A randomized, open-label and two-way crossover study to evaluate the effects of SIR1-365 after a single oral dose of 300 mg on the activities of CYP450 isoform 3A in healthy young subjects

INTERVENTION: SIR1‐365 is a potent and selective allosteric kinase inhibitor of RIP1 with favorable drug‐like properties in vitro and in vivo. RIP1 inhibitors may be beneficial for the treatments of degenerative diseases including neurodegenerative and systemic inflammatory diseases. However, no RIP1 inhibitors have been assessed yet in large clinical studies for any of those diseases. In vitro work has shown weak inhibition of SIR1‐365 on the activity of CYP450 isoform 3A4. Thus, the objective of this study is to evaluate the effects of SIR1‐365 after a single oral dose of 300 mg on the activities of CYP450 isoform 3A by comparing the PK profiles of midazolam (the sensitive index substrate for CYP450 isoform 3A) when administered alone or together with SIR1‐365. This will be a randomized, open‐label, single‐dose and two‐way crossover study to assess effects of SIR1‐365 after a single oral dose of 300 mg on the activities of CYP450 isoform 3A in healthy young subjects using sensitive index substrates (midazolam) for CYP450 isoform 3A. The total duration of participation for each subject will be up to 41 days including up to 27 days for screening, 7 days in the unit and a follow‐up phone call about 7 days after discharge from the unit. Approximately 10 male and 10 female healthy subjects will be randomized to the study according to a randomization schedule prepared before the start of the study. After an overnight fast for at least 10 hours, subjects in Sequence 1 will receive a single dose of midazolam oral solution at 5 mg alone (prepared from Midazolam injection ampoule 5mg/mL), while subjects in Sequence 2 will receive a single oral 300mg dose of SIR1‐365 tablets plus a single dose of midazolam oral solution at 5 mg. Both treatments will be administered under fas CONDITION: Inflammatory and Immune System ‐ Other inflammatory or immune system disorders Neurodegenerative disease;inflammatory disease; ; Neurodegenerative disease ; inflammatory disease Neurological ‐ Neurodegenerative diseases SECONDARY OUTCOME: Safety will be continuously monitored using composite of data available through physical exam and laboratory assessments. ; ; Clinical Laboratory tests include: ; ‐ Blood haematology ; ‐ Blood chemistry ; ‐ Blood coagulation ; ‐ Urinalysis ; ; A complete physical examination will include but not limited to the evaluation of the following organs or body systems: skin; head, eyes, ears, nose, and throat; thyroid; respiratory, cardiovascular, and central nervous systems; abdomen (liver and spleen); lymph nodes; and extremities.[Days 1, 2, 3, 4 , 5, 6 and 13 after intervention. A complete physical examination will be completed at day 6. Complete Vital Signs Measurements will be completed pre‐dose and 24 hours post dose (First dose administered on Days 1 & 5). Oxygen saturation will be measured (pulse oximetry) every 15 minutes up to 1 hour following administration of midazolam. 12‐lead Electrocardiogram (ECG) and Clinical Laboratory tests will be completed at Day 6. Adverse Events will be monitored at all visits.] INCLUSION CRITERIA: 1. Are capable of signing informed consent form (ICF) and complying with study procedures; 2. Male or female healthy subjects between the ages of 18 and 45 years old, inclusive; 4. Considered healt PRIMARY OUTCOME: To obtain the pharmacokinetic profile of midazolam and it’s metabolite 1‐hydroxymidazolam, when midazolam is administered alone. Pharmacokinetic parameters of AUC and Cmax will be calculated.[Fourteen blood samples will be collected at the following timepoints; 30 min before dosing, and 0.25 hour, 0.5 hour, 1 hour (+/‐2 min), 1.5 hour, 2 hours, 3 hours, 4 hours (+/‐ 5 min), 16 hours and 24 hours after dosing.] To obtain the pharmacokinetic profile of midazolam and it’s metabolite 1‐hydroxymidazolam, when midazolam is administered with SIR1‐365. Pharmacokinetic parameters of AUC and Cmax will be calculated.[Fourteen blood samples will be collected at the following timepoints; 30 min before dosing, and 0.25 hour, 0.5 hour, 1 hour (+/‐2 min), 1.5 hour, 2 hours, 3 hours, 4 hours (+/‐ 5 min), 16 hours and 24 hours after dosing.] 3. Women of childbearing potential (WOCBP) must have a negative pregnancy test at Screening and be practicing a medically acceptable method of contraception with an annual failure rate of less than 1% during the study and 30 days after discontinuation of study treatment. Women are considered not childbearing potential if they are > 1 year postmenopausal or surgically sterile (ie, hysterectomy, bilateral oophorectomy, or bilateral salpingectomy tubal ligation). If serum ßHCG is the standard of care, then this value can be used to determine eligibility. All male patients with female partners of child‐bearing potential must use two acceptable methods of contraception (one of which must be a barrier method), during and for 90 days after participation in the study.