4
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Effect of ceritinib on the pharmacokinetics of coadministered CYP3A and 2C9 substrates: a phase I, multicenter, drug–drug interaction study in patients with ALK + advanced tumors

      research-article

      Read this article at

      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

          Ceritinib is an ALK receptor tyrosine kinase inhibitor approved as first- and second-line treatment in adult patients with ALK + metastatic non-small cell lung cancer (NSCLC). The study investigated the drug–drug interaction (DDI) potential of ceritinib when coadministered with midazolam and warfarin as probe substrates for CYP3A and CYP2C9 activity, respectively.

          Methods

          This was a phase I, multicenter, open-label, single sequence, crossover DDI study in 33 adult patients with ALK + NSCLC or other advanced tumors. A single dose of a cocktail consisting of midazolam and warfarin was administered with and without concomitant administration of ceritinib. The primary objective was to evaluate the pharmacokinetics of midazolam and warfarin. Secondary objectives included pharmacokinetics, safety, tolerability, overall response rate (ORR), and duration of response (DOR) of ceritinib 750 mg once daily.

          Results

          Ceritinib inhibited CYP3A-mediated metabolism of midazolam, resulting in a markedly increased AUC (geometric mean ratio [90% confidence interval]) by 5.4-fold (4.6, 6.3). Ceritinib also led to an increase in the AUC of S-warfarin by 54% (36%, 75%). The pharmacokinetics and safety profile of ceritinib in this study are consistent with previous reports and no new safety signals were reported. Among the 19 patients with NSCLC, efficacy (ORR: 42.1% and DCR: 63.2%) was similar to that reported previously in studies of pretreated patients with ALK + NSCLC.

          Conclusion

          Ceritinib is a strong CYP3A inhibitor and a weak CYP2C9 inhibitor. These findings should be reflected as actionable clinical recommendations in the prescribing information for ceritinib with regards to concomitant medications whose pharmacokinetics may be altered by ceritinib.

          Electronic supplementary material

          The online version of this article (10.1007/s00280-020-04180-3) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references16

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

          Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.

          The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK. Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing. Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and P = .005) and were more likely to be men (P = .036 and P = .039). Patients with EML4-ALK-positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P < .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival. EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.

            Improvement in the clinical outcome of lung cancer is likely to be achieved by identification of the molecular events that underlie its pathogenesis. Here we show that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells. Mouse 3T3 fibroblasts forced to express this human fusion tyrosine kinase generated transformed foci in culture and subcutaneous tumours in nude mice. The EML4-ALK fusion transcript was detected in 6.7% (5 out of 75) of NSCLC patients examined; these individuals were distinct from those harbouring mutations in the epidermal growth factor receptor gene. Our data demonstrate that a subset of NSCLC patients may express a transforming fusion kinase that is a promising candidate for a therapeutic target as well as for a diagnostic molecular marker in NSCLC.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              First-line ceritinib versus platinum-based chemotherapy in advanced ALK -rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study

              The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients.
                Bookmark

                Author and article information

                Contributors
                felipe.kellermann_hurtado@novartis.com
                Journal
                Cancer Chemother Pharmacol
                Cancer Chemother Pharmacol
                Cancer Chemotherapy and Pharmacology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0344-5704
                1432-0843
                4 January 2021
                4 January 2021
                2021
                : 87
                : 4
                : 475-486
                Affiliations
                [1 ]GRID grid.418424.f, ISNI 0000 0004 0439 2056, Novartis Pharmaceuticals Corporation, ; East Hanover, NJ USA
                [2 ]GRID grid.417893.0, ISNI 0000 0001 0807 2568, Fondazione IRCCS-Istituto Nazionale Dei Tumori, ; Milano, Italy
                [3 ]GRID grid.81821.32, ISNI 0000 0000 8970 9163, Medical Oncology Department, , Hospital Universitario La Paz, IdiPAZ, ; Madrid, Spain
                [4 ]CIOCC-Grupo Hospitalario de Madrid, Hosp. de Sanchinarro, Madrid, Spain
                [5 ]Henry Ford Cancer Institute, Detroit, MI USA
                [6 ]GRID grid.475435.4, Department of Oncology, , Rigshospitalet, ; Copenhagen, Denmark
                Author information
                http://orcid.org/0000-0002-5254-972X
                http://orcid.org/0000-0003-2235-1250
                Article
                4180
                10.1007/s00280-020-04180-3
                7946667
                33394101
                9a1f1f31-3173-4018-8764-284ef4be0c8f
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 29 June 2020
                : 6 September 2020
                Funding
                Funded by: Novartis Pharmaceuticals Corporation (US)
                Categories
                Original Article
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2021

                Oncology & Radiotherapy
                alk inhibitor,ceritinib,drug–drug interaction,pharmacokinetics,cyp3a,cyp2c9,midazolam,warfarin

                Comments

                Comment on this article