Impact of Antiretroviral Treatment on Pharmacokinetics and Pharmacodynamics of Thienopyridines in Healthy Volunteers and HIV Patients (IMPACT/R)

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.

Study Overview

• Status: Terminated
• Conditions: Hiv
• Intervention / Treatment: Drug: Clopidogrel 300Mg Tablet; Drug: Prasugrel 60Mg

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Geneva, Switzerland, 1211
    • University Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: HIV clopidogrel; clopidogrel 300 mg single dose oral route	Drug: Clopidogrel 300Mg Tablet
EXPERIMENTAL: HIV prasugrel; prasugrel 60 mg single dose oral route	Drug: Prasugrel 60Mg
ACTIVE_COMPARATOR: Control clopidogrel; clopidogrel 300 mg single dose oral route	Drug: Clopidogrel 300Mg Tablet
ACTIVE_COMPARATOR: Control prasugrel; prasugrel 60 mg single dose oral route	Drug: Prasugrel 60Mg

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: Jules Desmeules

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (ACTUAL): April 1, 2017
• Study Completion (ACTUAL): April 1, 2017

Study Registration Dates

• First Submitted: February 6, 2017
• First Submitted That Met QC Criteria: February 10, 2017
• First Posted (ACTUAL): February 15, 2017

Study Record Updates

• Last Update Posted (ACTUAL): September 11, 2017
• Last Update Submitted That Met QC Criteria: September 8, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Purinergic P2 Receptor Antagonists; Purinergic Antagonists; Purinergic Agents; Clopidogrel; Prasugrel Hydrochloride
• Other Study ID Numbers: 13-096

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO