Objective: This is the first clinical study in Japanese healthy subjects to assess the safety, tolerability, and pharmacokinetics of lasmiditan, a selective serotonin 5-HT_1F receptor agonist being developed for the acute treatment of migraine.

Methods: This was a Phase 1, randomized, 3-period, subject- and investigator-blind, single-center crossover study. On Day 1 of each period of their assigned treatment sequence, Japanese subjects received single oral doses of lasmiditan 50, 100, 200, and 400 mg or placebo or repeated oral doses (2 single doses administered 2 hours apart) of lasmiditan 200 mg or placebo, and Caucasian subjects received single oral doses of lasmiditan 50, 100, and 200 mg or placebo.

Results: A total of 16 Japanese and 11 Caucasian subjects participated in this study. No deaths, serious adverse events (AEs) , or discontinuations due to AEs occurred. Frequently reported treatment-emergent AEs (TEAEs) were somnolence, dizziness, and hypoesthesia. The frequency of TEAEs in Japanese subjects was higher and dose-dependent compared with Caucasian subjects, in whom no such trend was observed. However, the Japanese AE data was comparable to an integrated summary of TEAEs in 556 non-Japanese healthy subjects with similar doses of lasmiditan administration. Increases in exposure to lasmiditan were observed with increasing dose. The pharmacokinetics of lasmiditan were similar between Japanese and Caucasian subjects, with a mean half-life of approximately 4 hours.

Conclusions: The similar safety and pharmacokinetic profiles of lasmiditan between Japanese and Caucasian subjects support further development of lasmiditan in Japanese populations at the same dose levels studied in Caucasian populations.

In recent years, large-scale genome analysis technology and information processing technology are rapidly progressing in the medical field, which leads a global-wide transformation of the entire medical care. The advancement of technologies also promotes utilization of clinical biomarkers, which play an important role in precision medicine, and clinical biomarker-based medical innovation is currently taking place in various fields in drug development.

This article discusses the efficient biomarker strategy to achieve precision medicine, and seeks the solutions of addressed issues. The development process of clinical biomarkers is divided into three phases: Discovery, Translational, and Qualification. Discovery section introduces the latest approaches which led to identification of clinical biomarker candidates through omics, and gap between utilization of clinical biomarker in clinical development and clinical application. Translational section introduces points to consider for analytical methods validation, and statistical points such as clinical sensitivity, specificity, and false discovery rate (FDR), for biomarker selection. This section also refers to the importance of genomic cohort studies, as well as the issues related to genome-wide association analysis. Qualification section discusses approaches to show clinical utility of biomarkers, by introducing enrichment strategies, master protocol strategies, etc. In addition, this section refers to new drug application and accelerated review led by biomarker strategies.

This article describes the current status and prospect of drug development based on the utilization of clinical biomarkers, which is an issue imposed on stakeholders who promote biomarker strategies, and we expect that it will help realize personalized therapy in the future.

Although ligand binding assays are commonly used for the determination of serum concentrations of monoclonal antibody drugs in humans, the serum concentrations measured by these assays are potentially increased by cross-reaction with endogenous proteins and decreased by the presence of neutralizing antibodies. Recently, proteomic approaches using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) have been employed for the measurement of monoclonal antibody drugs in human specimens. For serum concentrations of monoclonal antibody drugs, the proteomic approaches require complicated pretreatment processes including immunopurification, denaturation, reduction, alkylation, tryptic digestion, desalination, clean-up, and reconstitution. These pretreatment processes are time-consuming and potentially cause analytical variations. To date, the proteomic approaches using LC-MS/MS methods have not been fully applied to clinical practice. We have constructed quantitative analysis workflow that uses a signature peptide selected by Fourier transform mass spectrometer to ensure its uniqueness in human serum, extracts serum immunoglobulins with immobilized Protein G to reduce the matrix effect if needed, and employs immobilized trypsin for rapid protein digestion. The entire pretreatment and quantitation using the present LC-MS/MS method can be completed within one day. Additionally, the analytical performance data obtained from these methods meet the standards of international guidance. The present report describes the construction of quantitative analysis workflow for measurement of monoclonal antibody drugs in human serum. Our approaches would contribute to promote therapeutic drug monitoring of monoclonal antibody drugs in clinical practice.