Dataset Information

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

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 ?g, 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 (C_max) and area under the curve to the last measurement (AUC_t) 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 C_max, and 4.07 (micro), 4.33 (regular) for AUC_t. For the induction study, they were 0.26 (micro) and 0.21 (regular) for C_max, and 0.16 (micro) and 0.15 (regular) for AUC_t. 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.

SUBMITTER: Park GJ

PROVIDER: S-EPMC5384691 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Park Gab-Jin GJ Bae Soo Hyeon SH Park Wan-Su WS Han Seunghoon S Park Min-Ho MH Shin Seok-Ho SH Shin Young G YG Yim Dong-Seok DS

Drug design, development and therapy 20170330

<h4>Purpose</h4>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.<h4>Patients and methods</h4>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 microdo ...[more]

PMID: 28408803

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Project description:IntroductionAdverse drug reactions related to drug-drug interactions cause harm to patients. There is a body of research on signal detection for drug interactions in collections of individual case reports, but limited use in regular pharmacovigilance.ObjectiveThe aim of this study was to evaluate the feasibility of signal detection of drug-drug interactions in collections of individual case reports of suspected adverse drug reactions.MethodsThis study was conducted in VigiBase, the WHO global database of individual case safety reports. The data lock point was 31 August 2016, which provided 13.6 million reports for analysis after deduplication. Statistical signal detection was performed using a previously developed predictive model for possible drug interactions. The model accounts for an interaction disproportionality measure, expressed suspicion of an interaction by the reporter, potential for interaction through cytochrome P450 activity of drugs, and reported information indicative of unexpected therapeutic response or altered therapeutic effect. Triage filters focused the preliminary signal assessment on combinations relating to serious adverse events with case series of no more than 30 reports from at least two countries, with at least one report during the previous 2 years. Additional filters sought to eliminate already known drug interactions through text mining of standard literature sources. Preliminary signal assessment was performed by a multidisciplinary group of pharmacovigilance professionals from Uppsala Monitoring Centre and collaborating organizations, whereas in-depth signal assessment was performed by experienced pharmacovigilance assessors.ResultsWe performed preliminary signal assessment for 407 unique drug pairs. Of these, 157 drug pairs were considered already known to interact, whereas 232 were closed after preliminary assessment for other reasons. Ten drug pairs were subjected to in-depth signal assessment and an additional eight were decided to be kept under review awaiting additional reports. The triage filters had a major impact in focusing our preliminary signal assessment on just 14% of the statistical signals generated by the predictive model for drug interactions. In-depth assessment led to three signals communicated with the broader pharmacovigilance community, six closed signals and one to be kept under review.ConclusionThis study shows that signals of adverse drug interactions can be detected through broad statistical screening of individual case reports. It further shows that signal assessment related to possible drug interactions requires more detailed information on the temporal relationship between different drugs and the adverse event. Future research may consider whether interaction signal detection should be performed not for individual adverse event terms but for pairs of drugs across a spectrum of adverse events.

Dataset Information

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

Purpose

Patients and methods

Results

Conclusion

Publications

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

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