A Drug-Drug Interaction Study Evaluating the Perpetrator Potential of DC-806 on Cocktails of CYP450 Enzyme and Transporter Substrates in Healthy Participants

• DC-806 (Drug): Oral tablets
• Midazolam (Drug): Oral syrup
• Repaglinide (Drug): Oral tablets
• Digoxin (Drug): Oral tablets
• Rosuvastatin (Drug): Oral tablets

Primary outcomes

• Cohort 1: Maximum Observed Plasma Concentration (Cmax) of Midazolam [Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours postdose on Days 1 and 7]: The timepoints mentioned in the timeframe were relative to the administration of the 2-probe CYP substrate cocktail.
• Cohort 1: Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Time t, Where t is the Last Point With Concentrations Above the Lower Limit of Quantification (AUC0-t) of Midazolam [Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours postdose on Days 1 and 7]: Cohort 1: AUC0-t of Midazolam. The timepoints mentioned in the timeframe were relative to the administration of the 2-probe CYP substrate cocktail.
• Cohort 1: AUC From Time 0 to Infinity (AUC0-inf) of Midazolam [Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours postdose on Days 1 and 7]: The timepoints mentioned in the timeframe were relative to the administration of the 2-probe CYP substrate cocktail.
• Cohort 1: Cmax of 1-hydroxymidazolam [Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours postdose on Days 1 and 7]: Cohort 1: Cmax of 1-hydroxymidazolam, an active metabolite of midazolam. The timepoints mentioned in the timeframe were relative to the administration of the 2-probe CYP substrate cocktail.
• Cohort 1: AUC0-t of 1-hydroxymidazolam [Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours postdose on Days 1 and 7]: Cohort 1: AUC0-t of 1-hydroxymidazolam, an active metabolite of midazolam. The timepoints mentioned in the timeframe were relative to the administration of the 2-probe CYP substrate cocktail.
• Cohort 1: AUC0-inf of 1-hydroxymidazolam [Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48 hours postdose on Days 1 and 7]: Cohort 1: AUC0-inf of 1-hydroxymidazolam, an active metabolite of midazolam. The timepoints mentioned in the timeframe were relative to the administration of the 2-probe CYP substrate cocktail.
• Cohort 1: Cmax of Repaglinide [Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours postdose on Days 1 and 7]: The timepoints mentioned in the timeframe were relative to the administration of the 2-probe CYP substrate cocktail.
• Cohort 1: AUC0-t of Repaglinide [Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours postdose on Days 1 and 7]: The timepoints mentioned in the timeframe were relative to the administration of the 2-probe CYP substrate cocktail.
• Cohort 1: AUC0-inf of Repaglinide [Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24 hours postdose on Days 1 and 7]: The timepoints mentioned in the timeframe were relative to the administration of the 2-probe CYP substrate cocktail.
• Cohort 2: Cmax of Digoxin [Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96 hours postdose on Days 1 and 8]: The timepoints mentioned in the timeframe were relative to the administration of the 2-probe transporter substrate cocktail.
• Cohort 2: AUC0-t of Digoxin [Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96 hours postdose on Days 1 and 8]: The timepoints mentioned in the timeframe were relative to the administration of the 2-probe transporter substrate cocktail.
• Cohort 2: AUC0-inf of Digoxin [Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96 hours postdose on Days 1 and 8]: The timepoints mentioned in the timeframe were relative to the administration of the 2-probe transporter substrate cocktail.
• Cohort 2: Cmax of Rosuvastatin [Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96 hours postdose on Days 1 and 8]: The timepoints mentioned in the timeframe were relative to the administration of the 2-probe transporter substrate cocktail.
• Cohort 2: AUC0-t of Rosuvastatin [Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96 hours postdose on Days 1 and 8]: The timepoints mentioned in the timeframe were relative to the administration of the 2-probe transporter substrate cocktail.
• Cohort 2: AUC0-inf of Rosuvastatin [Predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 96 hours postdose on Days 1 and 8]: The timepoints mentioned in the timeframe were relative to the administration of the 2-probe transporter substrate cocktail.

Secondary outcomes

• Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [Cohort 1: Day 1 up to Day 16; Cohort 2: Day 1 up to Day 22]: A TEAE was defined as any adverse event that began on or after the first dose of study drug or began before the first dose of study drug and worsened on or after the first dose of study drug.

