{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T03:41:47Z","timestamp":1792381307687,"version":"4.4.0"},"reference-count":14,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T00:00:00Z","timestamp":1792281600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T00:00:00Z","timestamp":1792281600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    MK\u20101942 is a negative allosteric modulator of the metabotropic glutamate receptor 2 that was investigated for the treatment of Alzheimer's disease and depression. Nonclinical studies with recombinant human CYPs and genotyped human hepatocytes suggested that CYP2C19 is involved in the metabolism of MK\u20101942. Given the high incidence of different CYP2C19 polymorphisms in the Japanese population, a Phase 1 single and multiple dose study in healthy Japanese participants provided an opportunity to determine the involvement of CYP2C19 phenotype on the clinical PK of MK\u20101942. Also, since a first\u2010in\u2010human study in non\u2010Japanese showed a decrease in exposures after administration with high\u2010fat meal, we further tested an effect of low\u2010fat meal on PK in the Japan study. The study was designed with flexibility which enabled dose selection for the multiple dose panels, based on the totality of safety and PK data. Oral administration of single and multiple doses of MK\u20101942 in Japanese participants was generally well tolerated. AUC\n                    <jats:sub>0\u2010inf<\/jats:sub>\n                    was comparable between fasted and fed (low\u2010fat meal) state. Following a single dose of MK\u20101942, AUC\n                    <jats:sub>0\u2010inf<\/jats:sub>\n                    was ~70% increased in CYP2C19 poor metabolizer (PM) vs. extensive metabolizer (EM). Therefore, a decision was made to test the multiple dose separately for each CYP2C19 phenotype, rather than grouping them into a single panel. As opposed to the expectation from the single dose result, steady state exposures were similar among CYP2C19 phenotypes. These data supported the subsequent global Phase 2 study to permit a low\u2010fat meal around dosing and no dose adjustment for any CYP2C19 phenotype.\n                  <\/jats:p>","DOI":"10.1111\/cts.70748","type":"journal-article","created":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T03:26:44Z","timestamp":1792380404000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Phase 1 Study of\n                    <scp>MK<\/scp>\n                    \u20101942, a Negative Allosteric Modulator of\n                    <scp>mGluR2<\/scp>\n                    , in Healthy Japanese to Flexibly Assess Factors Including\n                    <scp>CYP2C19<\/scp>\n                    Phenotype"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1473-5617","authenticated-orcid":false,"given":"Chihiro","family":"Hasegawa","sequence":"first","affiliation":[{"name":"MSD K.K.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Doi","sequence":"additional","affiliation":[{"name":"MSD K.K.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomona","family":"Hirano","sequence":"additional","affiliation":[{"name":"MSD K.K.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayoshi","family":"Shirakawa","sequence":"additional","affiliation":[{"name":"MSD K.K.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saori","family":"Tsuchiya","sequence":"additional","affiliation":[{"name":"MSD K.K.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Yoshitsugu","sequence":"additional","affiliation":[{"name":"MSD K.K.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2464-8201","authenticated-orcid":false,"given":"Kenichi","family":"Furihata","sequence":"additional","affiliation":[{"name":"P\u2010One Clinic Keikokai Medical Corporation  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8199-0063","authenticated-orcid":false,"given":"Callie","family":"Miller","sequence":"additional","affiliation":[{"name":"Merck &amp; co., Inc.  Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9376-9649","authenticated-orcid":false,"given":"Sonal","family":"Singh","sequence":"additional","affiliation":[{"name":"Merck &amp; co., Inc.  Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamara","family":"Cabalu","sequence":"additional","affiliation":[{"name":"Merck &amp; co., Inc.  Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3099-4440","authenticated-orcid":false,"given":"Ka Lai","family":"Yee","sequence":"additional","affiliation":[{"name":"Merck &amp; co., Inc.  Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0911-8756","authenticated-orcid":false,"given":"Tjerk","family":"Bueters","sequence":"additional","affiliation":[{"name":"Merck &amp; co., Inc.  Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1785-1800","authenticated-orcid":false,"given":"Zoi","family":"Alexopoulou","sequence":"additional","affiliation":[{"name":"Merck &amp; co., Inc.  