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Drug – drug interaction of microdose and regular-dose omeprazole with a CYP2C19 inhibitor and inducer

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ABSTRACT

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.

No MeSH data available.


Pharmacokinetic parameter ratios (GMR) of DDI.Notes: Inhibition study with fluconazole (A); induction study with rifampin (B). Wilcoxon signed-rank test comparing GMR of pharmacokinetic parameters in microdose and regular-dose conditions.Abbreviations: AUC, area under the (plasma concentration–time) curve; Cmax, maximum plasma concentration; GMR, geometric mean ratio.
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f3-dddt-11-1043: Pharmacokinetic parameter ratios (GMR) of DDI.Notes: Inhibition study with fluconazole (A); induction study with rifampin (B). Wilcoxon signed-rank test comparing GMR of pharmacokinetic parameters in microdose and regular-dose conditions.Abbreviations: AUC, area under the (plasma concentration–time) curve; Cmax, maximum plasma concentration; GMR, geometric mean ratio.

Mentions: The magnitude of DDI was described using the GMR (with/without perpetrator) of the Cmax and the AUCt of omeprazole. Wilcoxon signed-rank tests were conducted to compare the GMRs in microdose and regular-dose conditions in the two studies. In both the inhibition and induction studies, the GMRs of Cmax and AUCt (with/without perpetrator) at microdoses and regular doses were not significantly different (Table 2 and Figure 3).


Drug – drug interaction of microdose and regular-dose omeprazole with a CYP2C19 inhibitor and inducer
Pharmacokinetic parameter ratios (GMR) of DDI.Notes: Inhibition study with fluconazole (A); induction study with rifampin (B). Wilcoxon signed-rank test comparing GMR of pharmacokinetic parameters in microdose and regular-dose conditions.Abbreviations: AUC, area under the (plasma concentration–time) curve; Cmax, maximum plasma concentration; GMR, geometric mean ratio.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5384691&req=5

f3-dddt-11-1043: Pharmacokinetic parameter ratios (GMR) of DDI.Notes: Inhibition study with fluconazole (A); induction study with rifampin (B). Wilcoxon signed-rank test comparing GMR of pharmacokinetic parameters in microdose and regular-dose conditions.Abbreviations: AUC, area under the (plasma concentration–time) curve; Cmax, maximum plasma concentration; GMR, geometric mean ratio.
Mentions: The magnitude of DDI was described using the GMR (with/without perpetrator) of the Cmax and the AUCt of omeprazole. Wilcoxon signed-rank tests were conducted to compare the GMRs in microdose and regular-dose conditions in the two studies. In both the inhibition and induction studies, the GMRs of Cmax and AUCt (with/without perpetrator) at microdoses and regular doses were not significantly different (Table 2 and Figure 3).

View Article: PubMed Central - PubMed

ABSTRACT

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.

No MeSH data available.