Evaluation of Drug-Drug Interactions and Food Effect on Leriglitazone Pharmacokinetics in Healthy Male Subjects with Gemfibrozil, Itraconazole, and Carbamazepine
- Trial ID
- 2025-521508-23-00
- Protocol
- MT-1-02
- Sponsor
- Minoryx Therapeutics S.L.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this Phase 1, open-label, single-center study is to determine the **drug-drug interaction** (DDI) effect on the single-dose pharmacokinetics (PK) of oral **leriglitazone** when coadministered with **gemfibrozil** (Part A), **itraconazole** (Part B), or **carbamazepine** (Part C) as precipitants. Additionally, the study aims to determine the effect of a high-fat breakfast on the single-dose PK of oral leriglitazone (Part D). Understanding these interactions is clinically relevant as it informs the safe and effective use of leriglitazone in patients, particularly those with **adrenoleukodystrophy**, by identifying potential alterations in drug metabolism and absorption.
Secondary objectives include: - Assessing the safety and tolerability of a single oral dose of leriglitazone when administered alone or concomitantly with gemfibrozil, itraconazole, carbamazepine, and following a high-fat breakfast. - Exploring the potential impact of **CYP2C8** and **CYP3A4** gene polymorphisms on the PK of leriglitazone in Parts A, B, and C. - Exploring the potential impact of **CYP3A5** gene polymorphism on the PK of leriglitazone when given concomitantly with CYP3A4 inhibitors, such as itraconazole, in Part B.
Participants
The clinical trial focuses on **adrenoleukodystrophy** and involves a study population of healthy male participants aged 18 to 50 years, with a body mass index (BMI) ranging from 18 to 30 kg/m². The sponsor has not provided information regarding the total number of participants. Participants were selected based on their ability to provide informed consent and their general health status, which was assessed through medical history, physical examination, and clinical laboratory tests. The trial excludes female subjects and does not involve a vulnerable population. Participants are required to abstain from alcohol, caffeine, and methylxanthine-containing beverages or food, such as coffee, tea, cola, chocolate, and energy drinks, starting 72 hours prior to admission and throughout their stay at the clinical research center. This lifestyle consideration is crucial for maintaining the integrity of the study results.
Plans and Procedures
The clinical trial is a **Phase I** open-label, single-center study designed to evaluate drug-drug interactions (DDI) and the food effect on oral **leriglitazone** in healthy male subjects. The trial involves the administration of leriglitazone alongside **gemfibrozil**, **itraconazole**, and **carbamazepine** to assess their impact on the pharmacokinetics (PK) of leriglitazone. The study is structured into four parts: Part A with gemfibrozil, Part B with itraconazole, Part C with carbamazepine, and Part D assessing the effect of a high-fat breakfast on leriglitazone. The primary endpoints include the maximum concentration (Cmax), area under the curve (AUC) from time zero to the last measurable concentration (AUC(0-last)), and AUC from time zero to infinity (AUC(0-inf)) of leriglitazone. Secondary endpoints involve additional PK parameters and the exploration of gene polymorphisms' impact on leriglitazone PK.
The trial is expected to commence recruitment on July 1, 2025, and conclude by December 29, 2025. Participants will be involved in the study for a duration that includes multiple visits: an initial screening visit to confirm eligibility, followed by study visits corresponding to each part of the trial, and a final end-of-study visit. The inclusion criteria specify healthy male participants aged 18 to 50 years with a body mass index (BMI) between 18 and 30 kg/m². Participants must be able to provide informed consent and agree to specific contraceptive measures if applicable. Exclusion criteria are not specified in the provided data.
Study visits are sequenced to ensure comprehensive data collection and participant safety. The screening visit involves medical history, physical examination, and laboratory tests to confirm eligibility. Subsequent visits align with each trial part, where participants receive the study drug and undergo PK sampling and safety assessments. The end-of-study visit includes final evaluations and debriefing. Participant involvement may be terminated early due to adverse events, non-compliance with study protocols, or withdrawal of consent. The trial is conducted under strict ethical guidelines, ensuring participant safety and data integrity throughout the study duration.
Treatment
The clinical trial involves the administration of several **experimental medications** and **non-experimental treatments** to evaluate drug-drug interactions and the effect of food on the pharmacokinetics of oral leriglitazone. The primary experimental medication is **leriglitazone**, administered as an oral suspension. This small molecule, identified by the sponsor product code Min-102, is provided by MINORYX. The administration route is oral, and the formulation is not pediatric. Leriglitazone is designated as an orphan drug, indicating its use in treating rare conditions.
**Itraconazole** is used as a comparator treatment in the study. It is administered in the form of capsules, with each capsule containing 100 mg of the active substance. The product, marketed under the name Orungal, is manufactured by JANSSEN-CILAG INTERNATIONAL NV. The administration route is oral, and the formulation is not pediatric. Itraconazole is a small molecule with a chemical origin, and it is classified under the ATC code J02AC02.
