Evaluate Effects of Multiple Doses of Rifampin and Clarithromycin on the Single Dose Pharmacokinetics of Deflazacort

A Phase 1, Open-Label, 2-Arm, Fixed-Sequence Study to Evaluate the Potential Effects of Multiple Doses of Rifampin (CYP3A4 Inducer) and Clarithromycin (CYP3A4 Inhibitor) on the Single Dose Pharmacokinetics of Deflazacort in Healthy Subjects

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.

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.

Inclusion Criteria:

• Healthy, adult, male or female, 18 55 years of age
• Continuous non smoker who has not used nicotine containing products for at least 3 months
• Body mass index (BMI) ≥ 18.5 and ≤ 32.0 kg/m2
• For a female of non childbearing potential: must have undergone a sterilization procedures or be postmenopausal with amenorrhea for at least 1 year prior to the first dose of study drug and FSH serum levels consistent with postmenopausal status
• A non vasectomized, male subject must agree to use a condom with spermicide or abstain from sexual intercourse during the study until 90 days
• If male, must agree not to donate sperm from the first dose of study drug until 90 days

Exclusion Criteria:

• Subject is mentally or legally incapacitated or has significant emotional problems at the time of the screening visit or expected during the conduct of the study

• History or presence of alcoholism or drug abuse within the past 2 years

• History or presence of hypersensitivity or idiosyncratic reaction to the study drugs or related compounds (e.g., steroids or their formulations including lactose)

• History or presence of:

  1. Symptomatic cardiomyopathy at screening
  2. Immunosuppression or other contraindications for corticosteroid treatment
  3. History of chronic systemic fungal or viral infections
  4. Galactose intolerance, Lapp lactose deficiency, or glucose-galactose malabsorption
  5. Diabetes mellitus
  6. Osteoporosis
  7. Myasthenia gravis
  8. Epilepsy
  9. Idiopathic hypocalcuria
  10. Hypothyroidism (TSH clinically significant)
  11. Gastrointestinal issues or ulcers
  12. Previous corticoids-induced myopathy
  13. Ocular herpes simplex

• Female subjects of childbearing potential

• Female subjects who are pregnant or lactating

• Positive urine drug or alcohol results

• Positive urine cotinine

• Positive results for HIV, HBsAg or HCV

• Seated blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg

• Seated heart rate is lower than 40 bpm or higher than 99 bpm

• QTc interval is > 430 msec (males) or > 450 msec (females)

• Has received any live or live-attenuated vaccine within 30 days

• Has received any immunosuppressive agents, coal tar, and/or radiation therapies within 30 days

• Has received injectable corticoids in the 12 weeks dose of study drug or any oral form of corticoids in 30 days

• Estimated creatinine clearance < 80 ml/min

• Unable to refrain from or anticipates the use of

  • Any drug, including prescription and non prescription medications, as well as herbal remedies known to be significant inhibitors of CYP 3A4 enzymes and/or P gp for 14 days
  • Any drugs known to be significant inducers of CYP 3A4 enzymes and/or P gp, including St. John's Wort, for 28 days

• Have been on a diet incompatible with the on study diet within 28 days

• Donation of blood or significant blood loss within 56 days

• Plasma donation within 7 days

• Participation in another clinical trial within 28 days