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Drug-drug interaction of microdose and regular-dose omeprazole with a CYP2C19 inhibitor and inducer
Gab-Jin Park1, Soo Hyeon Bae1, Wan-Su Park1
1Department of Clinical Pharmacology and Therapeutics, Seoul St Mary's Hospital, PIPET (Pharmacometrics Institute for Practical Education and Training), College of Medicine, Catholic University of Korea, Seoul, South Korea.
Purpose:
A microdose drug-drug interaction (DDI) study may be a valuable tool for anticipating drug interaction at therapeutic doses. This study aimed to compare the magnitude of DDIs at microdoses and regular doses to explore the applicability of a microdose DDI study.
Patients And Methods:
Six healthy male volunteer subjects were enrolled into each DDI study of omeprazole (victim) and known perpetrators: fluconazole (inhibitor) and rifampin (inducer). For both studies, the microdose (100 μg, cold compound) and the regular dose (20 mg) of omeprazole were given at days 0 and 1, respectively. On days 2-9, the inhibitor or inducer was given daily, and the microdose and regular dose of omeprazole were repeated at days 8 and 9, respectively. Full omeprazole pharmacokinetic samplings were performed at days 0, 1, 8, and 9 of both studies for noncompartmental analysis.
Results:
The magnitude of the DDI, the geometric mean ratios (with perpetrator/omeprazole only) of maximum concentration (Cmax) and area under the curve to the last measurement (AUCt) of the microdose and the regular dose were compared. The geometric mean ratios in the inhibition study were: 2.17 (micro) and 2.68 (regular) for Cmax, and 4.07 (micro), 4.33 (regular) for AUCt. For the induction study, they were 0.26 (micro) and 0.21 (regular) for Cmax, and 0.16 (micro) and 0.15 (regular) for AUCt. There were no significant statistical differences in the magnitudes of DDIs between microdose and regular-dose conditions, regardless of induction or inhibition.
Conclusion:
Our results may be used as partial evidence that microdose DDI studies may replace regular-dose studies, or at least be used for DDI-screening purposes.
Insights
Microdose drug-drug interaction (DDI) studies effectively predict interactions at regular doses. These findings suggest microdose studies can replace or aid in screening for DDIs.
Area of Science:
- Pharmacokinetics and Drug Metabolism
- Drug Interaction Studies
Background:
- Drug-drug interactions (DDIs) can alter drug efficacy and safety.
- Microdose studies offer a potential method for predicting DDIs at therapeutic doses.
Purpose of the Study:
- To compare the magnitude of DDIs at microdoses versus regular doses.
- To evaluate the applicability of microdose DDI studies for predicting clinical outcomes.
Main Methods:
- Six healthy males participated in DDI studies involving omeprazole as the victim drug.
- Omeprazole was administered at both microdose (100 μg) and regular (20 mg) doses, with and without CYP enzyme inhibitors (fluconazole) or inducers (rifampin).
- Pharmacokinetic sampling and noncompartmental analysis were performed to determine Cmax and AUCt.
Main Results:
- The magnitude of DDIs, assessed by geometric mean ratios of Cmax and AUCt, showed no significant statistical differences between microdose and regular-dose conditions.
- Inhibition study ratios for Cmax were 2.17 (micro) and 2.68 (regular); for AUCt, they were 4.07 (micro) and 4.33 (regular).
- Induction study ratios for Cmax were 0.26 (micro) and 0.21 (regular); for AUCt, they were 0.16 (micro) and 0.15 (regular).
Conclusions:
- Microdose DDI studies demonstrated comparable results to regular-dose studies.
- These findings support the use of microdose DDI studies as a replacement for, or a screening tool in, regular-dose DDI assessments.