**Gemfibrozil** is another comparator treatment used in the trial. It is administered as a film-coated tablet, with each tablet containing 600 mg of the active substance. The product, known as Gemfibrozilo STADA, is provided by LABORATORIO STADA, S.L. The administration route is oral use, and the formulation is not pediatric. Gemfibrozil is a small molecule with a chemical origin, classified under the ATC code C10AB04.
**Carbamazepine** is used in two different formulations as comparator treatments. The first formulation is a prolonged-release tablet, with each tablet containing 300 mg of the active substance, marketed as Neurotop retard 300 by G.L. PHARMA GMBH. The second formulation is also a prolonged-release tablet, with each tablet containing 200 mg of the active substance, marketed as Finlepsin 200 retard by TEVA PHARMACEUTICALS POLSKA SP. Z O.O. Both formulations are administered orally and are not pediatric. Carbamazepine is a small molecule with a chemical origin, classified under the ATC code N03AF01.
Participant compliance with the dosing schedule will be monitored throughout the trial. The study aims to assess the pharmacokinetic interactions of leriglitazone when co-administered with gemfibrozil, itraconazole, or carbamazepine, as well as the impact of a high-fat breakfast on leriglitazone's pharmacokinetics.
Efficacy
The efficacy of the clinical trial will be assessed by evaluating the **pharmacokinetics (PK)** of oral leriglitazone when coadministered with gemfibrozil, itraconazole, or carbamazepine, as well as the effect of food on its PK. The primary endpoints include the maximum concentration (Cmax), area under the curve from time zero to the last measurable concentration (AUC(0-last)), and area under the curve from time zero to infinity (AUC(0-inf)) of leriglitazone. These parameters will be measured to determine the drug-drug interaction (DDI) effect and the impact of a high-fat breakfast on leriglitazone's PK.
Secondary endpoints will further explore the PK profile of leriglitazone, including time to reach maximum concentration (tmax), terminal elimination rate constant (λz), half-life (t1/2), apparent clearance (CL/F), and apparent volume of distribution (Vz/F). Additionally, the PK of the metabolite M3 will be assessed through Cmax, tmax, AUC(0-inf), λz, and t1/2. Metabolite/parent ratios (MR) such as MRCmax, MRAUC(0-last), and MRAUC(0-inf) will also be evaluated. The trial will explore the potential impact of CYP2C8, CYP3A4, and CYP3A5 gene polymorphisms on the PK of leriglitazone, with endpoints including serum gene expression levels of these polymorphisms versus PK.
Safety assessments will include reported adverse events (AEs), changes in electrocardiograms (PR, QRS, QT, and QTcF), vital signs, and clinical safety laboratory tests. The trial is designed to provide comprehensive data on the PK interactions and safety profile of leriglitazone under various conditions, contributing to the understanding of its efficacy and safety in healthy male subjects.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Healthy male participants (aged 18 to 50 years [inclusive]) with a BMI between 18 and 30 kg/m2 (inclusive).
- Male participants who are voluntarily able to give informed consent.
- Non-sterilized male participants with female partners of childbearing potential are eligible to participate if they agree to ONE of the following from Screening (signing the Informed Consent Form [ICF]) until at least 90 days after the last dose of study intervention. A) Are abstinent from penile-vaginal intercourse. B) Agree to use a male condom and have their partner use a contraceptive method with a failure rate of < 1% per year when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant (see Section 10.4). In addition, male participants must refrain from donating sperm from Screening (signing the ICF) until at least 12 weeks after the last dose of study intervention. The ICF will include information regarding potential effects on human spermatogenesis.
- Participants without any clinically significant finding upon completion of medical history, physical examination, and clinical laboratory test results, in the opinion of an Investigator.
- Ability and willingness to abstain from alcohol, caffeine, and methylxanthine containing beverages or food (eg, coffee, tea, cola, chocolate, energy drinks) from 72 hours (3 days) prior to admission to the clinical research center and during the stay in the clinical research center.
Exclusion Criteria
- All female participants will be excluded.
- Participants of East Asian ancestry will be excluded from Part C to reduce the risk of severe AEs by carbamazepine (observed in those carrying HLA3101 or HLA-B1502).
- Males with female partners who are pregnant, lactating, or planning to attempt to become pregnant during the study or within 90 days after dosing of the study intervention.
- Participants who have a clinically relevant history or presence of respiratory, gastrointestinal, renal, hepatic, hematologic, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, and connective tissue diseases or disorders.
- Known type 1 or 2 diabetic.
- Participants who have a history or presence of relevant drug hypersensitivity or intolerance to pioglitazone, any other thiazolidinedione, leriglitazone, gemfibrozil, carbamazepine, and itraconazole.
- Participant is taking or has taken honokiol, pioglitazone, or other thiazolidinediones within 3 months prior to screening.
- Participant has a requirement for treatment with a prohibited concomitant medication.
- Participant has a condition that could modify the absorption of the study intervention.
- Participants with any history or presence of suicidal ideation.
- Participants with any history or presence of malignancy.
- Participants who have a history or presence of sleep apnea.
- Participants who have a clinically significant relevant surgical history within 3 months prior to screening. a) Participants with a history of bariatric surgery at any time are to be excluded.
