Drug-Drug Interaction Study of MLC1501 Using Cocktail of Drugs Acting as Sensitive Clinical Probes/Substrates of Cytochrome P450 Isoenzymes and Transporters in Healthy Subjects

Study Overview
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Brief Summary
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This is a single-centre phase I study to assess the Drug-Drug Interaction potential of MLC1501 with a cocktail of drugs acting as sensitive clinical probe substrates of Cytochrome P450 isoenzymes and Transporters in healthy subjects . The study will have 2 cohorts, one for the CYP study and the other for the Transporters study. Eligible subjects (n=24) will be assigned to one of the 2 cohorts in a 1:1 ratio.

Official Title
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Drug-Drug Interaction Study of MLC1501 Using Cocktail of Drugs Acting as Sensitive Clinical Probes/Substrates of Cytochrome P450 Isoenzymes and Transporters in Healthy Subjects

Conditions
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Stroke

Intervention / Treatment
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* Drug: MLC1501
* Drug: CYP Cocktail
* Drug: Transporter Cocktail


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy subjects, male or female 18 to 55 years old Body mass index of 18 to <30 kg/m2 Able to understand the study requirements and provide written informed consent for participation in the study. Exclusion Criteria: Any history of or presences of medical condition (such as hypertension, diabetes mellitus, hyperlipidaemia, or any cardiac, neurological, pulmonary, gastrointestinal, hepatic, hematologic, or renal disease). Concurrent use of any medication to treat any medical condition CYP cohort: Within 72hr of the first dose of repaglinide or 5 half-lives of dosing of any medication, whichever longer, and until the end of the study Transporter cohort: Within 72hr of first dose of Transporter cocktail or 5 half-lives of dosing of any medication, whichever longer, and until the end of the study Surgery within 4 weeks prior to Screening, as determined by the Investigator History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs including cholecystectomy (uncomplicated appendectomy and hernia repair will be allowed). Use of tobacco- or nicotine-containing products within 72 hours prior to dosing. Current substance or alcohol abuse/addiction Women who are pregnant or breastfeeding. Women who are of child-bearing potential unless they maintain abstinence during study period or use barrier method of contraception and male partner using condom. Systemically acting hormonal contraceptives are not allowed, however locally acting hormonal contraceptives i.e. intrauterine device (IUD) (including Mirena) is allowed. Menopausal/post-menopausal women without menstruation for 12 consecutive months or surgically sterilized women may also be included. Intake of oral contraceptive pills or hormone replacement therapy is not allowed. Male subjects with female partner of child-bearing potential unless they maintain abstinence during study period or use of barrier method of contraception with female partner using any method of contraception. Male subjects unless they are willing not to donate sperm 90 days from last study drug administration. Use or intend to use any medications or products known to alter drug absorption, metabolism, or elimination processes, vitamin, minerals, herbal/traditional medicines including St John's Wort. 20 days prior to the first dose, unless deemed acceptable by the Investigator. Caffeine-containing beverages, substance, alcohol, grapefruit juice/grapefruit containing products, Seville oranges/ juice/, chamomile, liquorice, broccoli or brussels sprouts within the 72hrs prior to dosing. Any known hypersensitivity/allergic reaction/anaphylaxis to food, animal stings, drugs inclusive of drugs used in CYP and transporter cocktail in the study /components of MLC1501, or members of the Fabaceae/Leguminosae family (e.g. legume, pea, bean), Polygalaceae family (e.g. milkwort, snakeroot), Apiaceae/ Umbelliferae family (e.g. anise, caraway, carrot, celery, dill, parsley, parsnip), or Quillaja bark (soapbark). Any abnormal physical examination findings or laboratory results (including serum electrolytes such as sodium, potassium and chloride) or abnormal ECG findings (like atrial fibrillation or flutter, supraventricular tachycardia, pre-excitation or wolff Parkinson white. Etc) at screening that is considered to be clinically significant by the study investigator. Any medical condition which, in the study investigator's opinion, may jeopardize the subject by his/her participation in this study, may hamper his/her ability to complete procedures required in the study, or affect the validity of the study results. Administration of an investigational drug (new chemical entity) or device trial within 90 days or 5 half-lives, whichever is longer, prior to the first dose, or concomitant participation in an investigation study involving no drug administration.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Subjects will be assigned to either CYP or Transporter cohort in ratio of 1:1.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CYP Cohort<br>MLC1501 & CYP cocktail drugs | Drug: MLC1501<br>* MLC1501 capsules (4 capcules (2000 mg) twice a day)<br>Drug: CYP Cocktail<br>* Repaglinide 0.25 mg, caffeine 100 mg, warfarin 10 mg (with vitamin K), omeprazole 40 mg, dextromethorphan 30 mg, midazolam 2 mg<br>|
| Experimental: Transporter Cohort<br>MLC1501 & Transporter cocktail drugs | Drug: MLC1501<br>* MLC1501 capsules (4 capcules (2000 mg) twice a day)<br>Drug: Transporter Cocktail<br>* Digoxin 0.25 mg, furosemide 1 mg, metformin 10 mg, rosuvastatin 10 mg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in area under curve (AUC) of individual substrates is being assessed between cocktail alone and cocktail + MLC1501 administration | Assayed in plasma samples collected at various time points after cocktail administration and cocktail + MLC1501 administration. | Through study completion, an average of 29 days and 18 days for CYP and Transporter cohort, respectively. | 
| Change in maximum concentration (Cmax) of individual substrates is being assessed between cocktail alone and cocktail + MLC1501 administration | Assayed in plasma samples collected at various time points after cocktail administration and cocktail + MLC1501 administration. | Through study completion, an average of 29 days and 18 days for CYP and Transporter cohort, respectively. | 
| Change in time taken to reach maximum concentration (Tmax) of individual substrates is being assessed between cocktail alone and cocktail + MLC1501 administration | Assayed in plasma samples collected at various time points after cocktail administration and cocktail + MLC1501 administration. | Through study completion, an average of 29 days and 18 days for CYP and Transporter cohort, respectively. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ratio of geometric means (GMR) between cocktail alone and cocktail + MLC1501 for the AUC and Cmax of the corresponding probe |  | Through study completion, an average of 29 days and 18 days for CYP and Transporter cohort, respectively. |