A Phase 1 Study of Ensitrelvir Fumaric Acid Tablets Evaluating the Safety, Pharmacokinetics and Food Effect in Healthy Adult Populations.

Background: A reported clinical pharmacokinetics and safety study of suspension formulation of ensitrelvir, a therapeutic agent used in severe acute respiratory syndrome coronavirus 2 infection, demonstrated favorable pharmacokinetics and was well tolerated in healthy male Japanese and White participants. Understanding the safety and pharmacokinetic features of ensitrelvir (using the formulation approved for clinical use) in various populations, and the effect of food, is crucial for optimal clinical use.

Objectives: The objectives of this study were to (1) assess the safety, tolerability, and pharmacokinetics of ensitrelvir following multiple-dose administration of ensitrelvir tablets in populations with different races, ages, and sex; and (2) assess the effect of food on the pharmacokinetics of ensitrelvir tablets in the fasted or fed state.

Inspiratory and Expiratory Computed Tomography Imaging Clusters Reflect Functional Characteristics in Chronic Obstructive Pulmonary Disease.

Purpose: Disease probability measure (DPM) is a useful voxel-wise imaging assessment of gas-trapping and emphysematous lesions in patients with chronic obstructive pulmonary disease (COPD). To elucidate the progression of COPD, we performed a cluster analysis using the following DPM parameters: normal (DPM), gas-trapping (DPM), and emphysematous lesions (DPM). Our findings revealed the characteristics of each cluster and the 3-year disease progression using imaging parameters.

Evaluation of the Drug-Drug Interaction Potential of Ensitrelvir Fumaric Acid with Cytochrome P450 3A Substrates in Healthy Japanese Adults.

Background: Management of drug-drug interactions (DDIs) for ensitrelvir, a novel 3-chymotrypsin-like protease inhibitor of SARS-CoV-2 infection is crucial. A previous clinical DDI study of ensitrelvir with midazolam, a clinical index cytochrome P450 (CYP) 3A substrate, demonstrated that ensitrelvir given for 5 days orally with a loading/maintenance dose of 750/250 mg acted as a strong CYP3A inhibitor.

Objectives: The objectives of this study were to investigate the effect of ensitrelvir on the pharmacokinetics of CYP3A substrates, dexamethasone, prednisolone and midazolam, and to assess the pharmacokinetics, safety, and tolerability of ensitrelvir following multiple-dose administration of ensitrelvir.

Evaluation of Drug-Drug Interactions of Ensitrelvir, a SARS-CoV-2 3CL Protease Inhibitor, With Transporter Substrates Based on In Vitro and Clinical Studies.

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.

Safety, Tolerability, and Pharmacokinetics of the Novel Antiviral Agent Ensitrelvir Fumaric Acid, a SARS-CoV-2 3CL Protease Inhibitor, in Healthy Adults.

Ensitrelvir is a novel selective inhibitor of the 3C-like protease of SARS-CoV-2, which is essential for viral replication. This phase 1 study of ensitrelvir assessed its safety, tolerability, and pharmacokinetics of single (part 1,  = 50) and multiple (part 2,  = 33) ascending oral doses. Effect of food on the pharmacokinetics of ensitrelvir, differences in pharmacokinetics of ensitrelvir between Japanese and white participants, and effect of ensitrelvir on the pharmacokinetics of midazolam (a cytochrome P450 3A [CYP3A] substrate) were also assessed.

Population pharmacokinetic and exposure-response analyses of d-amphetamine after administration of lisdexamfetamine dimesylate in Japanese pediatric ADHD patients.

Lisdexamfetamine dimesylate, a prodrug of d-amphetamine, has been approved for treatment of attention-deficit/hyperactivity disorder (ADHD). The purposes of this study were constructing a population pharmacokinetic model of d-amphetamine after dosing of lisdexamfetamine dimesylate and assessing influential factors on the pharmacokinetics of d-amphetamine in Japanese pediatric patients with ADHD. Additionally, the exposure-response relationship was evaluated for Japanese pediatric patients with ADHD using a clinical rating scale, the ADHD Rating Scale IV (ADHD RS-IV, efficacy endpoint) total score as a response index.

Pharmacokinetic modeling and simulation for dose rationale of doripenem in neonates and infants.

The aims of this study were to construct a population pharmacokinetic model of doripenem in neonates and infants and to assess the dosing regimen for patients <3 months of age using Monte-Carlo pharmacokinetic/pharmacodynamic (PKPD) simulations. In the population pharmacokinetic analysis using 187 plasma concentrations from 47 neonates and infants, a two-compartment model well described plasma doripenem concentrations with the most significant covariates of chronological age and gestational age identified for the pharmacokinetics of doripenem. Monte-Carlo simulations suggested that the selected dosages for neonates and infants based on chronological age and gestational age (5 or 10 mg/kg) would provide ≥90% target attainment of 40%fT against MIC of 2 μg/mL in all age groups.

Novel Respiratory Impedance-Based Phenotypes Reflect Different Pathophysiologies in Chronic Obstructive Pulmonary Disease Patients.

Purpose: The forced oscillation technique (FOT) is a non-invasive method to measure respiratory impedance, the respiratory resistance (Rrs) and reactance (Xrs). The disease probability measure (DPM) is a useful computed tomography (CT) imaging variable for the assessment of gas trapping and emphysema in patients with chronic obstructive pulmonary disease (COPD) using pairs of inspiratory and expiratory CT images. We aimed to develop FOT-based phenotypes and determine whether the phenotypes and their imaging characteristics could facilitate the understanding of COPD pathophysiology.

A phase 1, randomized, double-blind, placebo-controlled study to evaluate the safety, tolerability, and pharmacokinetics of single and multiple doses of lisdexamfetamine dimesylate in Japanese and Caucasian healthy adult subjects.

