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

Phase 1

Terminated

• Conditions: Hiv
• Interventions: Drug: Prasugrel 60Mg; Drug: Clopidogrel 300Mg Tablet

• Registration Number: NCT03054207
• Lead Sponsor: Jules Desmeules

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2015-06
• Status Verified: 2017-02
• Study First Submitted: 2017-02-06
• Study First Submitted QC: 2017-02-10
• Study First Posted: 2017-02-15
• Primary Completion: 2017-04
• Study Completion: 2017-04
• Last Update Submitted: 2017-09-08
• Last Update Posted: 2017-09-11

Recruitment & Eligibility

• Status: TERMINATED
• Sex: Male
• Target Recruitment: 21

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
HIV prasugrel	Prasugrel 60Mg	prasugrel 60 mg single dose oral route
Control clopidogrel	Clopidogrel 300Mg Tablet	clopidogrel 300 mg single dose oral route
Control prasugrel	Prasugrel 60Mg	prasugrel 60 mg single dose oral route
HIV clopidogrel	Clopidogrel 300Mg Tablet	clopidogrel 300 mg single dose oral route

Primary Outcome Measures

Name	Time	Method
Comparison of Platelet Reactivity Index between HIV patients and healthy volunteers	4hr	assess the effect of antiretroviral therapies on the response to antiplatelet treatment

Secondary Outcome Measures

Name	Time	Method
Comparison of AUC of plasmatic concentrations of prasugrel and clopidogrel between HIV patients and healthy volunteers	4 hr
Comparison of platelet inhibition between HIV patients and healthy volunteers	4hr
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
Comparison of Cmax of prasugrel and clopidogrel between HIV patients and healthy volunteers	4 hr

Trial Locations

Locations (1)

University Hospitals; 🇨🇭 Geneva, Switzerland