A Phase 1 Study of MK-1942, a Negative Allosteric Modulator of mGluR2, in Healthy Japanese to Flexibly Assess Factors Including CYP2C19 Phenotype.
- 1MSD K.K., Tokyo, Japan.
- 2P-One Clinic, Keikokai Medical Corporation, Tokyo, Japan.
- 3Merck & co., Inc., Rahway, New Jersey, USA.
Abstract
MK-1942 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-1942. 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-1942. Also, since a first-in-human study in non-Japanese showed a decrease in exposures after administration with high-fat meal, we further tested an effect of low-fat 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-1942 in Japanese participants was generally well tolerated. AUC0-inf was comparable between fasted and fed (low-fat meal) state. Following a single dose of MK-1942, AUC0-inf 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-fat meal around dosing and no dose adjustment for any CYP2C19 phenotype.
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BibTeX
@article{hasegawa2026phase,
title = {{A Phase 1 Study of MK-1942, a Negative Allosteric Modulator of mGluR2, in Healthy Japanese to Flexibly Assess Factors Including CYP2C19 Phenotype.}},
author = {Chihiro Hasegawa and Yohei Doi and Tomona Hirano and Masayoshi Shirakawa and Saori Tsuchiya and Hiroyuki Yoshitsugu and Kenichi Furihata and Callie Miller and Sonal Singh and Tamara Cabalu and Ka Lai Yee and Tjerk Bueters and Zoi Alexopoulou},
journal = {Clinical and translational science},
year = {2026},
month = oct,
doi = {10.1111/cts.70748},
url = {https://europepmc.org/article/MED/42894266},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - A Phase 1 Study of MK-1942, a Negative Allosteric Modulator of mGluR2, in Healthy Japanese to Flexibly Assess Factors Including CYP2C19 Phenotype.
AU - Chihiro Hasegawa
AU - Yohei Doi
AU - Tomona Hirano
AU - Masayoshi Shirakawa
AU - Saori Tsuchiya
AU - Hiroyuki Yoshitsugu
AU - Kenichi Furihata
AU - Callie Miller
AU - Sonal Singh
AU - Tamara Cabalu
AU - Ka Lai Yee
AU - Tjerk Bueters
AU - Zoi Alexopoulou
PY - 2026
DA - 2026/10/30
JO - Clinical and translational science
DO - 10.1111/cts.70748
UR - https://europepmc.org/article/MED/42894266
AB - MK-1942 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-1942. 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-1942. Also, since a first-in-human study in non-Japanese showed a decrease in exposures after administration with high-fat meal, we further tested an effect of low-fat 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-1942 in Japanese participants was generally well tolerated. AUC0-inf was comparable between fasted and fed (low-fat meal) state. Following a single dose of MK-1942, AUC0-inf 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-fat meal around dosing and no dose adjustment for any CYP2C19 phenotype.
SN - 1752-8054
SN - 1752-8062
ER -