Search

Drug-drug interaction potentials of ensitrelvir, a novel oral inhibitor of 3C-like protease of severe acute respiratory syndrome coronavirus 2, for drug transporters were evaluated by in vitro and clinical studies. The target drug transporters assessed were P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, and multidrug and toxin extrusion 1 and 2K. In vitro study revealed that ensitrelvir is a substrate for P-gp and BCRP and inhibits P-gp, BCRP, OATP1B1, OATP1B3, OCT1, and OAT3. Based on these results, a clinical drug-drug interaction study to evaluate the effect of ensitrelvir on the pharmacokinetics of P-gp, BCRP, OATP1B1, OATP1B3, and OCT1 substrates was conducted with a cocktail approach using digoxin (P-gp substrate), rosuvastatin (BCRP, OATP1B1, and OATP1B3 substrate), and metformin (OCT1 substrate). The cocktail was administered first, and after the washout period, the cocktail was coadministered with 500 mg of ensitrelvir. No treatment-emergent adverse events were observed. Pharmacokinetic analyses demonstrated that the ratios (90% confidence intervals) of "cocktail with ensitrelvir" to "cocktail without ensitrelvir" for maximum plasma concentration and area under the plasma concentration-time curve were, respectively, 2.17 (1.72-2.73) and 1.31 (1.13-1.52) for digoxin, 1.97 (1.73-2.25) and 1.65 (1.47-1.84) for rosuvastatin, and 1.03 (0.91-1.16) and 1.02 (0.94-1.11) for metformin. The results indicate that the exposure levels of digoxin and rosuvastatin increased when coadministered with ensitrelvir, but those of metformin were not changed. In conclusion, ensitrelvir has an impact on the exposure levels of P-gp, BCRP, OATP1B1, and OATP1B3 substrates., (© 2023 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Baloxavir marboxil (BXM), the oral prodrug of baloxavir acid (BXA), greatly reduces virus titers as well as influenza symptoms of uncomplicated influenza in patients., Objectives: To investigate the pharmacokinetic profiles of BXA and its efficacy against influenza A virus infection in ferrets., Methods: Ferrets were dosed orally with BXM (10 and 30 mg/kg twice daily for 1 day), oseltamivir phosphate (OSP) (5 mg/kg twice daily for 2 days) or vehicle to measure the antiviral effects of BXM and OSP. The pharmacokinetic parameters of BXA was determined after single oral dosing of BXM., Results: The maximum plasma concentrations of BXA were observed at 1.50 and 2.00 hours with the two BXM doses, which then declined with an elimination half-life of 6.91 and 4.44 hours, respectively. BXM at both doses remained detectable in the plasma in ferrets, which may be due to higher stability in liver microsomes. BXM (10 and 30 mg/kg twice daily) treatment at Day 1 post-infection (p.i.) reduced virus titers by ≥3 log10 of the 50% tissue culture infective doses by Day 2, which was significantly different compared with vehicle or OSP. Body temperature drops over time were significantly greater with BXM than with vehicle or OSP. Significant reduction in virus titers was also demonstrated when BXM was administrated after symptom onset at Day 2 p.i. compared with vehicle and OSP, although body temperature changes largely overlapped between Day 2 and Day 4., Conclusions: The results highlight the rapid antiviral action of BXM with post-exposure prophylaxis or therapeutic dosing in ferrets and offer support for further research on prevention of influenza virus infection and transmission., (© 2020 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Baloxavir marboxil (BXM) demonstrated a rapid and profound decline in infectious viral titer 1 day after BXM administration. Rapid reduction in virus titer is a characteristic of BXM. There may be a possibility that drug carryover effects have impacts on the observed antiviral effects due to the poor correlation that was observed between viral titer reduction and alleviation of influenza symptoms. Here, we report possible carryover effects of baloxavir acid (BXA), an active form of BXM, on infectious titer testing. Our findings indicate that there is little impact of BXA carryover on the infectious titer testing., (© 2020 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Objective: Individuals with multiple metabolic risk factors often experience concomitant sleep-disordered breathing (SDB). We aimed to determine the associations of SDB with individual components of metabolic syndrome independent of obesity., Methods: A cross-sectional study was conducted in 1137 employees aged 30-64 years. Apnea-hypopnea index (AHI) was assessed using a portable monitor for obstructive sleep apnea by admission. Of these, 451 participants took an oral glucose tolerance test to assess homeostatic model assessment of insulin resistance (HOMA-IR) and Matsuda insulin sensitivity index (ISI)., Results: The odds ratio (OR) of the highest category of the AHI (≥15 episodes per hour) compared to the lowest one (<5 episodes per hour) was significantly elevated for hypertension, for hypertriglyceridemia, and for low HDL-cholesterolemia when adjusted for age, sex, and alcohol and smoking status ( p < 0.05). After further adjustment for body mass index (BMI) or waist circumference, the associations for hypertension still remained statistically significant ( p < 0.05) while those for hypertriglyceridemia and low HDL-cholesterolemia were no longer significant. The association between higher insulin resistance as assessed by HOMA-IR and Matsuda ISI and higher categories of the AHI was also lost after adjustment for BMI., Conclusion: Obesity was a strong confounding factor in the association between SDB and most metabolic risk factors including insulin resistance, except for hypertension. Further longitudinal study is needed to examine the temporal or causal relationships between SDB and metabolic risk factors. This trial is registered with UMIN-CTR UMIN000028067.