- Participants who have a clinically significant relevant family history of diseases of genetic origin.
- Participants who have a history or presence of relevant atopy including any confirmed significant allergic reactions against any drug, or multiple drug allergies (non-active hay fever is acceptable), history of anaphylaxis, any foods allergies.
- Participants who have a history or presence of any other hypersensitivity reaction in general which may affect their safety in this study, including contact hypersensitivity to ECG electrodes.
- Participants who: a) Have any history of alcoholism and/or drug abuse. b) Have any known factor, condition, or disease that might interfere with treatment compliance, study conduct, or interpretation of the results such as drug or alcohol dependence or psychiatric disease. c) Test positive for alcohol or drugs of abuse at screening and/or on each admission. d) Consume more than 14 units of alcohol a week. 1 unit of alcohol is equivalent to 8 g of pure alcohol (unit = 1 glass of wine [125 mL] = 1 measure of spirits = ½ pint of beer).
- Participants who smoke regularly or have smoked cigarettes (or equivalent) and/or regularly use nicotine-based products within 6 months prior to first admission.
- Participants who demonstrate excess in xanthine (eg, coffee, tea, cola drinks, and chocolate) consumption (more than 8 cups of coffee or equivalent per day).
- Participants who have a clinically significant infection or known inflammatory process at screening or at admission on Day −1.
- Participants who have acute gastrointestinal symptoms at the time of screening or admission on Day −1 (eg, nausea, vomiting, diarrhea, or heartburn).
- Participants who have a chronic or acute infection (viral, bacterial, or other) at the time of screening or admission on Day −1.
- Participants with clinically significant laboratory safety test results at screening and/or on admission on Day −1, and in particular: a) Liver function tests outside 1.5 × ULN of the local reference range. b) Renal function tests outside of the ULN of the local reference range. c) Absolute neutrophile count outside of the local reference range. d) Hemoglobin level < 12 g/dL.
- Participants who have a positive test result for hepatitis B surface antigen, hepatitis B core antibody, hepatitis C antibody, or human immunodeficiency virus (I and II) antibody.
- Participants with an infection requiring antibiotic therapy within the last 1 month prior to screening.
- Participants who have received a live vaccine within 6 months prior to screening in this study or during the study.
- Participants who have received any other vaccine within 21 days prior to screening of this study or during the study.
- Participants whose screening supine BP ≥ 140 mmHg (systolic) or ≥ 90 mmHg (diastolic), following at least 5 minutes of supine rest. If BP is ≥ 140 mmHg (systolic) or ≥ 90 mmHg (diastolic), the BP should be repeated 2 more times and, if within limits, the participant can be enrolled
- Participants whose screening supine 12-lead ECG demonstrates a QTcF interval > 450 msec or a QRS interval > 120 msec. If the QTcF exceeds 450 msec, or the QRS exceeds 120 msec, the ECG should be repeated 2 more times and, if within limits, the participant can be enrolled
- Participants who have used any prescribed medications within 30 days of admission, or less than 5 half-lives (whichever is longer).
- Participants who have used over the counter medication (excluding routine vitamins, sporadic acetaminophen, but including megadose vitamin therapy [intake of 20 to 600 times the recommended daily dose], herbal, and dietary supplements) within 7 days of admission.
- Participants who have received strong inhibitors or inducers of CYP enzymes including natural products within 30 days of admission or within 5 half-lives of such drugs, whichever is the longest. See list of inhibitors/inducers at https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers.
- Participants who have received the last dose of an investigational product more than 3 months ago but who are on extended follow-up.
- Participants who have previously received leriglitazone in another study.
- Participants who have lost or donated > 500 mL of blood within 90 days prior to screening or intend to donate blood or blood products during the study.
- Participants who have consumed grapefruit, grapefruit juice, Seville oranges, Seville orange marmalade, Seville orange juice, or other products containing grapefruit or Seville oranges from 7 days prior to admission to the clinical research unit.
- Participants who are affiliated with the Sponsor, contract research organization, or clinical research center.
- Participants who are considered to be consenting under duress.
- Participants with dietary restrictions such as medical restrictions or those on a vegan diet.
- Participants who, in the opinion of an Investigator (or designee), should not participate in this study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Poland | Not Recruiting | 01 Jul 2025 | 73 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Finlepsin 200 retard, 200 mg, tabletki o przedłużonym uwalnianiu | Other | TABLETKI O PRZEDŁUŻONYM UWALNIANIU | ORAL | — | — | PRD732076 |
Orungal, 100 mg, kapsułki | Other | KAPSUŁKI | ORAL | — | — | PRD714252 |
Gemfibrozilo STADA 600 mg comprimidos recubiertos con película EFG | Other | COMPRIMIDOS RECUBIERTOS CON PELÍCULA | ORAL USE | — | — | PRD394377 |
Neurotop retard 300, 300 mg, tabletki o przedłużonym uwalnianiu | Other | TABLETKI O PRZEDLUZONYM UWALNIANIU | ORAL | — | — | PRD729506 |