Rahway New Jersey USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,18]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.jalz.2014.02.001","article-title":"Alzheimer's Disease Facts and Figures","volume":"10","author":"Alzheimer's Association","year":"2014","journal-title":"Alzheimer's & Dementia"},{"key":"e_1_2_10_3_1","first-page":"26","volume-title":"World Alzheimer Report 2014 \u2010 Dementia and Risk Reduction, an Analysis of Protective and Modifiable Factors","author":"Prince M.","year":"2014"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.neuropharm.2004.01.018","article-title":"Pharmacological Manipulation of mGlu2 Receptors Influences Cognitive Performance in the Rodent","volume":"46","author":"Higgins G. A.","year":"2004","journal-title":"Neuropharmacology"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0028-3908(01)00193-9","article-title":"Presynaptic Group II Metabotropic Glutamate Receptors Reduce Stimulated and Spontaneous Transmitter Release in Human Dentate Gyrus","volume":"42","author":"Dietrich D.","year":"2002","journal-title":"Neuropharmacology"},{"key":"e_1_2_10_6_1","unstructured":"A.Arasappan S.Hoyt R.Wilkening et\u00a0al. \u201cDiscovery of MK\u20101942 a Potent Selective and CNS\u2010Penetrant mGluR2 Negative Allosteric Modulator \u201d(2024). Poster presented at 9th RSC\/SCI Symposium on GPCRs in Medicinal Chemistry; Verona Italy."},{"key":"e_1_2_10_7_1","unstructured":"Z.Alexopoulou C.Miller T.Bueters et\u00a0al. \u201cPharmacokinetics Tolerability and Receptor Occupancy of MK\u20101942 a Negative Allosteric Modulator of mGluR2 in Phase 1 Studies of Healthy Individuals \u201dSubmitted."},{"key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/clpt.1985.194","article-title":"Interethnic Differences in Genetic Polymorphism of Debrisoquin and Mephenytoin Hydroxylation Between Japanese and Caucasian Populations","volume":"38","author":"Nakamura K.","year":"1985","journal-title":"Clinical Pharmacology & Therapeutics"},{"key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/0163-7258(89)90047-8","article-title":"Genetic Polymorphism of S\u2010Mephenytoin Hydroxylation","volume":"43","author":"Wilkinson G. R.","year":"1989","journal-title":"Pharmacology & Therapeutics"},{"key":"e_1_2_10_10_1","article-title":"Randomized, Double\u2010Blind, Placebo\u2010Controlled Trial of the mGlu2\/3 Negative Allosteric Modulator Decoglurant in Partially Refractory Major Depressive Disorder","volume":"81","author":"Umbricht D.","year":"2020","journal-title":"Journal of Clinical Psychiatry"},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1093\/ijnp\/pyab062","article-title":"Evaluation of the Safety, Tolerability, and Pharmacokinetic Profiles of TP0473292 (TS\u2010161), a Prodrug of a Novel Orthosteric mGlu2\/3 Receptor Antagonist TP0178894, in Healthy Subjects and Its Antidepressant\u2010Like Effects in Rodents","volume":"25","author":"Watanabe M.","year":"2022","journal-title":"International Journal of Neuropsychopharmacology"},{"key":"e_1_2_10_12_1","first-page":"1491","article-title":"Nonlinear Kinetics After High\u2010Dose Omeprazole Caused by Saturation of Genetically Variable CYP2C19","volume":"23","author":"Rost K. L.","year":"1996","journal-title":"Hepatology"},{"key":"e_1_2_10_13_1","unstructured":"US Food and Drug Administration \u201cAssessing the Effects of Food on Drugs in INDs and NDAs\u2010Clinical Pharmacology. Guidance for Industry \u201d(2022) https:\/\/www.fda.gov\/media\/121313\/download."},{"key":"e_1_2_10_14_1","unstructured":"M.SharpandL. L. C.Dohme \u201cA Phase 2a\/2b Randomized Placebo\u2010Controlled Clinical Study to Evaluate the Safety and Efficacy of MK\u20101942 as Adjunctive Therapy in Participants with Mild to Moderate Alzheimer's Disease Dementia (NCT05602727) \u201dhttps:\/\/ClinicalTrials.gov."},{"key":"e_1_2_10_15_1","unstructured":"Ministry of Health Labour and Welfare \u201cBasic Principles for Conducting Phase 1 Studies in Japanese Prior to Initiating Multi\u2010Regional Clinical Trials Including Japan for Drugs in Which Early Clinical Development is Preceding Outside Japan PSB\/PED Notification No. 1225\u20132 (Director Pharmaceutical Evaluation Division Pharmaceutical Safety Bureau December 25 2023) \u201d(2023) https:\/\/www.pmda.go.jp\/files\/000266727.pdf."}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70748","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.70748","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70748","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T03:26:56Z","timestamp":1792380416000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.70748"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,18]]},"references-count":14,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2026,11]]}},"alternative-id":["10.1111\/cts.70748"],"URL":"https:\/\/doi.org\/10.1111\/cts.70748","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,18]]},"assertion":[{"value":"2026-05-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70748"}}