10
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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 (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.

          Related collections

          Most cited references 19

          • Record: found
          • Abstract: found
          • Article: not found

          Influence of CYP2C19 pharmacogenetic polymorphism on proton pump inhibitor-based therapies.

          Proton pump inhibitors (PPIs), such as omeprazole, lansoprazole, rabeprazole, esomeprazole, and pantoprazole, are mainly metabolized by CYP2C19 in the liver. There are genetically determined differences in the activity of this enzyme. The genotypes of CYP2C19 are classified into the three groups, rapid extensive metabolizer (RM), intermediate metabolizer (IM), and poor metabolizer (PM). The pharmacokinetics and pharmacodynamics of PPIs depend on CYP2C19 genotype status. Plasma PPI levels and intragastric pHs during PPI treatment in the RM group are lowest, those in the IM group come next, and those in the PM group are highest of the three groups. These CYP2C19 genotype-dependent differences in pharmacokinetics and pharmacodynamics of PPIs influence the cure rates for the gastro-esophageal reflux disease and H. pylori infection by PPI-based therapies. For the better PPI-based treatment, doses and dosing schemes of PPIs should be optimized based on CYP2C19 genotype status.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Microdosing and drug development: past, present and future.

            Microdosing is an approach to early drug development where exploratory pharmacokinetic data are acquired in humans using inherently safe sub-pharmacologic doses of drug. The first publication of microdose data was 10 years ago and this review comprehensively explores the microdose concept from conception, over the past decade, up until the current date.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              A nanogram dose of the CYP3A probe substrate midazolam to evaluate drug interactions.

              The objective of the study was to establish an in vivo method for assessing cytochrome P450 3A (CYP3A) activity using therapeutically inert nanogram doses of midazolam. We administered four escalating single doses of oral midazolam (0.0001-3 mg) to 12 healthy participants, stratified according to CYP3A5 carrier status, to assess pharmacokinetics linearity. We then evaluated the interactions with the CYP3A inhibitor ketoconazole (400 mg q.d.) after nanogram and regular doses of midazolam. Area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) were linear over the entire range of doses. Ketoconazole reduced midazolam oral clearance by 92.8%. AUC and C(max) increased by 1,540 and 363%, respectively. CYP3A5 carrier status had no influence on midazolam oral clearance or its inhibition by ketoconazole. This is the first study showing that midazolam pharmacokinetics is linear in a 30,000-fold concentration range, and therefore that nano- and microgram doses of midazolam can reliably predict the pharmacokinetics of midazolam in therapeutic doses and can be used to assess CYP3A activity even in the presence of strong CYP3A inhibitors.
                Bookmark

                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2017
                30 March 2017
                : 11
                : 1043-1053
                Affiliations
                [1 ]Department 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
                [2 ]College of Pharmacy, Chungnam National University, Daejeon, South Korea
                Author notes
                Correspondence: Dong-Seok Yim, Department of Clinical Pharmacology and Therapeutics, Seoul St Mary’s Hospital, 222 Banpo-daero, Seocho-gu, Seoul 06591, South Korea, Tel +82 2 2258 7327, Fax +82 2 2258 7876, Email yimds@ 123456catholic.ac.kr
                Article
                dddt-11-1043
                10.2147/DDDT.S131797
                5384691
                © 2017 Park et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Clinical Trial Report

                Pharmacology & Pharmaceutical medicine

                drug–drug interaction, microdose, cyp2c19

                Comments

                Comment on this article