Sex: All, ages: 18 Years to 55 Years, accepts healthy volunteers

Inclusion Criteria:

1. Sex: male or female; females must be of nonchildbearing potential, or postmenopausal.
2. Age: 18 to 55 years, inclusive, at screening.
3. Body mass index: 18.0 to 32.0 kg/m\^2, inclusive, at screening.
4. Weight: ≥50 kg at screening.
5. Status: healthy participants.
6. At screening, females must be of nonchildbearing potential (defined as at least 12 consecutive months with no menses prior to screening, a serum follicle-stimulating hormone test to confirm postmenopausal status, or being surgically sterilized); nonpregnancy will be confirmed for all females by a serum pregnancy test conducted at screening, and by a urine pregnancy test at admission and at follow-up.
7. Male participants, if not permanently surgically sterilized, must inform all sexual partners of their participation in a research study and agree to use a highly effective method of contraception and not donate sperm from admission to the clinical site until 30 days after the last study drug administration.
8. All prescribed medication must have been stopped at least 14 days prior to admission to the clinical site.
9. All over-the-counter medication, vitamin preparations and other food supplements, or herbal medications (e.g., St. John's wort) must have been stopped at least 7 days (or 5 half-lives for certain medications, whichever is longer) prior to admission to the clinical site. Occasional use of acetaminophen/paracetamol (e.g., up to 2 grams per day) is permitted during this period and throughout the study.
10. Ability and willingness to abstain from alcohol-, caffeine-, and methylxanthine- containing beverages or food (e.g., coffee, tea, cola, chocolate, energy drinks) from 48 hours (2 days) prior to admission to the clinical site and during confinement at the clinical site.
11. Willingness to abstain from any strenuous physical exercise from 96 hours (4 days) prior to admission and during confinement at the clinical site.
12. Good physical and mental health on the basis of medical history, physical examination, clinical laboratory assessments, 12-lead electrocardiograms, and vital signs, as judged by the Investigator.
13. Willing and able to sign the informed consent form.

Exclusion Criteria:

1. Employee of Contract Research Organization or the Sponsor.
2. History of relevant drug and/or food allergies, in the opinion of the Investigator.
3. Females who are currently breastfeeding.
4. Smoking more than 5 cigarettes, 1 cigar, or 1 pipe daily within 3 months prior to screening.
5. Unwilling or unable to abstain from tobacco products within the 48 hours (2 days) prior to admission and during confinement in the clinical site.
6. History of alcohol abuse or drug addiction (including soft drugs like cannabis products) within 1 year prior to screening.
7. Positive drug and/or alcohol screen (opiates, methadone, cocaine, amphetamines \[including ecstasy\], cannabinoids, barbiturates, benzodiazepines, tricyclic antidepressants, and alcohol) at screening or admission to the clinical site.
8. History within the previous 12 months of alcohol consumption exceeding 2 standard drinks per day on average. Alcohol consumption will be prohibited 48 hours prior to admission to the clinical site and during confinement at the clinical site.
9. Positive screen for hepatitis B surface antigen, hepatitis C virus antibodies, or human immunodeficiency virus 1 and 2 antibodies.
10. Consumption of any nutrients known to modulate CYP450 enzymes activity (e.g., grapefruit or grapefruit juice, pomelo juice, star fruit, or Seville \[blood\] orange products) within 14 days prior to the first administration of study drug and during the study (including washout period/clinic furlough until after discharge in the last study period).
11. Participation in a drug study within 30 days prior to study drug administration in the current study. Participation in 4 or more other drug studies in the 12 months prior to study drug administration in the current study.
12. History of donation of more than 450 mL of blood within 60 days prior to dosing in the clinical site or planned donation before 30 days has elapsed since intake of study drug.
13. Plasma or platelet donation within 7 days of dosing and through follow-up.
14. Significant and/or acute illness within 5 days prior to study drug administration that may impact safety assessments, in the opinion of the Investigator.
15. Unsuitable veins for infusion or blood sampling as determined by the Investigator or study staff.
16. Any other condition or prior therapy that, in the Investigator's opinion, would confound or interfere with the evaluation of safety, tolerability, or PK of the study drug, interfere with study compliance, or preclude informed consent.

