Asia-Inclusive Global Development of Enpatoran: Results of an Ethno-Bridging Study, Intrinsic/Extrinsic Factor Assessments and Disease Trajectory Modeling to Inform Design of a Phase II Multiregional Clinical Trial.

Enpatoran is a novel, highly selective, and potent dual toll-like receptor (TLR)7 and TLR8 inhibitor currently under development for the treatment of autoimmune disorders including systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), and myositis. The ongoing phase II study (WILLOW; NCT05162586) is evaluating enpatoran for 24 weeks in patients with active SLE or CLE and is currently recruiting. To support development of WILLOW as an Asia-inclusive multiregional clinical trial (MRCT) according to International Conference on Harmonisation E5 and E17 principles, we have evaluated ethnic sensitivity to enpatoran based on clinical pharmacokinetic (PK), pharmacodynamic (PD), and safety data from an ethno-bridging study (NCT04880213), supplemented by relevant quantitative PK, PD, and disease trajectory modeling (DTM) results, and drug metabolism/disease knowledge. A single-center, open-label, sequential dose group study in White and Japanese subjects matched by body weight, height, and sex demonstrated comparable PK and PD properties for enpatoran in Asian vs. non-Asian (White and other) subjects across single 100, 200, and 300 mg orally administered doses. DTM suggested no significant differences in SLE disease trajectory for Asian vs. non-Asian individuals. Aldehyde oxidase (AOX) is considered to be a key contributor to enpatoran metabolism, and a literature review indicated no relevant ethnic differences in AOX function based on in vitro and clinical PK data from marketed drugs metabolized by AOX, supporting the conclusion of low ethnic sensitivity for enpatoran. Taken together, the inclusion of Asian patients in MRCTs including WILLOW was informed based on a Totality of Evidence approach.

The Sense of Agency in Driving Automation.

Driving automation has been developing rapidly during the latest decade. However, all current technologies of driving automation still require human drivers' monitoring and intervention. This means that during driving automation, the control by human driver and by the driving automation system are blended. In this case, if the human driver loses the sense of agency over the vehicle, he/she may not be able to actively engage in driving, and may excessively rely on the driving automation system. This review focuses on the subjective feeling of agency of the human driver over the vehicle in such situations. We address the possible measures of agency in driving automation, and discuss the insights from literatures on the sense of agency in joint control, robotics, automation, and driving assistance. We suggest that maintaining the sense of agency for human driver is important for ethical and safety reasons. We further propose a number of avenues for further research, which may help to better design an optimized driving automation considering human sense of agency.

A phase I study of sorafenib in combination with S-1 plus cisplatin in patients with advanced gastric cancer.

BACKGROUND: Sorafenib inhibits several receptor tyrosine kinases involved in tumor progression and angiogenesis. S-1, an oral fluorouracil antitumor drug, plus cisplatin (CDDP) is the standard regimen for advanced gastric adenocarcinoma (AGC) in Japan. The purpose of this phase I study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of sorafenib in combination with S-1 plus CDDP. METHODS: Patients with histologically confirmed previously untreated AGC were evaluated for eligibility and treated with sorafenib (400 mg bid, days 1-35), S-1 (40 mg/m(2) bid, days 1-21), and CDDP (60 mg/m(2), day 8). Treatment was continued until disease progression or unacceptable toxicity. Pharmacokinetics for sorafenib, 5-FU, and CDDP were investigated in cycle 1. RESULTS: Thirteen patients were enrolled and received at least one dose of the study treatment. No specific or serious adverse event was newly reported in this study. Five patients had partial response and 8 had stable disease as the best response. Pharmacokinetic analysis showed no significant differences in the exposures of sorafenib when administered alone or in combination with S-1 and CDDP. CONCLUSIONS: The present phase I study demonstrates the acceptable toxicity and preliminary efficacy of combined treatment with S-1, CDDP, and sorafenib.

Evaluation of interethnic differences in repinotan pharmacokinetics by using population approach.

Repinotan is a selective full serotonin receptor agonist at the 5-HT1A subtype which has been studied in phase I and II studies involving over 500 healthy subjects and patients. Repinotan is primarily metabolized by CYP2D6 which is known to be subject to polymorphism and ethnic differences in its quantitative and qualitative expression pattern. In order to investigate the effect of ethnicity on repinotan pharmacokinetics (PK) between a Caucasian and Japanese population and to explain PK variability, this population PK evaluation was conducted. A population PK model was established based on the data of 1314 blood samples from 241 patients from 3 Phase II studies. This analysis has characterized the repinotan PK, with particular attention to ethnicity. Using the MIXTURE subroutine of NONMEM, evidence was provided for different CL groups. Repinotan plasma levels in the 'High CL' subgroup, which comprised the majority of patients, did not show relevant differences between a Japanese and Caucasian population. In the 'Low CL' subgroup, Japanese and Caucasian populations were different. These findings are consistent with the published literature, which reports ethnic differences in the distribution of CYP2D6 activity. The finding of a greater percentage of patients with intermediate CL in the Japanese population falling between poor and extensive metabolizers is consistent with the distribution pattern of CYP2D6 in the Japanese population. The results of this evaluation can be used to assist in designing future trials.