A Phase 1, Three-Part Open-Label Drug-Drug Interaction Study in Healthy participants to Determine the Effects of Itraconazole on the Pharmacokinetics of JNT-517 (Victim) and the Effects of JNT-517 (Perpetrator) on the Pharmacokinetics of Midazolam and Pravastatin
CTI Clinical Trial and Consulting Services Australia Pty Ltd
36 participants
Jun 11, 2024
Interventional
Conditions
Summary
This study is designed as a 3-part study in healthy participants to test the drug-to –drug interaction of experimental drug, JNT-517 with itraconazole, midazolam and pravastatin, respectively. JNT-517 is believed to reduce levels of phenylalanine in the by increasing its removal with urine and reducing uptake of phenylalanine in the gut.
Eligibility
Inclusion Criteria6
- Males and females 18 to 55 years of age, inclusive.
- Medically healthy with no clinically significant medical history, physical examination, laboratory results, vital signs, or ECGs.
- Body mass index (BMI) of 18-40 kg/m2 and total body weight >50 kg (110 lbs).
- Non-smoker for at least 2 weeks prior to dosing and willing to abstain during the study.
- Participants with psychiatric illness must be well-controlled for the last 6 months prior to the Screening visit and if on medication, on stable medications for the last 3 months.
- Capable of giving signed informed consent and able to comply with study procedures
Exclusion Criteria43
- Any acute or chronic medical condition that would prevent the participant from complying with
- the procedures or place the participant at risk if they participate in the study.
- Positive for hepatitis B or C or human immunodeficiency virus.
- Any history of malignancy in the last 5 years, excluding non-melanoma skin cancer.
- Any history of liver disease
- Any surgical or medical conditions that may affect study drug absorption, distribution,
- metabolism, or excretion.
- Creatinine clearance <90 mL/min by the Chronic Kidney Disease Epidemiology Collaboration
- (CKD-EPI) creatine equation.
- Received another investigational drug within 30 days or, if known, 5 half-lives of the
- investigational drug (whichever is longer).
- Alcohol consumption within 5 days of Check in and/or unwilling to abstain during the study.
- Has consumed herbal preparations/medications, including but not limited to St. John's wort, kava,
- ephedra (ma huang), gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, or ginseng,
- within 7 days prior to study drug dosing.
- Intake of nutritional supplements, juice, other foods or beverages that may affect the various drug
- metabolizing enzymes and transporters (eg, alcohol, grapefruit, starfruit, Seville oranges, or their
- products) are not permitted for 7 days before dosing and throughout the study.
- Smoker (defined as an individual who has used nicotine-containing products, including cigarettes
- and e-cigarettes) within the last 2 weeks prior to dosing and a positive cotinine test on Day –1.
- Consumption of caffeinated beverages or food within 72 hours prior to Check-in.
- Use or intend to use any prescription medications/products within 14 days prior to dosing, unless
- deemed acceptable by the Investigator (or designee), or use or intend to use any nonprescription
- medications/products including vitamins and minerals within 7 days prior to Check in, unless
- deemed acceptable by the Investigator (or designee).
- Use or intend to use slow release medications/products considered to still be active within 14
- days prior to Check in, unless deemed acceptable by the Investigator (or designee).
- Use of any medications that are inhibitors or inducers of cytochrome P450 (CYP)3A4 or
- inhibitors of the transporter P-glycoprotein (P-gp) within 4 weeks prior to randomization and
- unwilling and/or unable to avoid these medications throughout the treatment duration.
- Use of any medication that is a substrate of CYP3A4, or a substrate of the transporters P-gp,
- breast cancer resistance protein (BCRP), organic anion transporter 3 (OAT3), multidrug and toxin
- extrusion (MATE)1, or MATE2-K within 4 weeks prior to randomization and unwilling and/or
- unable to avoid these medications throughout the treatment duration.
- History of drug/alcohol abuse in the last year.
- Positive drug screen.
- Unable to tolerate oral medication.
- Allergy to JNT-517 or any component of the investigational product.
- Allergy to itraconazole (Part A), midazolam (Part B), or pravastatin (Part C)
- Previous exposure to JNT-517 in another clinical trial
- Received >50 mL of blood or plasma within 30 days of Screening or >500 mL of blood or plasma
- within 60 days of Screening.
- Blood donation of >500 mL within 56 days prior to Screening
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Interventions
This is a Phase 1, open-label, 3-part study to evaluate the drug-drug interaction of itraconazole with JNT-517 as the victim and the interaction of JNT-517 as the perpetrator with midazolam and pravastatin, respectively. The 3 parts of the study may be conducted in parallel and no particular order. Part A - Itraconazole interaction: Day 4 to Day 9 - Twice a day 150 mg oral dose of itraconazole tablets will be administered. Day 10 - Single 200 mg oral dose of itraconazole capsules will be administered. Day 1, Day 4 and Day 10 - Single 150 mg oral dose of JNT-517 tablets will be administered. Part B - Midazolam interaction: Day 1 and Day 16 - Single 2 mg oral dose of midazolam solution will be administered. Day 3 to Day 15 - Twice a day 150 mg oral dose of JNT-517 tablets will be administered. Day 16 - Single 150 mg oral dose of JNT-517 tablets will be administered. Part C - Pravastatin interaction: Day 1 - Single oral dose of pravastatin 40 mg tablet will be administered. Day 5 - Single oral dose of pravastatin 40 mg tablet will be administered. Day 4 - Single 150 mg oral dose of JNT-517 tablets will be administered, Day 5 - Twice a day 150 mg oral dose of JNT-517 tablets will be administered. Part A will begin with a sentinel group of 2 participants who will receive JNT-517 alone on Day 1 and in combination with Itraconazole on Day 4 before the rest of the participants are dosed with the study medications. In the absence of any safety findings in the sentinel group within 48 hours after the combination dosing of JNT-517 and itraconazole on Day 4, the rest of the cohort of participants may begin dosing with JNT-517. Dosing in Parts B and C may commence anytime after the 2 sentinel participants in Part A. Healthy volunteers will stay in the clinical research unit for the entire duration of dosing and will take study drug under direct supervision of the clinical research unit staff. This ensures compliance to study drug intake by participants. A healthy volunteer can only participant in one of the 3 parts of the study,
Locations(1)
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ACTRN12624000718549