Aim: To characterize subjects with a nonpositive insulinogenic index and longitudinally observe changes in their glucose tolerance., Subjects and Methods: A historical cohort study was conducted using data from the medical checkups of public school workers. Indices of insulin secretion and insulin sensitivity derived from oral glucose tolerance test (OGTT) and the incidences of diabetes and impaired glucose tolerance (IGT) were compared among subgroups of subjects with different insulinogenic index (change in insulin/change in glucose over the first 30 min on the OGTT)., Results: Of the 1464 nondiabetic subjects at baseline, 72 (4.9%) subjects had a nonpositive insulinogenic index: 42 of those subjects had a nonpositive glucose response (ΔGlu 0-30  ≤ 0) and 30 had a nonpositive insulin response (ΔIns 0-30  ≤ 0). Compared with subjects who had normal glucose tolerance (NGT) with insulinogenic index ≥ 0.4, subjects with a nonpositive glucose response had a higher first-phase Stumvoll and lower incidences of diabetes and IGT based on a log-rank test ( p < 0.05), whereas subjects with a nonpositive insulin response had lower indices of insulin secretion and a higher incidence of diabetes ( p < 0.05)., Conclusions: These results demonstrate that in the first 30 min on the OGTT, subjects with a nonpositive insulinogenic index due to a nonpositive glucose response (ΔGlu 0-30  ≤ 0) had a lower risk for future diabetes and that subjects with nonpositive insulin response (ΔIns 0-30  ≤ 0) had a higher risk for future one.

We aimed to clarify how the trajectories of 1-hour postload plasma glucose (PG) and 2-hour PG were different in the development of type 2 diabetes. Using data of repeated health checkups in Japanese workers from April 2006 to March 2016, longitudinal changes of fasting, 1-hour, and 2-hour PG on the oral glucose tolerance test were analyzed with a linear mixed effects model. Of the 1464 nondiabetic subjects at baseline, 112 subjects progressed to type 2 diabetes during the observation period (progressors). In progressors, 1-hour PG and 2-hour PG showed gradual increases with slopes of 1.33 ± 0.2 and 0.58 ± 0.2 mg/dL/year, respectively, followed by a steep increase by which they attained diabetes. Until immediately before the diabetes transition, age- and sex-adjusted mean level of 2-hour PG was 149 ± 2.7 mg/dL, 34 ± 2.7 (30%) higher compared to nonprogressors, while that of 1-hour PG was 206 ± 4.1 mg/dL, 60 ± 4.3 mg/dL (41%) higher compared to nonprogressors. In conclusion, diabetes transition was preceded by a mild elevation of 2-hour PG for several years or more. The elevation in 1-hour PG was larger than that of 2-hour PG until immediately before the transition to diabetes.