Pharmacokinetic Interaction Between Ritonavir and Prasugrel in Healthy Volunteers

HIV patients are at particular risk to develop cardiovascular disease (CVD) as they exhibit multiple known risk factors for CVD. Of specific concern is the fact that use of the non nucleosidic reverse transcriptase inhibitors (NNRTI) and/or protease inhibitors (PI) drug classes is associated with dyslipidemia known to increase the risk of coronary heart disease particularly among older subjects with normalized CD4 cell counts and suppressed HIV replication. HIV patients could thus potentially receive anti-aggregant therapy concomitantly with their antiretroviral treatment. Prasugrel is an anti-aggregating agent indicated to prevent the recurrence of ischemic events after coronary arteries stenting. It is a pro-drug mainly metabolized by cytochromes P450 (CYP) 3A and 2B6 and to a lesser extent by CYP2C9 and 2C19. Ritonavir is an anti-protease and CYP3A4 and CYP2B6 inhibitor used in anti-HIV therapy. The aim of the present study is to assess the potential drug-drug interaction between prasugrel and the CYP3A/2B6 inhibitor ritonavir. Ten healthy volunteers will receive prasugrel 10mg alone or after 100mg ritonavir. The effect of ritonavir on prasugrel pharmacokinetics will be assessed. The two sessions will be separated by a one-week "wash out" period. During each session, CYP3A, 2B6, 2C9 and 2C19 activities will be assessed by a micrococktail approach with microdoses of midazolam, bupropion, flurbiprofen and omeprazole. The pharmacokinetics of prasugrel active metabolite will be assessed during the two sessions.

Study Overview

• Status: Completed
• Conditions: Healthy Volunteers
• Intervention / Treatment: Drug: Prasugrel; Drug: Ritonavir

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Geneva 14, Switzerland, 1211
    • University Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Healthy male volunteers aged from 18 to 60 years
• BMI between 18 and 25
• Understanding of French language and able to give an inform consent.

Exclusion Criteria:

• smoker
• hypersensitivity to prasugrel or ritonavir or constituents of the tablets - - regular alcohol consumption
• concomitant disease
• intake of any drug or particular food (grapefruit) that can affect or metabolized by the CYP3A, 2C19, 2B6 and 2C9 within 1 month before the study
• 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)
• bleeding familial history or antecedent or haemorrhagic disease
• previous gastro-intestinal ulcer or active ulcer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Prasugrel 10mg po	Drug: Prasugrel; Assessment of prasugrel metabolic ratio and phenotyping of CYP2B6/2C9/2C19/3A4
Experimental: Prasugrel 10mg po + ritonavir 100mg po	Drug: Prasugrel; Assessment of prasugrel metabolic ratio and phenotyping of CYP2B6/2C9/2C19/3A4; Drug: Ritonavir; Assessment of prasugrel metabolic ratio and phenotyping of CYP2B6/2C9/2C19/3A4 in presence of ritonavir

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasmatic prasugrel metabolites concentrations (ng/mL) in presence/absence of ritonavir	The concentrations will be measured at 9 differents times during 6 hours (0,1min,30min,1H,1H30,2H,3H,4H,6H). The measurements will be repeated one week later for 6 hours	One week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CYP2B6 phenotype in presence/absence of ritonavir	The phenotype will be assessed by taking a blood sample once and one week later	One week
CYP2C9 phenotype in presence/absence of ritonavir	The phenotype will be assessed by taking a blood sample once and one week later	one week
CYP2C19 phenotype in presence/absence of ritonavir	The phenotype will be assessed by taking a blood sample once and one week later	one week
CYP3A4 phenotype in presence/absence of ritonavir	The phenotype will be assessed by taking a blood sample once and one week later	one week

Collaborators and Investigators

• Sponsor: University Hospital, Geneva

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): September 1, 2011

Study Registration Dates

• First Submitted: April 21, 2011
• First Submitted That Met QC Criteria: April 29, 2011
• First Posted (Estimate): May 3, 2011

Study Record Updates

• Last Update Posted (Estimate): October 6, 2011
• Last Update Submitted That Met QC Criteria: October 5, 2011
• Last Verified: April 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Platelet Aggregation Inhibitors; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Prasugrel Hydrochloride
• Other Study ID Numbers: MICRO-PRASU-RITONAVIR