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Hi
I am trying to design a protocol to study the disposition of midazolam (iv and oral) as a measure of CYP3A4 activity. This will be done in an academic or commercial CRC. I would appreciate if you can share some insights about various aspects of midazolam study, specifically the safety concerns.
Many thanks
Fatemeh Akhlaghi
University of Rhode Island
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Hi Fatemeh,
I just finished a clinical study with midazolam in both healthy subjects
and a group of patients. During the screening we did an ECG in each
subject along with labs, physical exam, etc., to make sure there were no
undiagnosed heart arrhythmias. In addition, we monitored pulse ox
continuously and heart rate, resp rate, and BP every 15 minutes for the
first two hours after midazolam administration during each study session.
Supplemental oxygen was given for pulse ox less than 94%, but this was
only required in one subject out of 32. In my experience midazolam is
safe when used at the relatively low doses seen in drug metabolism
studies, but of course all possible risks need to be presented to the
subject in the consent form.
Jennifer Bonner, PharmD
University of Pittsburgh
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Fatemeh, our experience is similar to Jennifer's - midazolam is an important component in the Cooperstown Cocktail studies that we have done in male and female normal healthy volunteers, and we've not encountered any safety issues, although participants are fully informed of that possibility at the informed consent.
-dean
Dean W. Knuth Jasper Clinical Research & Development, Inc. 526 Jasper Street Kalamazoo MI 49007
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Dear Ms. Fatemeh Akhlaghi,
When we did a Bioequivalence study with Midazolam, we dosed the subjects at the bedside and all the blood samples were taken as Bed side samples. Pulse oximeter monitoring was done continously for a period of 10 hours and vitals signs were checked ever 1 hour.
Surprising one subject had prolonged sedation period following midazolam in our study and when the subject inquired again regarding the medication history, he revealed that he consumed Erythromycin tablets prescribed for Upper respiratory tract infection by a private practitioner. He hide this medication history from the investigator during the screening. Later, it was concluded that the Erythromycin, a potent inhibitor of CYP 3A4 decreased the plasma clearance of Midazolam resulting in prolonged sedation in this subject.
Regarding intravenous administration, Midazolam may result in respiratory depression and respiratory arrest following IV. In some cases, if the respiratory depression and respiratory arrest not recognized promptly and treated effectively, death or hypoxic encephalopathy may result. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured before initiation of intravenous dosing.
Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease (23.3% of patients following IV and 10.8% of patients following IM administration) and apnoea (15.4% of patients following IV administration), as well as variations in blood pressure and pulse rate. Also, check the study methodology adopted in the PK/PD study done in healthy volunteers with midazolam described in the article
Daniel PW et al., Pharmacokinetics and Pharmacodynamics of a New Intranasal Midazolam Formulation in Healthy Volunteers. Anaesthesia and Analgesia. August 2006.Volume 103; Pages 344 - 349.
Quote:
Continuous pulse oximetry monitoring was done for all subjects for the first 6 h and as clinically indicated thereafter. Any observation of oxygen saturation <90% was recorded as an adverse event. In addition to spontaneously reported subjective symptoms, which were allowed at any time, subjects were also questioned as to their adverse event experience each time that vital signs were recorded .
Unquote
The full text of above mentioned article can be accessed from the following weblink
http://www.anesthesia-analgesia.org/content/103/2/344.long
Regards,
Dr.S.Gunasakaran, MD
Principal Investigator, Azidus.
Global Moderator,
Clinical Research Society
http://www.clinicalresearchsociety.org/forum/
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