting Antivirals such as telaprevir has greatly improved treatment outcome of HCV infected patients.Telaprevir has been studied with one antidepressant, escitalopram: plasma concentrations of the antidepressant were reduced by 35% and without dose adjustment this may lead to inadequate treatment of depressive symptoms. There is a need for more data on telaprevir drug interactions with other antidepressants. For a number of reasons, paroxetine may be a good candidate for use together with telaprevir-containing HCV treatment. The interaction between paroxetine and telaprevir has not been studied before.

Detailed Description
-----------------
HCV infected patients are often in need for an antidepressant. Inadequate treatment of depression during HCV treatment has a negative effect on adherence to HCV treatment, with suboptimal response as a potential result. The introduction of Direct Acting Antivirals such as telaprevir has greatly improved treatment outcome of HCV infected patients. Telaprevir, however, causes some significant drug-drug interactions and hence co-administration of other medications should preferably only be done based on clinical evidence that such a combination is safe. Telaprevir has been studied with one antidepressant, escitalopram: plasma concentrations of the antidepressant were reduced by 35% and without dose adjustment this may lead to inadequate treatment of depressive symptoms. Dose titration of escitalopram may be needed but it may take several weeks before a patient has reached a therapeutic dose. There is a need for more data on telaprevir drug interactions with other antidepressants. First, the data above show that a negative interaction occurs with escitalopram and dose-titration of the antidepressant may take too long to prevent the (re-)occurrence of depressive symptoms. Second, not all patients benefit from escitalopram and those with (prior) treatment failure on escitalopram may require an alternative agent. Third, although escitalopram is generally well-tolerated, side effects may occur and necessitate treatment discontinuation. Finally, especially in the previous intravenous drug users on methadone, escitalopram might not be the antidepressant of choice, since escitalopram as well as methadone are drugs that can lead to QTc interval prolongation and have a risk of Torsades de Pointes. For a number of reasons, paroxetine may be a good candidate for use together with telaprevir-containing HCV treatment. First, paroxetine has been shown to prevent depressive symptoms in patients initiating HCV treatment with elevated depressive symptoms at baseline. Second, paroxetine is an inhibitor of and is metabolized by CYP2D6 while telaprevir is an inhibitor of and is metabolized by CYP3A, and therefore no drug-drug interaction is expected. Third, paroxetine is one of the most widely prescribed antidepressants with a well-established efficacy and safety profile.

Official Title
-----------------
The ROLE of ParoXetine in Patients Taking Telaprevir-based Hepatitis C Therapy: Lack of a Drug-drug Interaction? (ROLEX)

Conditions
-----------------
Hepatitis C Infection, Depression

Intervention / Treatment
-----------------
* Drug: Paroxetine
* Drug: telaprevir


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject is at least 18 and not older than 65 years at screening. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations. Subject has a chronic HCV infection with genotype 1. Subject is eligible for telaprevir containing HCV treatment. Subject is on a stable dose of 20 mg paroxetine once daily for at least 4 weeks. Exclusion Criteria: Documented history of sensitivity/idiosyncrasy to medicinal products or excipients. Pregnant female (as confirmed by a human chorionic gonadotropin (HCG) test performed less than 6 weeks before Day -1) or breast-feeding female. Female subjects of childbearing potential without adequate contraception, e.g. hysterectomy, bilateral tubal ligation, (non-hormonal) intrauterine device, total abstinence, double barrier methods, or two years post-menopausal. They must agree to take precautions in order to prevent a pregnancy throughout. Relevant history or current condition that might interfere with drug absorption, distribution, metabolism or excretion. Inability to understand the nature and extent of the trial and the procedures required. Participation in a drug trial within 60 days prior to the first dose of telaprevir. Use of relevant concomitant medication, as assessed by a hospital pharmacist (member of the study team). Hemoglobin < 12 g/dL (females) or < 13 g/dL (males) (7.4 respectively 8.0 mM). Poor- or ultrarapid metabolizer CYP2D6 (based on genetic testing)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: paroxetine alone<br>paroxetine 20 mg tablet once daily oral | Drug: Paroxetine<br>* paroxetine 20 mg once daily<br>|
| Experimental: paroxetine + telaprevir<br>paroxetine 20 mg tablet once daily + telaprevir 1125 mg (3 tablets 375mg) twice daily oral | Drug: Paroxetine<br>* paroxetine 20 mg once daily<br>Drug: telaprevir<br>* telaprevir 1125 mg twice daily<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| paroxetine area under the curve (AUC) | paroxetine AUC will be compared intrasubject: day 14 + telaprevir / day -1 (without telaprevir) | day -1 and day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| paroxetine Cmax and C24 | Comparison of Cmax and C24 of paroxetine intrasubject. Day 14 (+telaprevir) / Day -1 (without telaprevir) | Day -1 and Day 14 | 
| Number of Participants with Adverse Events as a Measure of Safety and Tolerability | Adverse events will be scored during the study | Day -1 to Day 28 | 
| short term HCV RNA response | At week 4 HCV RNA will be determined | week 4 | 
| telaprevir area under the curve (AUC) | Telaprevir pharmacokinetics (PK) will be determined with paroxetine concomitant use. To be compared to historical data | Day 14 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
telaprevir, paroxetine, interaction, pharmacokinetics