Evaluate Effects of Multiple Doses of Rifampin and Clarithromycin on the Single Dose Pharmacokinetics of Deflazacort
Condition: Healthy Volunteers
Study type: Interventional
Phase: Phase 1

Summary: 
      The primary objective of the study is to determine the potential effects of multiple doses of
      rifampin and clarithromycin on the single dose pharmacokinetics (PK) of the deflazacort
      active metabolite (21 desacetyl-DFZ) in healthy adult subjects.
    

Detailed description: 
      This is an open label, parallel 2-arm, 2-period, fixed-sequence study in 58 healthy adult
      non-tobacco using male and female subjects divided into 2 cohorts, with 29 subjects in each
      arm of the study (Cohorts A and B).

      Cohort A:

      On Day 1 of Period 1 a single oral dose of deflazacort (Treatment A) will be administered
      followed by PK sampling for 24 hours for 21 desacetyl DFZ and, if data permit, deflazacort.

      In Period 2, multiple oral doses of rifampin will be administered once daily (QD) for 10
      consecutive days with a single oral dose of deflazacort coadministered on Day 10 (Treatment
      B). Pharmacokinetic sampling for 21-desacetyl-DFZ and, if data permit, deflazacort will be
      taken for 24 hours following deflazacort dosing on Day 10. Morning urine collection will be
      used to measure 6β-hydroxycortisol and free cortisol concentrations on Days 1, 4, 8, and 10
      to evaluate the level of cytochrome P450 (CYP) enzyme induction.

      Cohort B:

      On Day 1 of Period 1 a single oral dose of deflazacort (Treatment C) will be administered
      followed by PK sampling for 24 hours for 21-desacetyl-DFZ and, if data permit, deflazacort.

      In Period 2, multiple oral doses of clarithromycin will be administered twice daily (BID) for
      4 consecutive days with a single oral dose of deflazacort coadministered on the morning of
      Day 4 (Treatment D). Pharmacokinetic sampling for 21 desacetyl-DFZ and, if data permit,
      deflazacort will be taken for 24 hours following deflazacort dosing on Day 4.

      Both Cohorts A and B:

      There will be at least 24 hours between the dose in Period 1 and the first dose in Period 2.

      Safety will be monitored throughout the study by repeated clinical and laboratory
      evaluations.

      The clinic will attempt to contact subjects using their standard procedures approximately 14
      days after the last study drug administration to determine if any adverse events (AEs) have
      occurred since the last dose of study drug. Subjects who terminate the study early will be
      contacted if the Principal Investigator (PI) deems necessary.

      Cohort A:

      Treatments A and B are described as follows:

      Treatment A (Period 1): 18 mg deflazacort (3 x 6 mg tablets) at Hour 0 on Day 1, following an
      overnight fast.

      Treatment B (Period 2): 600 mg rifampin (2 x 300 mg capsules) administered at Hour 0 after an
      overnight fast every 24 hours for 10 days (within ± 1 hour of dosing time on Day 1), with 18
      mg deflazacort (3 x 6 mg tablets) coadministered on Day 10.

      Cohort B:

      Treatments C and D are described as follows:

      Treatment C (Period 1): 18 mg deflazacort (3 x 6 mg tablets) at Hour 0 on Day 1, following an
      overnight fast.

      Treatment D (Period 2): 500 mg clarithromycin (1 x 500 mg tablets) administered at Hour 0 and
      Hour 12, under fasting conditions, approximately every 12 hours, for 4 days (within ± 1 hour
      of dosing times on Day 1), with 18 mg deflazacort (3 x 6 mg tablets) coadministered at Hour 0
      on the morning of Day 4. The final dose of clarithromycin will be given at Hour 12 in the
      evening of Day 4.

      All study drugs in both cohorts will be administered orally with approximately 240 mL of
      water.
    

Intervention name(s): Deflazacort and rifampin; Deflazacort and Clarithromycin
Intervention type(s): Drug; Drug
Intervention description(s): Deflazacort, a glucocorticoid with anti-inflammatory and immunosuppressive effects, is used in treating a variety of diseases. Pharmacologically it is an inactive pro-drug which is metabolized completely and rapidly to the active drug 21-desacetyldeflazacort (21 desacetyl-DFZ). The elimination of this metabolite is primarily via the urine in humans. Its potency is approximately 70 to 90% of prednisone and 6 mg of deflazacort has approximately the same anti-inflammatory potency as 5 mg of prednisolone or prednisone. Rifampin is a potent inducer of drug metabolism by inducing a variety of hepatic and intestinal CYP enzymes, especially CYP3A4. Rifampin is a semi-synthetic antibiotic.; Deflazacort, a glucocorticoid with anti-inflammatory and immunosuppressive effects. It is an inactive pro-drug which is metabolized completely and rapidly to the active drug 21 desacetyl-DFZ. The elimination of this metabolite is primarily via the urine in humans. Its potency is approximately 70 to 90% of prednisone. Clarithromycin is a semi-synthetic macrolide antibiotic. Clarithromycin is active in vitro against a variety of aerobic and anaerobic gram-positive and gram-negative bacteria as well as most mycobacterium avium complex (MAC) bacteria. Additionally, the 14-OH clarithromycin metabolite also has clinically significant antimicrobial activity. Clarithromycin is indicated for the treatment of mild to moderate infections such as pharyngitis/tonsillitis.
Other intervention name(s): DFZ; biaxin
Intervention MeSH terms: Clarithromycin; Rifampin; Deflazacort
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment