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

Abstract

PurposeA 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 methodsSix 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.ResultsThe 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.ConclusionOur 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.

Application of Microdosed Intravenous Omeprazole to Determine Hepatic CYP2C19 Activity

“…In our study, in which we administered the same doses intravenously, metabolic ratios were similar, and the dose-normalized exposure with the 20-mg dose was only 7% larger than exposure with the microdose, and this difference was not statistically significant. When comparing our results with the findings of single oral omeprazole doses, 11 these findings indicated that the intravenous route of administration is much less susceptible to PK nonlinearity and suggest that microdose omeprazole is well suited as a probe drug especially considering the new drug-drug interaction guideline of the FDA.…”

“…For omeprazole, limited microdose data in healthy volunteers indicate a more than proportional concentration increase of oral omeprazole between doses of 0.1 and 20 mg. As a consequence, plasma drug exposure (AUC 0-∞ ) after microdoses was only 0.35-0.39 of the dose-normalized AUC of the regular dose. 11 Thus, the difference of omeprazole plasma concentration between microdose and regular dose was almost 3-fold. In our study, in which we administered the same doses intravenously, metabolic ratios were similar, and the dose-normalized exposure with the 20-mg dose was only 7% larger than exposure with the microdose, and this difference was not statistically significant.…”

“…We intended to cover a large range of different omeprazole clearance values and hence decided to also enroll PMs of CYP2C19. However, no formal case number estimation was performed; rather, sample size was based on comparable earlier studies that had successfully addressed similar questions with 6, 11 8, 21 or 10 participants 13 and had also evaluated the interaction with an azole. AUC for both omeprazole doses used with and without voriconazole as perpetrator was compared using a bioequivalence analysis with the calculation of the geometric mean ratio (GMR) and its 2-sided 90%CI.…”

“…9,10 Oral microdose omeprazole probes (0.1 mg) have recently been tested, which indeed revealed a nonlinear dose-concentration relationship between a microdose and a regular (20mg) omeprazole dose. 11 Because CYP2C19 is also expressed in the gut, 12 nonlinearity could originate from saturation in the gut and might be less pronounced after intravenous administration. Therefore, we conducted a clinical trial to test the dose-concentration relationship between an intravenous microdose (0.1 mg) and an intravenous regular dose (20 mg) of omeprazole in healthy CYP2C19 extensive metabolizers (EMs) and poor metabolizers (PMs) and in addition aimed to reproduce a well-established drug interaction of the CYP2C19 inhibitor voriconazole on omeprazole microdose and regular-dose PK.…”

Biotransformation of Ilaprazole in Human Liver Microsomes and Human: Role of CYP3A4 in Ilaprazole Clearance and Drug-Drug Interaction

“…A majority of PPIs are metabolized mainly by CYP2C19 and partially by CYP3A4 (Klotz et al, 2004;Klotz, 2006;de Bortoli et al, 2013). The pharmacokinetics of PPIs such as omeprazole can be significantly affected by CYP2C19 polymorphism (Qiao et al, 2006;Hunfeld et al, 2008) and coadministered CYP2C19 inhibitors (Park et al, 2017). Ilaprazole overcomes the CYP2C19-related limitations of other PPIs.…”