Clinical Trial to Evaluate Drug-drug Interactions Between Darunavir/Cobicistat and Etravirine in Hiv- Infected Patients
Condition: HIV-1 Infection
MeSH terms: Infections
Study type: Interventional
Phase: Phase 1

Summary: 
      This study aims to provide information about the safety and pharmacokinetic drug-drug
      interactions between darunavir/cobicistat (800/150mg QD) and etravirine (400mg QD) in
      HIV-infected patients, as well as evaluate the efficacy of concomitant administration of
      darunavir/cobicistat and etravirine.
    

Detailed description: 
      Toxicity associated with use of nucleoside reverse transcriptase inhibitors (NRTIs) for the
      treatment of VIH-infection has prompted increasing interest in new antiretroviral treatment
      strategies without NRTIs (nuc-sparing regimens).

      Ritonavir boosted protease inhibitors (PI/r) like, lopinavir, atazanavir, saquinavir and
      darunavir may be candidates for maintenance mono-therapy due to their high potency and
      genetic barrier for drug resistance and possibility for once daily dosing. However, although
      several controlled and uncontrolled studies have been conducted to examine the safety and
      tolerance of PI/r monotherapy for maintenance in HIV-infected patients, many of these studies
      were small or did not use controls; and evidence on the efficacy and safety of PI/r
      monotherapy is therefore limited. Moreover, several trials have reported a higher rate of
      intermittent viremia in patients with PI/r monotherapy. A metaanalysis including 10
      randomised controlled clinical trials reported an absolute increase in the risk of
      virological failure at one year with PI/r monotherapy of roughly 10% to 13%. Therefore, PI/r
      monotherapy is not an option for clinicians and patients who do not want to accept such a
      risk.

      If a nuc-sparing regimen is to be used, dual regimens may be an alternative to PI/r
      monotherapy. This approach could be able to prevent NRTI-derived toxicity while maintaining
      antiviral efficacy. Consequently, a growing interest in this strategy has emerged during
      recent years.

      Ideally, a dual antiretroviral regimen should be efficacious and safe, it should permit
      once-daily administration with a low pill burden, and it should have a high genetic barrier
      towards the development of drug resistance mutations in patients who might eventually develop
      virological failure. The combination of the boosted PI darunavir plus the non-nucleoside
      reverse transcriptase inhibitor etravirine fulfills most of these requirements, and it may be
      an attractive dual antiretroviral treatment regimen. Although clinical experience with this
      combination is still limited, promising results from previous studies support current
      interest on the use of this dual therapy in clinical practice. Moreover, a fixed-dose
      combination (FDC) tablet containing darunavir and the new pharmacokinetic enhancer cobicistat
      (Rezolsta®) has been recently launched on the market. Among potential advantages, this FDC
      may contribute to decrease pill burden as well as to avoid medication errors. However,
      according to prescribing information, darunavir/cobicistat and etravirine should not be
      combined due to potential drug-drug interactions.

      Darunavir and cobicistat are both metabolized by the isoenzyme CYP3A4 of the cytochrome P450,
      which is inhibited by cobicistat. On the other hand, etravirine, which is mainly metabolized
      by 2C19 (but also by CYP3A4 in a minor extent), is a CYP3A4 inducer. Based on this rationale,
      etravirine could decrease the exposure to cobicistat, eventually leading to concentrations of
      cobicistat which might be insufficient to boost darunavir.

      Although no clinically relevant changes in drug concentrations were evidenced in specific
      trials evaluating the presence of drug-drug interactions between darunavir/ritonavir and
      etravirine, the combination of darunavir/cobicistat with etravirine might be more sensitive
      to the CYP3A inducing effect of etravirine. However, specific data on this potential
      drug-drug interaction are still lacking. Consequently, the combination of
      darunavir/cobicistat with etravirine is currently not recommended per prescribing until
      formal pharmacokinetic data supporting this combination are generated.
    

Intervention name(s): darunavir/cobicistat; etravirine
Intervention type(s): Drug; Drug
Intervention description(s): 800/150 mg, once daily during 35 days + etravirine 400 mg, once daily during 14 days; 400 mg, once daily during 28 days + darunavir/cobicistat 800/150 mg, once daily during 7 days
Other intervention name(s): Rezolsta; Intelence
Intervention MeSH terms: Darunavir; Cobicistat; Cobicistat mixture with darunavir; Etravirine
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: HIV infection; Darunavir/cobicistat; Etravirine, drug-drug interactions; Population PK analysis