Aim: To assess safety, tolerability, and pharmacokinetics of lisdexamfetamine dimesylate in Japanese and Caucasian healthy adults.

Methods: A phase 1, double-blind, randomized, placebo-controlled, single- and multiple-dose study in Japanese and Caucasian subjects. Subjects received lisdexamfetamine 20 mg or placebo on Day 1, then lisdexamfetamine 20 mg/d (Days 4-8), 50 mg/d (Days 9-13), 70 mg/d (Days 14-18), or matching placebo.

Population Pharmacokinetics of Doripenem in Pediatric Patients and Monte-Carlo Pharmacokinetic-Pharmacodynamic Simulations for Dosing Regimen Assessment.

The aims of this study were to evaluate the pharmacokinetics of doripenem (Finibax, Doribax, S-4661), a parenteral carbapenem antibiotic, in pediatric patients based on concentrations of doripenem in plasma after administration of 20 mg/kg 2 or 3 times daily and to evaluate the dosing regimens by using Monte-Carlo pharmacokinetic-pharmacodynamic simulations. Population pharmacokinetic analysis was performed by using 190 plasma concentrations of doripenem from 99 patients (2 months-13 years old). The two-compartment model well described the doripenem plasma concentrations in pediatric patients.

Pharmacokinetics, Safety, and Tolerability of Single and Multiple Doses of Guanfacine Extended-Release Formulation in Healthy Japanese and Caucasian Male Adults.

Background And Objective: Guanfacine extended-release (guanfacine XR) could be a useful treatment option for children and adolescent patients with attention-deficit/hyperactivity disorder (ADHD). As an initial step in the development in Japan, the pharmacokinetics, safety and tolerability were assessed in healthy Japanese and non-Hispanic Caucasian adults.

Methods: A Phase 1, double-blind, randomized, placebo-controlled, single- and multiple-oral dose escalation study of guanfacine XR was conducted.

Population pharmacokinetics of peramivir in healthy volunteers and influenza patients.

Unlabelled: Peramivir is an intravenous anti-influenza agent that inhibits viral growth by selectively inhibiting neuraminidase in human influenza A and B viruses. To characterize its pharmacokinetics, a population pharmacokinetic analysis of peramivir was performed using 3,199 plasma concentration data samples from 332 subjects in six clinical studies in Japan and the United States, including studies with renal impairment subjects, elderly subjects, and influenza patients. A three-compartment model well described the plasma concentration data for peramivir, and creatinine clearance was found to be the most important factor influencing clearance.

Prediction of Pharmacokinetics and Pharmacodynamics of Doripenem in Pediatric Patients.

The aim of this paper was to predict the pharmacokinetics of doripenem in pediatrics from adult pharmacokinetic data and to investigate dosing regimens in pediatrics using Monte-Carlo pharmacokinetics/pharmacodynamics (PK/PD) simulations prior to the initiation of pediatric clinical trials. The pharmacokinetics in pediatrics was predicted by using a previously reported approach for β-lactam antibiotics. Monte-Carlo simulation was employed to assess dosing regimens in pediatrics based on the predicted pharmacokinetic profiles and the minimum inhibitory concentration (MIC) distributions of Haemophilus influenzae and Streptococcus pneumoniae, which frequently cause infectious pediatric diseases.

Population pharmacokinetics of doripenem in Japanese subjects and Monte-Carlo simulation for patients with renal impairment.

Integrated analysis of all plasma concentration data obtained from phase 1 studies in Japanese subjects, including a high dose study and special population studies, was conducted to thoroughly re-investigate the pharmacokinetics of doripenem by means of a population approach. Dose adjustments for patients with renal impairment were assessed by Monte-Carlo pharmacokinetics/pharmacodynamics simulation. The population pharmacokinetics of doripenem was evaluated using 921 plasma concentration data from 92 subjects from eight phase 1 studies in Japan.

Pharmacokinetic analysis of doripenem in elderly patients with nosocomial pneumonia.

Doripenem is a parenteral carbapenem antibiotic with broad-spectrum antimicrobial activity. A pharmacokinetic (PK) analysis of a 1-h intravenous (i.v.

[Incidence of insertion difficulty using Proseal LMA and the efficacy of recommended insertion maneuvers].

Background: According to the instruction manual, the sniffing position (SP) and the slight lateral approach (SLA) are the recommended insertion methods using Proseal laryngeal mask airway (PLMA). However, the efficacy of these methods has not been assessed.

Methods: The incidence and the reason of the insertion with difficulty were assessed in 50 adult patients.

Glucuronidation converting methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921) to a potent apical sodium-dependent bile acid transporter inhibitor, resulting in a hypocholesterolemic action.

Methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921) is a novel inhibitor of the ileal apical sodium-dependent bile acid transporter (ASBT/SLC10A2) developed for the treatment of hypercholesterolemia. The present study investigated the hypocholesterolemic action of S-8921 glucuronide (S-8921G) in rats. The plasma concentration of S-8921G was higher than that of S-8921 after single oral administration of S-8921 in normal rats, and S-8921G was excreted into the bile (13% dose).

[Diagnosis of intracranial hypotension syndrome by a bolus or continuous epidural injection of normal saline solution].

A 75-year-old man had neck sprain by traffic accident. He had headache but not orthostatic at first. He also had dysesthesia and pain of upper limbs, neck pain, and nausea.

Anesthetic management of a patient with Gerstmann-Sträussler-Scheinker syndrome (mutation of prion protein).

Gerstmann-Sträussler-Scheinker Syndrome (GSS) is a rare, infectious syndrome related to a mutation in the prion protein. A 60-yr-old, 152-cm, 31-kg woman with GSS was scheduled for open gastrostomy. This is the first report about an anesthetic experience in a patient with GSS.