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

Completed · Phase 1

Conditions studied: HIV, Asthma

In brief

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.

Key facts

Study ID

NCT00936793

Run by

National Institutes of Health Clinical Center (CC)

People needed

53

Starts

2009-07-06

Expected to finish

2011-06-10

Last updated by the study team

2017-07-02

Who can join

Age: 18 and older, up to 60. Sex: any. Healthy volunteers: not accepted.

You may not qualify if…

• Concomitant routine therapy with any prescription, over-the-counter, herbal, or holistic medications, including hormonal contraceptives by any route, any corticosteroid by any route, any inhaled medications, and any investigational drugs, for 30 days prior to study participation. An exception to this requirement is the use of topical medications that are not significantly absorbed systemically, e.g. topical minoxidil.
• Concomitant therapy (chronic or intermittent) with any prescription, over-the-counter, or herbal drugs will not be allowed during the study duration
• Intermittent use of acetaminophen, non-steroidal anti-inflammatory medications (i.e., ibuprofen), and loperamide will be allowed to be taken according to each manufacturer's recommendations during the study, but should not be taken on the days of pharmacokinetic blood sampling
• A daily multivitamin with minerals will be allowed during the study
• Use of topical medications that are not significantly absorbed systemically wil be allowed if approved by the Principal Investigator.
• Inability to obtain venous access for blood sample collection
• The presence or history of any of the following:
• adrenal disease (e.g., Addison's disease, Cushing's syndrome, etc.),
• diabetes mellitus (clinical diagnosis based on current guidelines),
• HIV infection,
• pulmonary disease (e.g., asthma, chronic obstructive pulmonary disease, etc.),
• cardiac disease (e.g., hypertension [systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg], heart failure, arrhythmia, etc.),
• renal disease (chronic or acute renal failure or insufficiency),
• hepatitis (as assessed by patient interview) or hepatic impairment,
• pancreatitis,
• bleeding disorders (e.g., hemophilia),
• internal bleeding (such as gastrointestinal or intracranial),
• peptic ulcer disease requiring maintenance pharmacologic therapy,
• osteoporosis,
• osteonecrosis,
• atopy or atopic dermatitis,
• hormone-sensitive cancers or conditions,
• malignancy,
• organ transplant,
• seizure disorders,

Where it is running

• National Institutes of Health Clinical Center, 9000 Rockville Pike — Bethesda, Maryland, United States

Full record on ClinicalTrials.gov

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