The Effects of the Direct Acting Antiviral Agent Boceprevir on the Pharmacokinetics of Maraviroc in Healthy Volunteers
Condition: Healthy
Study type: Interventional
Phase: Phase 1

Summary: 
      Infection by both HIV and hepatitis C virus (HCV)is frequent due to similar transmission
      modes. Near 20% of people living with HIV are also infected by HCV. People living with HIV
      are treated by anti-HIV medications that may interact with numerous other medications,
      including new medications against HCV.

      Boceprevir is one of these new HCV medications and it is now considered as part of the
      standard of care for people infected with HCV. Previous research has shown boceprevir may
      influence the capacity of the liver to breakdown (metabolize) certain medications and when
      these medications are used in combination with boceprevir, their blood concentrations may be
      increased or decreased which could increase the risk of side effects or decrease efficacy.
      Among the drugs having a potential for an interaction with boceprevir is maraviroc, an
      anti-HIV medication. If concentrations of maraviroc increase, people may experience more side
      effects. However, if concentrations of maraviroc decrease, people living with HIV may have a
      lower suppression of the virus. This could increase the risk for the HIV virus to develop
      resistance, that is that the treatment will no longer be effective. No studies have been
      conducted to investigate the effects of boceprevir on blood concentrations of maraviroc. This
      research project addresses this research question. This project, however, cannot be done with
      people living with HIV since resistance may develop in these people if the concentrations of
      maraviroc decrease. It is for this reason that the investigators wish to recruit healthy
      people not infected with HIV nor HCV.

      Eleven healthy volunteers will be included. They will receive maraviroc 150 mg (1 tablet)
      every 12 hours from days 1 to 19 inclusively. On day 5, a total of ten blood samples will be
      drawn during the following 12 hours (at 0, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8 and 12 hours after
      maraviroc morning dose intake) to measure the blood concentrations of maraviroc. Boceprevir
      800 mg (4 capsules) every 8 hours with food will be started on day 6 and continued until day
      19 inclusively. On day 19, after the morning maraviroc and boceprevir dose, another ten blood
      samples will be drawn over a 12 hour period. A phone follow-up will be done on day 26. Thus,
      the total study duration for subjects is 26 days. The investigators will compare the blood
      concentrations of maraviroc when given alone to the blood concentrations of maraviroc when
      given with boceprevir.
    

Detailed description: 
      Co-infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is frequent
      because of shared modes of viral transmission. Near 20% of HIV-infected patients are also
      infected with HCV, the prevalence of HCV in the HIV population varying according to the route
      of transmission. Despite the decrease in mortality and morbidity in HIV-infected individuals
      since the introduction of potent combination antiretroviral therapy (cART), HCV-related
      end-stage liver disease (ESLD) now represents a leading cause of death in these patients.

      HCV treatment outcomes in terms of sustained virologic response (SVR) are usually worse in
      co-infected patients, pegylated interferon-alpha (PEG IFN-alpha) / ribavirin treatment
      leading to success in only 40 to 50% of mono-infected patients and 30 % of co-infected
      patients. In patients co-infected with HIV, present guidelines recommend a fixed course of
      PEG IFN-alpha / ribavirin for 48 weeks to optimize HCV treatment.

      The recent introduction of boceprevir and telaprevir, two direct acting antiviral agents
      (DAAs) against HCV, changed the standard of care for the treatment of chronic HCV infection
      with genotype 1, whereby now the AASLD practice guidelines recommend the use of boceprevir or
      telaprevir in combination with PEG IFN-alpha/ribavirin in both HCV mono-infected treatment
      naïve and experienced patients. No studies have yet been published in HCV-HIV co-infected
      patients.

      Boceprevir is a novel HCV NS3 serine protease inhibitor (PI). In clinical studies of
      treatment-naïve and experienced patients, this agent, in combination with standard of care
      (PEG IFN-alpha/ribavirin), achieved much greater SVR rates, reaching rates higher than 70 %
      in clinical studies.

      Boceprevir has to be taken 800 mg (four 200 mg capsules) three times a day (every 7-9 hours)
      with food. Boceprevir is usually well tolerated according to single and multiple dose
      pharmacokinetics studies in healthy volunteers with adverse effects similar to placebo. The
      serious adverse effects related to boceprevir are seen when boceprevir is coadministered with
      PEG-IFN alpha/ribavirin. These include anemia, neutropenia and thrombocytopenia.

      An interim analysis of a randomized double-blind placebo-controlled study of the use of
      boceprevir/PEG IFN-alpha/ribavirin in HCV treatment naïve HCV/HIV co-infected patients showed
      that 70.5 % of patients on boceprevir/PEG IFN-alpha/ribavirin had an undetectable HCV RNA at
      24 weeks as compared to 34.4% of patients on PEG IFN-alpha/ribavirin.

