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

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.


Mean plasma concentration–time profile of omeprazole.Notes: Inhibition study with fluconazole (A); induction study with rifampin (B).
© Copyright Policy
Related In: Results  -  Collection

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

f2-dddt-11-1043: Mean plasma concentration–time profile of omeprazole.Notes: Inhibition study with fluconazole (A); induction study with rifampin (B).

Mentions: The mean plasma concentration–time profiles of omeprazole in the two studies are shown in Figure 2, and summarized PK-parameter/exposure changes are listed in Tables 3 and 4. Individual plasma concentration-time profiles of omeprazole are shown in Figure S1 and Figure S2. The Cmax and AUCt of omeprazole only in inhibition/induction studies were 1.23±0.7 and 1.88±0.85 ng/mL for microdoses and 528.49±426.85 and 480.81±393.83 ng⋅h/mL for regular doses, respectively. Those PK parameters as baseline characteristics without DDI were not different statistically between the two studies: P=0.18 and P=0.589 for Cmax and AUCt (microdose) and P=0.937 and P=0.818 for Cmax and AUCt (regular dose).


Drug – drug interaction of microdose and regular-dose omeprazole with a CYP2C19 inhibitor and inducer
Mean plasma concentration–time profile of omeprazole.Notes: Inhibition study with fluconazole (A); induction study with rifampin (B).
© Copyright Policy
Related In: Results  -  Collection

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

f2-dddt-11-1043: Mean plasma concentration–time profile of omeprazole.Notes: Inhibition study with fluconazole (A); induction study with rifampin (B).
Mentions: The mean plasma concentration–time profiles of omeprazole in the two studies are shown in Figure 2, and summarized PK-parameter/exposure changes are listed in Tables 3 and 4. Individual plasma concentration-time profiles of omeprazole are shown in Figure S1 and Figure S2. The Cmax and AUCt of omeprazole only in inhibition/induction studies were 1.23±0.7 and 1.88±0.85 ng/mL for microdoses and 528.49±426.85 and 480.81±393.83 ng⋅h/mL for regular doses, respectively. Those PK parameters as baseline characteristics without DDI were not different statistically between the two studies: P=0.18 and P=0.589 for Cmax and AUCt (microdose) and P=0.937 and P=0.818 for Cmax and AUCt (regular dose).

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.