NCT00936793

Drug Interaction Study Between Inhaled Beclomethasone and Protease Inhibitors in Healthy Volunteers

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 53 (actual)
• Sponsor: National Institutes of Health Clinical Center (CC) · NIH
• Sex: All
• Age: 18 Years – 60 Years
• Healthy volunteers: Not accepted

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.

Conditions

• HIV
• Asthma

Interventions

Type	Name	Description
DRUG	Darunavir
DRUG	Ritonavir
DRUG	Beclomethasone Dipropionate HFA

Timeline

• Start date: 2009-07-06
• Primary completion: 2011-06-10
• Completion: 2011-06-10
• First posted: 2009-07-10
• Last updated: 2017-07-02

Locations

1 site across 1 country: United States