Aims: Soticlestat is a first-in-class selective inhibitor of cholesterol 24-hydroxylase, the enzyme that converts brain cholesterol to 24S-hydroxycholesterol (24HC), a positive allosteric modulator of N-methyl-D-aspartate receptors. Soticlestat is under development as treatment for rare developmental and epileptic encephalopathies.Methods: In this first-in-human study, 48 healthy men and women received single ascending doses of soticlestat oral solution or placebo. Subsequently, nine healthy subjects received soticlestat tablets under fed and fasting conditions to assess the relative oral bioavailability and effects of food. Serial blood and urine samples were collected for pharmacokinetic and pharmacodynamic assessments.Results: Soticlestat appeared to be well tolerated up to a single dose of 1350 mg.Adverse events (AEs) were mild in intensity, and dose-dependent increase in AE prevalence was not apparent. Soticlestat administered via oral solution was rapidly absorbed (median time to maximum plasma concentration [C max ] 0.250-0.520 h).Mean C max and area under plasma concentration-time curve from zero to infinity increased by 183-and 581-fold, respectively, over a 90-fold dose increase. Mean terminal elimination half-life was 0.820-7.16 hours across doses. Renal excretion was negligible. Administration of soticlestat tablets, and with food, lowered C max but did not affect overall exposure. Plasma 24HC concentrations generally decreased with increasing dose.Conclusions: Soticlestat appeared to be well tolerated after a single oral administration of up to 1350 mg and dose-dependently reduced plasma 24HC concentrations.Systemic exposure increased in a greater than dose-proportional manner over the dose range evaluated but was not affected by formulation or administration with food.

Epidermal growth factor receptor (EGFR) inhibitors, such as gefitinib, are examples of targeted anticancer drugs whose drug sensitivity is related to gene mutations that adds a pharmacogenetic (PG) dimension to any pharmacokinetic (PK) and pharmacodynamic (PD) analysis. The goal of this investigation was to cast the combined PG/PK/ PD variables into models that could be used to design equivalent PK/PD dosing regimens for gefitinib in genetically distinct tumor models. To this end, groups of mice bearing either s.c. LN229-wild-type EGFR or LN229-EGFRvIII mutant tumors, an EGFR inhibitor-sensitizing mutation, were given gefitinib at doses of 10 mg/kg i.v., 50 mg/kg intraarterially, and 150 mg/kg p.o. In each group, gefitinib plasma and tumor concentrations were quantitated, as were tumoral amounts of phosphorylated extracellular signal-regulated kinase (ERK) 1/2 (pERK), a PD end point that was shown to respond in a dosedependent manner in each tumor type. Hybrid physiologically based PK/PD models were developed for each tumor type, which consisted of a forcing function describing the plasma drug concentration profile, a tumor compartment depicting drug disposition in tumor, and a mechanistic target-response PD model characterizing pERK in the tumor. Gefitinib showed analogous PK properties in each tumor type yet different PD characteristics consistent with the EGFR status of the tumors. Using the PK/PD model for each tumor type, simulations were done to define multipledose regimens for gefitinib that yielded equivalent PD profiles of pERK in each tumor type. The novel concept of PK/PD equivalent dosing regimens could be applied in drug development and to delineate PG differences in drug activity.

Funding information Takeda Pharmaceutical Company LimitedAims: Soticlestat, a first-in-class inhibitor of cholesterol 24-hydroxylase (also known as cytochrome P450 46A1), is currently in development for the treatment of developmental and epileptic encephalopathies. Here, we report safety, tolerability, pharmacokinetic and pharmacodynamic outcomes from a phase I, randomized, doubleblind, placebo-controlled, multiple-rising-dose study of soticlestat in healthy adults.Methods: Five cohorts of healthy subjects (n = 8 each, randomized 6:2 soticlestat: placebo) received oral soticlestat 100-600 mg once daily (QD) or 300 mg twice daily (BID) for 10-14 days. Serial blood and urine samples were obtained on days 1, 7 (blood only) and 14.Results: Soticlestat in the dose range 100-400 mg/day for up to 14 days was generally well tolerated. In total, 45 treatment-emergent adverse events (TEAEs) were reported; most (91%) were transient and mild in intensity. Two subjects experienced TEAEs leading to discontinuation: one receiving soticlestat 600 mg QD reported a severe event of acute psychosis; another receiving 300 mg BID reported a mild event of confusional state. Steady-state exposure to soticlestat increased in a slightly greater than dose-proportional manner across the dose range 100-400 mg QD. Peak plasma concentrations were reached within 0.33-0.5 hour, and soticlestat elimination half-life was approximately 4 hours. Renal excretion of soticlestat was negligible.Soticlestat 100-400 mg QD reduced 24S-hydroxycholesterol levels by 46.8 (coefficient of variation [CV%] À9.2) to À62.7% (CV% À7.3) at steady state; values of enzymatic inhibition were compatible with antiepileptic effects observed in preclinical models. Conclusion:The pharmacokinetic and pharmacodynamic profiles of soticlestat characterized here provided a data-driven rationale for clinical trial dose selection.

are employed by Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. S. Wang has ownership interests in Takeda Pharmaceutical Company Limited. K. Stumpo has equity ownership in Astra Zeneca and Teva, and has family members with stock ownership in Bristol-Myers Squibb, AstraZeneca, GSK. I. Proscurshim is a former employee of Agenus. F. Bosch declares consultancy for, and has received honoraria and paid expert testimony from Roche, Novartis, Janssen, AbbVie, Gilead, and Mundipharma, and has

Background Carbapenemase-resistant Enterobacteriaceae (CRE) cause many serious infections resulting in increasing treatment cost, prolonged hospitalization, and mortality rate. Reduced expression and/or mutations of porins and the presence of carbapenemase promote Enterobacteriaceae survival under carbapenem treatments. Development of accurate methods for the detection of antimicrobial resistance is required not only for therapy but also to monitor the spread of resistant bacteria or resistance genes throughout the hospital and community. In this study, we aimed to evaluate the phenotypic methods, Modified Hodge test (MHT), modified carbapenem inactivation method (mCIM), and EDTA-CIM (eCIM) for the detection of carbapenemase-producing Enterobacteriaceae (CPE). Results The results showed that mCIM had a sensitivity of 100% and a specificity of 100%, whereas the MHT had a sensitivity of 84.8% and a specificity of 97.8% for the 195 CRE isolates tested (105 CPE and 90 non-CPE isolates). The sensitivity of the mCIM/eCIM to detect metallo-carbapenemases in this study was 89.3% and the specificity was 98.7% as compared to the genotypic PCR detection. Conclusions These findings indicate that the mCIM combined with eCIM is useful for detecting and distinguishing different types of carbapenemase in Enterobacteriaceae.