      Boceprevir metabolism is mediated mainly by aldo-keto reductases and by CYP3A4 and CYP3A5.
      Boceprevir is also a substrate of p-glycoprotein (P-gp). Boceprevir is by itself known to be
      a strong inhibitor of CYP3A4/3A5 and drugs metabolized by this pathway may have increased
      exposure when administered with this product. In vitro data has shown that boceprevir does
      not induce CYP3A4/5. Surprisingly, however, a recent warning by the FDA (FDA Medwatch,
      February 9th 2012) and a Dear Health Care Professional Letter from Merck & Co, Inc. (USA)
      have revealed that boceprevir decreases the exposure of HIV ritonavir-boosted protease
      inhibitors that are CYP3A4 substrates. This unpublished data suggests that boceprevir in vivo
      may be acting as a CYP3A4 inducer. Contradictory in vitro and in vivo drug interaction study
      results are not uncommon. The clinical impact of these interactions is at the moment unclear.
      This has implications for possible drug-drug interactions if boceprevir is used in
      combination with cART in HIV/HCV co-infected patients.

      Among the antiretroviral drugs that seem promising to be used in HIV/HCV co-infected patients
      is maraviroc. A recent conference abstract suggests that adding maraviroc to an
      antiretroviral regimen in HIV/HCV-co-infected patients naïve to anti-HCV therapy decreases
      liver fibrosis. Maraviroc is usually given as 300 mg twice daily with or without food but the
      dose may change depending on the patient's concomitant medications. Maraviroc does not
      inhibit any of the major CYP450 enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and
      CYP3A4) and does not show any effects on plasma concentrations of other molecules.
      Maraviroc's major metabolic routes are oxidation and N-dealkylation and in vitro studies
      demonstrated that maraviroc is primarily metabolized by CYP3A4. Concomitant use of maraviroc
      with known CYP3A4 inhibitors requires maraviroc dosage to be reduced to 150 mg twice a day
      while its use with CYP3A4 inducers necessitates maraviroc to be used 600 mg twice daily.

      Maraviroc was well tolerated in the various clinical trials with a drop-out rate of 4 to 6 %
      similar to placebo. The most common side effects are upper respiratory tract infections (22,8
      %), cough (13,8%), fever (12,9 %), rash (10,8 %), muscle-related symptoms (9,9 %), dizziness
      and postural dizziness (8,7 %), abdominal pain (8.2 %), insomnia (7,7 %) and constipation
      (5,9%) (19). Maraviroc should be used with caution in patients with an increased risk of
      cardiovascular events as cases of myocardial infarction, postural hypotension and syncope
      have been reported. Postural hypotension is dose-related and unlikely to occur at labeled
      doses. However, postural hypotension may be of concern if drug-drug interactions occur
      without proper dose adjustments of maraviroc. The use of maraviroc 150 mg BID in steady-state
      drug-drug interaction studies in healthy volunteers in the presence of potent CYP3A4
      inhibitors has been well tolerated.

      No study regarding the use of maraviroc with boceprevir has been conducted. Given the similar
      metabolic routes taken by these molecules, that is CYP3A4, it is likely that these molecules
      will interact. It is unknown if boceprevir will increase or decrease maraviroc systemic
      exposure. To limit potential toxicity and study discontinuations, however, we have chosen to
      do the study with maraviroc 150 mg twice daily. The study will evaluate the effects of
      boceprevir on the pharmacokinetics of maraviroc in healthy volunteers. As maraviroc does not
      inhibit nor induce CYP 450 isoenzymes, maraviroc is not expected to influence boceprevir
      pharmacokinetics. For this reason, we have chosen not to measure boceprevir concentrations.

      This is a phase 1, single center, open-label, crossover single-sequence drug-drug interaction
      study in healthy Caucasian males. The study population is limited to Caucasian males to limit
      interpatient pharmacokinetic variability. Eleven healthy volunteers will be included. They
      will receive maraviroc 150 mg every 12 hours from days 1 to 19 inclusively. On day 5, 12 hour
      intensive pharmacokinetic sampling will be done to measure maraviroc in the absence of
      boceprevir. Boceprevir 800 mg every 8 hours with food will be started on day 6 and continued
      until day 19 inclusively. On day 19, 12 hour intensive pharmacokinetic sampling will be
      repeated to measure maraviroc concentrations in the presence of boceprevir. The maraviroc
      concentration will be at steady-state by day 5. Furthermore, 14 days of boceprevir will be
      sufficient to study inhibition and induction. A phone follow-up will be done on day 26. Thus,
      the total study duration for subjects is 26 days.

      The primary objective of the study is to evaluate the effects of boceprevir on the
      pharmacokinetics of maraviroc in healthy volunteers. The secondary objective is to determine
      the appropriate maraviroc dose to be taken when given concomitantly with boceprevir.
    

Intervention name(s): Maraviroc (5 days); Maraviroc and boceprevir (14 days)
Intervention type(s): Drug; Drug
Intervention description(s): Subjects will receive maraviroc 150 mg tablets (1 tablet) every 12 hours from days 1 to 5 inclusively.; From days 6 to 19, inclusively, boceprevir 800 mg (4 capsules of 200 mg) every 8 hours with food will be given with maraviroc 150 mg (1 tablet of 150 mg) every 12 hours.
Other intervention name(s): Celsentri (DIN #: 02299844) CAS# 376348-65-1; Celsentri (DIN #: 02299844) CAS# 376348-65-1; Victrelis (DIN#:02370816) CAS# 394730-60-0
Intervention MeSH terms: Maraviroc
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: maraviroc; boceprevir; HIV; HCV; drug interaction; pharmacokinetics