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

NCT03054207 | Terminated Phase 1

• 1 other identifier: 13-096
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

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.

Conditions

Hiv

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• 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

Study Arms (4)

HIV clopidogrel

EXPERIMENTAL

clopidogrel 300 mg single dose oral route

Drug: Clopidogrel 300Mg Tablet

HIV prasugrel

EXPERIMENTAL

prasugrel 60 mg single dose oral route

Drug: Prasugrel 60Mg

Control clopidogrel

ACTIVE COMPARATOR

clopidogrel 300 mg single dose oral route

Drug: Clopidogrel 300Mg Tablet

Control prasugrel

ACTIVE COMPARATOR

prasugrel 60 mg single dose oral route

Drug: Prasugrel 60Mg

Interventions

Clopidogrel 300Mg Tablet DRUG

Control clopidogrel; HIV clopidogrel

Prasugrel 60Mg DRUG

Control prasugrel; HIV prasugrel

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• Jules Desmeules: lead

Study Sites (1)

University Hospitals

Geneva, 1211, Switzerland

Location

MeSH Terms

Conditions

Acquired Immunodeficiency Syndrome

Interventions

Clopidogrel; Tablets; Prasugrel Hydrochloride

Condition Hierarchy (Ancestors)

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Ticlopidine; Thienopyridines; Thiophenes; Sulfur Compounds; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Dosage Forms; Pharmaceutical Preparations; Piperazines

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: February 6, 2017
• First Posted: February 15, 2017
• Study Start: June 1, 2015
• Primary Completion: April 1, 2017
• Study Completion: April 1, 2017
• Last Updated: September 11, 2017

Record last verified: 2017-02

Data Sharing

• IPD Sharing: Will not share

Locations

CH (1)