Pharmacokinetic Drug-drug Interaction Study Between RaltEgravir and CITALopram in Healthy Subjects (RECITAL).

Study Overview
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Brief Summary
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Depression is the most common mental health disorder among HIV-patients. Recognizing and treating depression is important in order to improve quality of life and health outcomes in those living with HIV. In clinical practice selective serotonin reuptake inhibitors (SSRIs) are used most frequently in HIV patients with depressive symptoms. A complicating factor in the concomitant use of antiretroviral agents and antidepressant therapy is the occurrence of drug-drug interactions. Citalopram can be seen as one of the preferred SSRIs in HIV-infected patients because citalopram has a relatively favourable drug interaction profile compared to other SSRIs. Raltegravir is an HIV-1 integrase inhibitor and is frequently being used as antiretroviral agent in combination with tenofovir/emtricitabine in HIV-patients. Raltegravir has shown sustained antiretroviral activity, is generally well tolerated and has little propensity to interact with other drugs because it does not inhibit or induce CYP450 enzymes. Theoretically, no clinically relevant drug interaction is expected between raltegravir and citalopram as raltegravir is not a CYP2D6 substrate and thus will not be affected by the possible inhibition of CYP2D6 by citalopram. Raltegravir is metabolized by UGT but citalopram is not known to influence UGT. A possible interaction may occur through inhibition of P-gp mediated transport of raltegravir by citalopram. However, even when no drug interaction is expected theoretically, it may be recommended to collect sufficient clinical evidence to support this hypothesis because unexpected interactions with raltegravir have been observed in the past. In order to be able to recommend raltegravir and citalopram concomitant use, a pharmacokinetic study in healthy volunteers is proposed.

Official Title
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Pharmacokinetic Drug-drug Interaction Study Between RaltEgravir and CITALopram in Healthy Subjects (RECITAL).

Conditions
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HIV, Depression

Intervention / Treatment
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* Drug: raltegravir
* Drug: citalopram


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is at least 18 and not older than 55 years at screening. Subject does not smoke more than 10 cigarettes, 2 cigars, or 2 pipes per day for at least 3 months prior to Day 1. Subject has a Quetelet Index (Body Mass Index) of 18 to 30 kg/m2, extremes included. Subject is able and willing to sign the Informed Consent Form prior to screening evaluations. Subject is in good age-appropriate health condition as established by medical history, physical examination, electrocardiography, results of biochemistry, haematology and urinalysis testing within 4 weeks prior to Day 1. Results of biochemistry, haematology and urinalysis testing should be within the laboratory's reference ranges. If laboratory results are not within the reference ranges, the subject is included on condition that the Investigator judges that the deviations are not clinically relevant. This should be clearly recorded. Subject has a normal blood pressure and pulse rate, according to the Investigator's judgement. Exclusion Criteria: Documented history of sensitivity/idiosyncrasy to medicinal products or excipients. Positive HIV test. Positive hepatitis B or C test. Pregnant female (as confirmed by an hCG test performed less than 4 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 the entire conduct of the study. Therapy with any drug (for two weeks preceding Day 1), except for acetaminophen. Relevant history or presence of pulmonary disorders (especially COPD), cardiovascular disorders, neurological disorders (especially seizures and migraine), psychiatric disorders, gastro-intestinal disorders, renal and hepatic disorders, hormonal disorders (especially diabetes mellitus), coagulation disorders. Relevant history or presence of QT syndrome, prolonged QTc time, bradycardia, hypokalaemia or hypomagnesaemia, recent acute myocardial infarction, or uncompensated heart failure. Relevant history or current condition that might interfere with drug ab-sorption, distribution, metabolism or excretion. History of or current abuse of drugs, alcohol or solvents. Inability to understand the nature and extent of the study and the pro-cedures required. Participation in a drug study within 60 days prior to Day 1. Donation of blood within 60 days prior to Day 1. Febrile illness within 3 days before Day 1.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: raltegravir alone<br>raltegravir 400 mg BID for 5 days | Drug: raltegravir<br> <br> * Other names: isentress;|
| Active Comparator: citalopram alone<br>citalopram 10 mg QD for 3 days, followed by citalopram 20 mg QD for 13-14 days | Drug: citalopram<br> <br> |
| Experimental: raltegravir + citalopram<br>raltegravir 500 mg BID and citalopram 20 mg QD for 5 days | Drug: raltegravir<br> <br> * Other names: isentress;Drug: citalopram<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| raltegravir AUC and citalopram AUC | To assess the effect of multiple dose citalopram on the steady state pharmacokinetics of raltegravir and vice versa by intrasubject comparison in healthy subjects. The comparison of steady state raltegravir (400 mg BID for 5 days) pharmacokinetics (AUC0-12h, Cmax, C12h) with steady state citalopram (20 mg QD) vs. raltegravir alone by intrasubject comparison. The comparison of steady state citalopram (20 mg QD) pharmacokinetics (AUC0-24h, Cmax, C24h) with steady state raltegravir (400 mg BID) vs. citalopram alone by intrasubject comparison. | at steady state: day 5 of raltegravir treatment and day 16 or later for citalopram | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events | Adverse events will be scored and laboratory measurements for safety will be collected frequently from screening onwards (maximum 4 weeks before the start of the study) until the last study visit (Day 60) or longer if applicable. | up to approximately 13 weeks (from screening until the last study visit) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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raltegravir, citalopram, pharmacokinetics, drug-drug interaction