Midazolam microdose to determine systemic and pre-systemic metabolic CYP3A activity in humans
Nicolas Hohmann1, Franziska Kocheise, Alexandra Carls
1Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Heidelberg, Germany.
Aim:
We aimed to establish a method to assess systemic and pre-systemic cytochrome P450 (CYP) 3A activity using ineffective microgram doses of midazolam.
Methods:
In an open, one sequence, crossover study, 16 healthy participants received intravenous and oral midazolam at microgram (0.001 mg intravenous and 0.003 mg oral) and regular milligram (1 mg intravenous and 3 mg oral) doses to assess the linearity of plasma and urine pharmacokinetics.
Results:
Dose-normalized AUC and Cmax were 37.1 ng ml(-1 ) h [95% CI 35.5, 40.6] and 39.1 ng ml(-1) [95% CI 30.4, 50.2] for the microdose and 39.0 ng ml(-1 ) h [95% CI 36.1, 42.1] and 37.1 ng ml(-1) [95% CI 26.9, 51.3] for the milligram dose. CLmet was 253 ml min(-1) [95% CI 201, 318] vs. 278 ml min(-1) [95% CI 248, 311] for intravenous doses and 1880 ml min(-1) [95% CI 1590, 2230] vs. 2050 ml min(-1) [95% CI 1720, 2450] for oral doses. Oral bioavailability of a midazolam microdose was 23.4% [95% CI 20.0, 27.3] vs. 20.9% [95% CI 17.1, 25.5] after the regular dose. Hepatic and gut extraction ratios for microgram doses were 0.44 [95% CI 0.39, 0.49] and 0.53 [95% CI 0.45, 0.63] and compared well with those for milligram doses (0.43 [95% CI 0.37, 0.49] and 0.61 [95% CI 0.53, 0.70]).
Conclusion:
The pharmacokinetics of an intravenous midazolam microdose is linear to the applied regular doses and can be used to assess safely systemic CYP3A activity and, in combination with oral microdoses, pre-systemic CYP3A activity.
Insights
Microgram doses of midazolam can safely assess systemic and pre-systemic cytochrome P450 (CYP) 3A activity. This method provides linear pharmacokinetics comparable to regular doses, enabling reliable activity measurements.
Area of Science:
- Pharmacology
- Drug Metabolism
- Clinical Pharmacology
Background:
- Cytochrome P450 (CYP) 3A enzymes are crucial for drug metabolism.
- Accurate assessment of CYP3A activity is vital for drug development and personalized medicine.
- Current methods may involve higher doses or complex procedures.
Purpose of the Study:
- To establish a safe and effective method for assessing systemic and pre-systemic CYP3A activity.
- To utilize ineffective microgram doses of midazolam for this assessment.
- To evaluate the linearity of midazolam pharmacokinetics at microgram versus milligram doses.
Main Methods:
- An open-label, one-sequence, crossover study was conducted.
- Sixteen healthy participants received intravenous and oral midazolam at microgram and milligram doses.
- Plasma and urine pharmacokinetics were analyzed to assess linearity.
Main Results:
- Dose-normalized AUC and Cmax showed linearity between microgram and milligram doses.
- Metabolic clearance (CLmet) was comparable for both dose ranges.
- Oral bioavailability and hepatic/gut extraction ratios were similar for microgram and milligram doses, indicating comparable CYP3A activity.
Conclusions:
- Intravenous midazolam microdoses exhibit linear pharmacokinetics relative to regular doses.
- This microdose approach can be safely employed to assess systemic CYP3A activity.
- Combined with oral microdoses, this method can also evaluate pre-systemic CYP3A activity.
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