Dose Adaptation to Offset the Interaction Between Ticagrelor and Ritonavir by Population-based PK Modeling
Condition: Healthy
Study type: Interventional
Phase: Phase 2

Summary: 
      Ticagrelor is a new generation antiplatelet agent with higher efficacy as compared to
      clopidogrel and prasugrel in treatment of patients with moderate and high ischemic risks.
      Ticagrelor is active as such and its hepatic metabolism by CYP3A generates also an active
      metabolite. Because of the remarkable progress in HIV therapies the number of older age
      patients is on the rise, requiring adequate cardiovascular treatment. Since frontline HIV
      therapies include ritonavir, a strong inhibitor of CYP3A enzyme, ticagrelor is
      contraindicated in these patients because of the expected interaction and bleeding risk. A
      lower efficacy of clopidogrel and prasugrel, which are both pro-drugs, in the presence of
      ritonavir has been already demonstrated. Therefore, administration of a lower dose of
      ticagrelor may be a good alternative in HIV patients in order to lessen the impact of this
      pharmacokinetic interaction. The aim of this study is to adjust the dose of ticagrelor in
      case of co-treatment with ritonavir to achieve the same pharmacokinetic profile as
      administered alone using a physiologically-based pharmacokinetic (PBPK) model.

      As the first step, a pharmacokinetic (PK) model for ticagrelor and its active metabolite will
      be created based on available in vitro and in vivo parameters in healthy volunteers.

      An open-label, 2 sessions cross over study will be conducted with 20 healthy male volunteers
      at Clinical Research Center (CRC) of Geneva University Hospitals (HUG). During the first
      session of the clinical trial, a single dose 180 mg ticagrelor will be administered to the
      volunteers and obtained pharmacokinetic data will be fitted into the model for optimization.
      Thereafter a simulated trial by the Simcyp® simulator in presence of a single dose 100 mg
      ritonavir will allow evaluating the impact of CYP3A inhibition on the concentration-time
      profile of ticagrelor and its active metabolite. The necessary dose of ticagrelor to minimize
      the magnitude of this interaction will be calculated. This new dose will be co-administered
      with ritonavir in the same volunteers during the second session of the clinical trial. The
      purpose is to obtain the same PK profile with single dose of 180 mg ticagrelor administered
      alone and with an adapted dose of ticagrelor co-administered with a single dose 100 mg
      ritonavir. Moreover, the pharmacodynamic effect of ticagrelor will be measured in both
      sessions of the clinical trial using two specific platelet function tests: the
      VAsodilator-Stimulated Phosphoprotein assay (VASP) and VerifyNow® P2Y12. With the same PK
      profile, the same pharmacodynamic activity is expected. The modulation of activity of CYP3A
      and P-gp by ritonavir will be also monitored using micro dose midazolam and fexofenadine as
      probe substrates.

      The purpose of this study is to use the Simcyp® Simulator mechanistic PBPK modeling to
      broaden the application field of ticagrelor, especially in HIV patients. Since PK models are
      often created after clinical observations, the prospective aspect of this study is of
      particular value as the model will be first created and then applied to an unknown clinical
      scenario.
    


Intervention name(s): ticagrelor 180 mg administrated alone; Ticagrelor adjusted dose + ritonavir 100mg
Intervention type(s): Drug; Drug
Intervention MeSH terms: Ritonavir; Ticagrelor
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Other
Keywords: Anti-HIV Agents; cardiovascular agents; drug interactions