Drug Interaction Study of ZYN002 Transdermal Gel and Probe Substrates

A Phase 1, Open Label, Drug Interaction Study to Evaluate the Effect of ZYN002 on the Pharmacokinetics of CYP3A4, CYP2C19, CYP2C9, CYP2D6, CYP1A2, CYP2C8, and CYP2B6 Probe Substrates, and Valproate in Healthy Adult Participants

This study is an open-label drug-drug interaction (DDI) study of ZYN002 transdermal gel and multiple drugs.

Study Overview

• Status: Completed
• Conditions: Drug Interaction
• Intervention / Treatment: Drug: Part 1; Drug: Part 2

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • CMAX Clinical Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part 1: Interaction of ZYN002 and substrates; Substrates: midazolam, omeprazole, losartan, dextromethorphan, caffeine, repaglinide, and bupropion	Drug: Part 1; ZYN002 (transdermal), midazolam (oral), omeprazole (oral), losartan (oral), dextromethorphan (oral), caffeine (oral), repaglinide (oral), bupropion (oral); Other Names: Synthetic cannabidiol (sCBD)
Experimental: Part 2: Interaction of ZYN002 and VPA	Drug: Part 2; ZYN002 (transdermal), VPA (oral); Other Names: sCBD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum measure plasma concentration (Cmax) of probe substrates and metabolites	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.	Days 1-3 (Period 1), Days 24-26 (Period 3)
Cmax of repaglinide and metabolite	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.	Days 3 and 4 (Period 1), Days 26 and 27 (Period 3)
Cmax of bupropion and metabolite	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.	Days 4-10 (Period 1), Days 27-33 (Period 3)
Cmax of CBD, delta-9-tetrahydrocannabinol (THC), and CBD metabolites	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.	Days 24-33 (Period 3)
Amount excreted in urine over the collection period (Ae0-12) of CBD and its metabolites	Urine samples collected over a 12-hour period.	Day 17 (Period 2), Days 24 and 32 (Period 3)
Cmax of VPA and metabolite	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.	Days 1-4 (Period 1), Days 18-21 (Period 3)
Cmax of CBD, THC, and CBD metabolites	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.	Days 18-21 (Period 3)
Ae0-12 of VPA and metabolites	Urine samples collected over a 12-hour period.	Days 1-4 (Period 1), Day 17 (Period 2), Days 18-20 (Period 3)
Ae0-12 of ZYN002 and metabolites	Urine samples collected over a 12-hour period.	Day 17 (Period 2), Days 18 and 20 (Period 3)

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Harmony Biosciences Management, Inc.
• Investigators: Principal Investigator: Thomas Polasek, MD, PhD, CMAX Clinical Research; Study Director: Kristen Bzdek, MD, Harmony Biosciences Management, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 6, 2025
• Primary Completion (Actual): October 4, 2025
• Study Completion (Actual): November 4, 2025

Study Registration Dates

• First Submitted: April 9, 2025
• First Submitted That Met QC Criteria: April 9, 2025
• First Posted (Actual): April 16, 2025

Study Record Updates

• Last Update Posted (Actual): February 9, 2026
• Last Update Submitted That Met QC Criteria: February 5, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Anticonvulsants; Cannabidiol
• Other Study ID Numbers: ZYN2-CL-007

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No