Drug Interaction Study Between Inhaled Beclomethasone and Protease Inhibitors in Healthy Volunteers
Condition: HIV; Asthma
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 1

Summary: 
      Patients with human immunodeficiency virus (HIV) and respiratory disease commonly require
      protease inhibitors (PIs) and orally inhaled corticosteroids. Inhaled corticosteroids alone
      do not generally cause systemic adverse effects because of low systemic bioavailability, but
      the combination of inhaled fluticasone and various PIs has led to increased systemic
      fluticasone levels and multiple cases of secondary adrenal insufficiency. A study in healthy
      volunteers showed > 350-fold increase in fluticasone area under the curve when ritonavir
      (RTV) 100mg twice daily was coadministered with intranasal fluticasone compared to intranasal
      fluticasone alone. The mechanism of this drug interaction is presumably secondary to PI
      inhibition of cytochrome P450 3A4, the enzyme responsible for fluticasone metabolism. As a
      result, inhaled fluticasone is not recommended in combination with most PIs unless the
      benefit outweighs the risk. One possible alternative to fluticasone is inhaled
      beclomethasone, which has not been studied in combination with PIs. Although beclomethasone
      also undergoes metabolism via CYP3A4 in vitro to its more active metabolite,
      beclomethasone-17-monopropionate, it appears to be largely hydrolyzed by esterases in vivo.
      Furthermore, the pharmacokinetic properties of beclomethasone-17-monopropionate, such as
      relatively short half-life, low maximum plasma concentration, and low volume of distribution,
      suggest that systemic accumulation leading to significant adverse effects is unlikely even in
      the presence of a CYP3A4 inhibitor such as a PI.

      In this open-label study, 46 subjects will receive inhaled beclomethasone for 6 weeks from
      Days 1 to 42. Subjects will be randomized into 1 of 3 groups, such that from Days 15 to 42,
      18 subjects will add no additional study drugs, 14 subjects will add RTV 100mg twice daily,
      and 14 subjects will add DRV/r 600/100mg twice daily. Pharmacokinetic sampling for
      beclomethasone and beclomethasone-17-monopropionate levels will occur on Days 14 and 28.
      Pre-cosyntropin cortisol levels and a low-dose adrenocorticotropic hormone (ACTH) stimulation
      test will be performed on all subjects on Days 1, 14, 28, and 42. Data from this
      investigation will determine whether RTV and/or DRV/r, potent CYP 3A4 inhibitors, alter the
      pharmacokinetics of beclomethasone and its active metabolite,
      beclomethasone-17-monopropionate (primary objective), and whether or not a possible increase
      in systemic bioavailability of beclomethasone and beclomethasone-17-monopropionate alters
      pre-cosyntropin cortisol levels and responses to ACTH stimulation test over a 4-week period
      (secondary objective). Results from this investigation will provide pharmacokinetic and
      pharmacodynamic data to assist clinicians in determining whether inhaled beclomethasone is an
      appropriate option in HIV-infected patients requiring concomitant therapy with an inhaled
      corticosteroid and PIs.
    

Detailed description: 
      Patients with human immunodeficiency virus (HIV) and respiratory disease commonly require
      protease inhibitors (PIs) and orally inhaled corticosteroids. Inhaled corticosteroids alone
      do not generally cause systemic adverse effects because of low systemic bioavailability, but
      the combination of inhaled fluticasone and various PIs has led to increased systemic
      fluticasone levels and multiple cases of secondary adrenal insufficiency. A study in healthy
      volunteers showed > 350-fold increase in fluticasone area under the curve when ritonavir
      (RTV) 100mg twice daily was coadministered with intranasal fluticasone compared to intranasal
      fluticasone alone. The mechanism of this drug interaction is presumably secondary to PI
      inhibition of cytochrome P450 3A4, the enzyme responsible for fluticasone metabolism. As a
      result, inhaled fluticasone is not recommended in combination with most PIs unless the
      benefit outweighs the risk. One possible alternative to fluticasone is inhaled
      beclomethasone, which has not been studied in combination with PIs. Although beclomethasone
      also undergoes metabolism via CYP3A4 in vitro to its more active metabolite,
      beclomethasone-17-monopropionate, it appears to be largely hydrolyzed by esterases in vivo.
      Furthermore, the pharmacokinetic properties of beclomethasone-17-monopropionate, such as
      relatively short half-life, low maximum plasma concentration, and low volume of distribution,
      suggest that systemic accumulation leading to significant adverse effects is unlikely even in
      the presence of a CYP3A4 inhibitor such as a PI.

      In this open-label study, 30 subjects will receive inhaled beclomethasone for 6 weeks from
      Days 1 to 42. Subjects will be randomized into 1 of 3 groups, such that from Days 15 to 42,
      10 subjects will add no additional study drugs, 10 subjects will add RTV 100mg twice daily,
      and 10 subjects will add DRV/r 600/100mg twice daily. Pharmacokinetic sampling for
      beclomethasone and beclomethasone-17-monopropionate levels will occur on Days 14 and 28.
      Pre-cosyntropin cortisol levels and a low-dose adrenocorticotropic hormone (ACTH) stimulation
      test will be performed on all subjects on Days 1, 14, 28, and 42. Data from this
      investigation will determine whether RTV and/or DRV/r, potent CYP 3A4 inhibitors, alter the
      pharmacokinetics of beclomethasone and its active metabolite,
      beclomethasone-17-monopropionate (primary objective), and whether or not a possible increase
      in systemic bioavailability of beclomethasone and beclomethasone-17-monopropionate alters
      pre-cosyntropin cortisol levels and responses to ACTH stimulation test over a 4-week period
      (secondary objective). Results from this investigation will provide pharmacokinetic and
      pharmacodynamic data to assist clinicians in determining whether inhaled beclomethasone is an
      appropriate option in HIV-infected patients requiring concomitant therapy with an inhaled
      corticosteroid and PIs.
    

Intervention name(s): Darunavir; Ritonavir; Beclomethasone Dipropionate HFA
Intervention type(s): Drug; Drug; Drug
Intervention MeSH terms: Ritonavir; Darunavir; Beclomethasone
Allocation: Non-Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Drug Interaction; Asthma; HIV; Beclomethasone; Protease Inhibitors; HV; Healthy Volunteer; HIV Infections