A drug-drug interaction study of DNL343 and midazolam in healthy volunteers
Research type
Research Study
Full title
A Drug-Drug Interaction Study of the Effect of DNL343 on Midazolam Pharmacokinetics in Healthy Participants
IRAS ID
1007175
Contact name
Gabrielle Brill
Contact email
Sponsor organisation
Denali Therapeutics Inc.
Eudract number
2022-003926-38
ISRCTN Number
ISRCTN26840121
Research summary
Summary of Research\nThe purpose of this study is to investigate the study drug DNL343. The main objectives of this study are as follows:\n\n- To investigate if there are any effects/interactions between DNL343 and midazolam (a drug commonly used before medical procedures and surgery to cause drowsiness and sometimes used in the treatment of anxiety and insomnia), and to evaluate how these interactions affect the safety of DNL343 and midazolam.\n\n- To investigate the concentration of midazolam and DNL343 in the blood, how this changes over a period of time and to measure how this concentration differs when midazolam and DNL343 are taken alone versus in combination.\n\n- To investigate the concentration of a metabolite (products produced when a drug is broken down in the body) of midazolam, in the blood, and to measure how this concentration differs when midazolam is taken on its own versus in combination with DNL343. \n\n- To determine the safety and tolerability (degree to which side effects of a drug can be tolerated) of DNL343 when it is administered on two occasions; once when it is taken alone and once when it is administered in combination with midazolam.\n\nThis study is classed as a drug-drug interaction study. This means that you will be given a drug (midazolam) which has known effects and a known method of breakdown (metabolism) in the body and also given the study drug (DNL343) to determine if there is any effect or interaction between the drugs in the body.\n\nIn the study, participants will take a single dose of midazolam on Day 1, followed by DNL343 once daily for 13 days from Day 2 up to Day 14 before taking a single dose of both DNL343 and midazolam together on Day 15. Blood samples will be taken at set time points in order to measure the concentration of midazolam and DNL343 in the blood and to evaluate how the concentration of midazolam and DNL343 differs when the drugs are taken alone versus when taken in combination.\n\nSummary of Results\n“The purpose of this study was to investigate the study drug DNL343 and determine if there were any effects/interactions between DNL343 and midazolam (a drug commonly used before medical procedures and surgery to cause drowsiness and sometimes used in the treatment of anxiety and insomnia).\n\nThe primary objective of the study was to investigate the concentration of midazolam and DNL343 in the blood, how this changed over a period of time, and to measure how this concentration differed when midazolam was taken alone versus in combination with DNL343.\n\nThe study consisted of 16 participants and included a screening visit (between 28 and 2 days prior to first dose of midazolam), one treatment period consisting of 18 days with 17 overnight stays and a post-study follow-up visit approximately 8 days following discharge from the clinical unit on Day 17.\n\nThis study was classed as a drug-drug interaction study. This means that participants were given a drug (midazolam), which has known effects and a known method of breakdown (metabolism) in the body, and also given the study drug (DNL343) to determine if there was any effect or interaction between the drugs in the body and whether administration of DNL343 affected the safety, tolerability or concentration of midazolam in the blood. Blood samples were taken at set time points throughout the study to measure the concentration of midazolam and DNL343 in the blood and to evaluate how the concentration of midazolam and DNL343 differed when the midazolam was taken alone versus in combination with DNL343.\n\nWhen a single dose of midazolam was administered with DNL343, the overall blood levels of midazolam were approximately 61% lower compared to midazolam administered alone.\n\nBased upon the results of the study, DNL343 is considered a moderate inducer of CYP3A and has the potential to lower the blood levels of other drugs which use the CYP3A enzyme as part of their metabolism and breakdown in the body. In summary, the data gathered during the study was considered sufficient to meet the objectives of the study.“
REC name
Wales REC 2
REC reference
23/WA/0041
Date of REC Opinion
10 Mar 2023
REC opinion
Further Information Favourable Opinion