Impact of Antiretroviral Treatment on Pharmacokinetics and Pharmacodynamics of Thienopyridines in Healthy Volunteers and HIV Patients

Study Overview
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Brief Summary
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HIV patients are at particular risk to develop cardiovascular disease (CVD) as they exhibit multiple risk factors by the nature of their pathology. In addition, the long term exposition to antiretroviral drugs has been associated to an increased risk for CVD. HIV patients can thus potentially receive antiplatelet therapy concomitantly with their antiretroviral treatment. Clopidogrel and prasugrel are thienopyridine antiplatelet agents indicated to prevent the recurrence of ischemic events after coronary arteries stenting. These pro-drugs are mainly bioactivated by cytochromes P450 (CYP) 3A and 2B6 for prasugrel and CYP2C19, CYP3A and CYP2B6 for clopidogrel. Ritonavir is commonly used to boost the bioavailability of other HIV drugs through inhibition of CYP3A4 as well as CYP2B6 and CYP2C9. This interaction could therefore reduce clopidogrel and prasugrel efficacy by reducing the formation of their active metabolites. The aim of the present study is to assess the potential drug-drug interaction between clopidogrel/prasugrel and ritonavir. Two groups of 12 male subjects will be constituted (12 HIV patients under ritonavir boosted therapy and 12 healthy volunteers) in a randomized cross-over clinical trial. All subjects will also be genotyped for the CYP2C19. The pharmacokinetics of clopidogrel active metabolite and prasugrel active metabolite will be assessed. Furthermore, the pharmacodynamic response will be evaluated by two gold standard platelet inhibition tests, namely VAsodilator-Stimulated Phosphoprotein Assay (VASP) and VerifyNow® assays. The primary endpoint of this study is to compare the pharmacodynamic response to clopidogrel and prasugrel in HIV patients to that of healthy volunteers.

Official Title
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Impact of Antiretroviral Treatment on Pharmacokinetics and Pharmacodynamics of Thienopyridines in Healthy Volunteers and HIV Patients

Conditions
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Hiv

Intervention / Treatment
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* Drug: Clopidogrel 300Mg Tablet
* Drug: Prasugrel 60Mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males >18 years Understanding of French language and able to give an inform consent Anti-HIV therapy with ritonavir or cobicistat (for HIV group) Stable antiretroviral treatment since at least 2 weeks (for HIV group) Viremia <100 copies/ml (for HIV group) Exclusion Criteria: renal failure: calculated creatinine Clearance (cockcroft) < 50ml/min hepatic impairment (ASAT, ALAT, bilirubin, gamma-GT more than 2-fold increase) smoker >1 pack/day hypersensitivity to any of the drugs used intake of any drug or particular food (grapefruit) that can affect CYP activities inhibitors (in the last 10 days before the start of the study or 4 half-life after the last intake) pathologies or drugs associated with an increased bleeding risk such as aspirin, non-steroidal anti-inflammatory drugs, steroids and serotonin reuptake inhibitors (in the last 10 days before the start of the study or 4 half-life after the last intake) bleeding familial history or antecedent or haemorrhagic disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HIV clopidogrel<br>clopidogrel 300 mg single dose oral route | Drug: Clopidogrel 300Mg Tablet<br> <br> |
| Experimental: HIV prasugrel<br>prasugrel 60 mg single dose oral route | Drug: Prasugrel 60Mg<br> <br> |
| Active Comparator: Control clopidogrel<br>clopidogrel 300 mg single dose oral route | Drug: Clopidogrel 300Mg Tablet<br> <br> |
| Active Comparator: Control prasugrel<br>prasugrel 60 mg single dose oral route | Drug: Prasugrel 60Mg<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of Platelet Reactivity Index between HIV patients and healthy volunteers | assess the effect of antiretroviral therapies on the response to antiplatelet treatment | 4hr | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of platelet inhibition between HIV patients and healthy volunteers |  | 4hr | 
| Comparison of AUC of plasmatic concentrations of prasugrel and clopidogrel between HIV patients and healthy volunteers |  | 4 hr | 
| Comparison of Cmax of prasugrel and clopidogrel between HIV patients and healthy volunteers |  | 4 hr | 
| Comparison of Tmax of plasmatic concentrations of prasugrel and clopidogrelpatients and healthy between HIV patients and healthy volunteersvolunteers |  | 4 hr | 
| Comparison of Half life of prasugrel and clopidogrel between HIV patients and healthy volunteers |  | 4 hr | 
| Comparison of Clearance of prasugrel and clopidogrel between HIV patients and healthy volunteers |  | 4 hr |