Participant flow

Outcome results

• Cohort 1: Maximum Observed Plasma Concentration (Cmax) of Midazolam (Primary), Geometric mean, nanograms per milliliter (ng/mL): Cohort 1: DC-806 / Midazolam (CYP3A4 Substrate) + Repaglinide (CYP2C8 Substrate) 8.27 +/- 27.9
• Cohort 1: Area Under the Plasma Concentration-time Curve (AUC) From Time Zero to Time t, Where t is the Last Point With Concentrations Above the Lower Limit of Quantification (AUC0-t) of Midazolam (Primary), Geometric mean, hour*nanograms per milliliter (h*ng/mL): Cohort 1: DC-806 / Midazolam (CYP3A4 Substrate) + Repaglinide (CYP2C8 Substrate) 18.4 +/- 27.4
• Cohort 1: AUC From Time 0 to Infinity (AUC0-inf) of Midazolam (Primary), Geometric mean, hour*nanograms per milliliter (h*ng/mL): Cohort 1: DC-806 / Midazolam (CYP3A4 Substrate) + Repaglinide (CYP2C8 Substrate) 21.4 +/- 24.5
• Cohort 1: Cmax of 1-hydroxymidazolam (Primary), Geometric mean, nanograms per milliliter (ng/mL): Cohort 1: DC-806 / Midazolam (CYP3A4 Substrate) + Repaglinide (CYP2C8 Substrate) 2.94 +/- 64.5
• Cohort 1: AUC0-t of 1-hydroxymidazolam (Primary), Geometric mean, hour*nanograms per milliliter (h*ng/mL): Cohort 1: DC-806 / Midazolam (CYP3A4 Substrate) + Repaglinide (CYP2C8 Substrate) 5.05 +/- 106.6
• Cohort 1: AUC0-inf of 1-hydroxymidazolam (Primary), Geometric mean, hour*nanograms per milliliter (h*ng/mL): Cohort 1: DC-806 / Midazolam (CYP3A4 Substrate) + Repaglinide (CYP2C8 Substrate) 13.2 +/- 100.7
• Cohort 1: Cmax of Repaglinide (Primary), Geometric mean, nanograms per milliliter (ng/mL): Cohort 1: DC-806 / Midazolam (CYP3A4 Substrate) + Repaglinide (CYP2C8 Substrate) 7.68 +/- 50.2
• Cohort 1: AUC0-t of Repaglinide (Primary), Geometric mean, hour*nanograms per milliliter (h*ng/mL): Cohort 1: DC-806 / Midazolam (CYP3A4 Substrate) + Repaglinide (CYP2C8 Substrate) 13.3 +/- 62.4
• Cohort 1: AUC0-inf of Repaglinide (Primary), Geometric mean, hour*nanograms per milliliter (h*ng/mL): Cohort 1: DC-806 / Midazolam (CYP3A4 Substrate) + Repaglinide (CYP2C8 Substrate) 14.7 +/- 69.7
• Cohort 2: Cmax of Digoxin (Primary), Geometric mean, nanograms per milliliter (ng/mL): Cohort 2: DC-806 / Digoxin (P-gp Substrate) + Rosuvastatin (BCRP/OATP1B1 Substrate) 0.948 +/- 25.0
• Cohort 2: AUC0-t of Digoxin (Primary), Geometric mean, hour*nanograms per milliliter (h*ng/mL): Cohort 2: DC-806 / Digoxin (P-gp Substrate) + Rosuvastatin (BCRP/OATP1B1 Substrate) 14.2 +/- 24.2
• Cohort 2: AUC0-inf of Digoxin (Primary), Number, hour*nanograms per milliliter (h*ng/mL): Cohort 2: DC-806 / Digoxin (P-gp Substrate) + Rosuvastatin (BCRP/OATP1B1 Substrate) 14.6
• Cohort 2: Cmax of Rosuvastatin (Primary), Geometric mean, nanograms per milliliter (ng/mL): Cohort 2: DC-806 / Digoxin (P-gp Substrate) + Rosuvastatin (BCRP/OATP1B1 Substrate) 2.85 +/- 60
• Cohort 2: AUC0-t of Rosuvastatin (Primary), Geometric mean, hour*nanograms per milliliter (h*ng/mL): Cohort 2: DC-806 / Digoxin (P-gp Substrate) + Rosuvastatin (BCRP/OATP1B1 Substrate) 29.7 +/- 64.5
• Cohort 2: AUC0-inf of Rosuvastatin (Primary), Geometric mean, hour*nanograms per milliliter (h*ng/mL): Cohort 2: DC-806 / Digoxin (P-gp Substrate) + Rosuvastatin (BCRP/OATP1B1 Substrate) 26.7 +/- 47.8
• Cohorts 1 and 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) (Secondary), Count of participants, Participants: Cohort 1: Midazolam + Repaglinide (Days 1 to 3) 0; Cohort 1: DC-806 (Days 4 to 6) 2; Cohort 1: DC-806 + Midazolam + Repaglinide (From Day 7) 2; Cohort 1: Overall [(DC-806 / Midazolam (CYP3A4 Substrate) + Repaglinide (CYP2C8 Substrate)] 2; Cohort 2: Digoxin + Rosuvastatin (Days 1 to 4) 2; Cohort 2: DC-806 (Days 5 to 7) 2; Cohort 2: DC-806 + Digoxin + Rosuvastatin (From Day 8) 1; Cohort 2: Overall [(DC-806 / Digoxin (P-gp Substrate) + Rosuvastatin (BCRP/OATP1B1 Substrate)] 5

Adverse events

Time frame: Cohort 1: Day 1 up to Day 16; Cohort 2: Day 1 up to Day 22.

Other adverse events by term

• Study Protocol (PDF, 2023-09-27)
• Statistical Analysis Plan (PDF, 2023-11-08)