A Phase 1 Study of MK ‐1942, a Negative Allosteric Modulator of mGluR2 , in Healthy Japanese to Flexibly Assess Factors Including CYP2C19 Phenotype

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. AUC 0‐inf was comparable between fasted and fed (low‐fat meal) state. Following a single dose of MK‐1942, AUC 0‐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.