Drug Interaction Study of ZYN002 Transdermal Gel and Probe Substrates

This study is a Phase 1, open-label, 2-part, fixed-sequence, 3-period DDI study to evaluate the effect of ZYN002 transdermal gel on the pharmacokinetics (PK) of probe substrates and their metabolites. In addition, this study is designed to evaluate the safety and tolerability of ZYN002 transdermal gel after multiple-dose topical application to healthy adult participants.

Part 1 - DDI with probe substrates for cytochrome P450 (CYP)3A4, CYP2C19, CYP2C9, CYP2D6, CYP1A2 administered as single oral doses followed by the staggered dosing of probe substrates for CYP2C8 and for CYP2B6 administered as single oral doses.

Part 2 - DDI with valproate (valproic acid \[VPA\]), a probe substrate for β-oxidation and glucuronidation.

• Part 1 (Drug), also known as Synthetic cannabidiol (sCBD): ZYN002 (transdermal), midazolam (oral), omeprazole (oral), losartan (oral), dextromethorphan (oral), caffeine (oral), repaglinide (oral), bupropion (oral)
• Part 2 (Drug), also known as sCBD: ZYN002 (transdermal), VPA (oral)

Primary outcomes

• Maximum measure plasma concentration (Cmax) of probe substrates and metabolites [Days 1-3 (Period 1), Days 24-26 (Period 3)]: Blood samples collected at pre dose, and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, and 48 hours post dose.
• Cmax of repaglinide and metabolite [Days 3 and 4 (Period 1), Days 26 and 27 (Period 3)]: Blood samples collected at pre dose, and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours post dose.
• Cmax of bupropion and metabolite [Days 4-10 (Period 1), Days 27-33 (Period 3)]: Blood samples collected at pre dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 48, 72, 96, 120, and 144 hours post dose.
• Cmax of CBD, delta-9-tetrahydrocannabinol (THC), and CBD metabolites [Days 24-33 (Period 3)]: Blood samples collected at pre dose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, and 144 hours post dose.
• Amount excreted in urine over the collection period (Ae0-12) of CBD and its metabolites [Day 17 (Period 2), Days 24 and 32 (Period 3)]: Urine samples collected over a 12-hour period.
• Cmax of VPA and metabolite [Days 1-4 (Period 1), Days 18-21 (Period 3)]: Blood samples collected at pre dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours post dose.
• Cmax of CBD, THC, and CBD metabolites [Days 18-21 (Period 3)]: Blood samples collected at pre dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, and 72 hours post dose.
• Ae0-12 of VPA and metabolites [Days 1-4 (Period 1), Day 17 (Period 2), Days 18-20 (Period 3)]: Urine samples collected over a 12-hour period.
• Ae0-12 of ZYN002 and metabolites [Day 17 (Period 2), Days 18 and 20 (Period 3)]: Urine samples collected over a 12-hour period.

Secondary outcomes

• Number of participants with skin irritation in ZYN002 application areas [Up to 33 days]: Skin assessment examination
• Number of participants with abnormal physical examination results [Up to 33 days]: Targeted physical examination
• Number of participants with abnormal clinical laboratory results [Up to 33 days]: Laboratory testing
• Number of participants with abnormal vital sign results [Up to 33 days]: Vital Sign measures
• Number of participants with abnormal continuous pulse oximetry results [Up to 33 days]: Continuous pulse oximeter
• Number of participants with abnormal electrocardiogram (ECG) [Up to 33 days]: 12-lead ECG

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

Inclusion Criteria:

1. Male or female adults, 18-55 years of age, inclusive, at the time of Screening.
2. Judged by the Investigator to be in generally good health at Screening based upon the results of a medical history, physical examination, 12-lead ECG, and clinical laboratory test results. Laboratory results outside of the reference range, but acceptable, must be documented as not clinically significant (NCS) at the discretion of the Investigator.
3. Participants must have a body mass index between 18 and 30 kg/m² at the time of Screening.
4. Females of childbearing potential must have a negative pregnancy test result at the Screening Visit and on Day -1 before admission to the CRU. Females who are not of childbearing potential are defined as being postmenopausal for >=12 months or having a history of hysterectomy and/or bilateral oophorectomy and/or bilateral tubal ligation.

Exclusion Criteria:

1. A) Females who are pregnant, nursing or planning to become pregnant or females of childbearing potential, who are unwilling to use medically acceptable method of contraception or B) Males with a female partner who is pregnant, nursing, or planning to become pregnant or a female partner of childbearing potential who is unwilling to use a medically acceptable method of contraception.
2. Are homozygous for CYP2C19*2 or heterozygous carriers of CYP2C19*2/CYP2C19*3 or CYP2C9*2/CYP2C9*3 or CYP2D6*2/CYP2D6*3 haplotypes categorized as poor metabolizers.
3. Has consumed alcohol 48 hours prior to Day 1 or during the study.
4. Has eaten any food or drink/beverage containing, grapefruit or grapefruit juice, apple, cranberry, Seville orange or orange juice, vegetables from the mustard family (e.g., kale, spinach, broccoli, watercress, collard greens, kohlrabi, brussels sprouts, parsley, mustard greens, endive, red cabbage, asparagus, or mustard), and chargrilled meats within one week prior to study start (Day -1).

• Thomas Polasek, MD, PhD, Principal investigator, CMAX Clinical Research
• Kristen Bzdek, MD, Study director, Harmony Biosciences Management, Inc.