Antibody Avidity Maturation Following Recovery From Infection or the Booster Vaccination Grants Breadth of SARS-CoV-2 Neutralizing Capacity.

BACKGROUND: Cross-neutralizing capacity of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants is important in mitigating (re-)exposures. Role of antibody maturation, the process whereby selection of higher affinity antibodies augments host immunity, to determine SARS-CoV-2 neutralizing capacity was investigated. METHODS: Sera from SARS-CoV-2 convalescents at 2, 6, or 10 months postrecovery, and BNT162b2 vaccine recipients at 3 or 25 weeks postvaccination, were analyzed. Anti-spike IgG avidity was measured in urea-treated ELISAs. Neutralizing capacity was assessed by surrogate neutralization assays. Fold change between variant and wild-type neutralization inferred the breadth of neutralizing capacity. RESULTS: Compared with early-convalescent, avidity indices of late-convalescent sera were significantly higher (median, 37.7 [interquartile range 28.4-45.1] vs 64.9 [57.5-71.5], P < .0001). Urea-resistant, high-avidity IgG best predicted neutralizing capacity (Spearman r = 0.49 vs 0.67 [wild-type]; 0.18-0.52 vs 0.48-0.83 [variants]). Higher-avidity convalescent sera better cross-neutralized SARS-CoV-2 variants (P < .001 [Alpha]; P < .01 [Delta and Omicron]). Vaccinees only experienced meaningful avidity maturation following the booster dose, exhibiting rather limited cross-neutralizing capacity at week 25. CONCLUSIONS: Avidity maturation was progressive beyond acute recovery from infection, or became apparent after the booster vaccine dose, granting broader anti-SARS-CoV-2 neutralizing capacity. Understanding the maturation kinetics of the 2 building blocks of anti-SARS-CoV-2 humoral immunity is crucial.

A multicenter, double-blind, randomized, parallel-group, placebo-controlled study to evaluate the efficacy and safety of camostat mesilate in patients with COVID-19 (CANDLE study).

BACKGROUND: In vitro drug screening studies have indicated that camostat mesilate (FOY-305) may prevent SARS-CoV-2 infection into human airway epithelial cells. This study was conducted to investigate whether camostat mesilate is an effective treatment for SARS-CoV-2 infection (COVID-19). METHODS: This was a multicenter, double-blind, randomized, parallel-group, placebo-controlled study. Patients were enrolled if they were admitted to a hospital within 5 days of onset of COVID-19 symptoms or within 5 days of a positive test for asymptomatic patients. Severe cases (e.g., those requiring oxygenation/ventilation) were excluded. Patients were enrolled, randomized, and allocated to each group using an interactive web response system. Randomization was performed using a minimization method with the factors medical institution, age, and underlying diseases (chronic respiratory disease, chronic kidney disease, diabetes mellitus, hypertension, cardiovascular diseases, and obesity). The patients, investigators/subinvestigators, study coordinators, and other study personnel were blinded throughout the study. Patients were administered camostat mesilate (600 mg qid; four to eight times higher than the clinical doses in Japan) or placebo for up to 14 days. The primary efficacy endpoint was the time to the first two consecutive negative tests for SARS-CoV-2. RESULTS: One-hundred fifty-five patients were randomized to receive camostat mesilate (n = 78) or placebo (n = 77). The median time to the first test was 11.0 days (95% confidence interval [CI]: 9.0-12.0) in the camostat mesilate group and 11.0 days (95% CI: 10.0-13.0) in the placebo group. Conversion to negative viral status by day 14 was observed in 45 of 74 patients (60.8%) in the camostat mesilate group and 47 of 74 patients (63.5%) in the placebo group. The primary (Bayesian) and secondary (frequentist) analyses found no significant differences in the primary endpoint between the two groups. No additional safety concerns beyond those already known for camostat mesilate were identified. CONCLUSIONS: Camostat mesilate did not substantially reduce the time to viral clearance, based on upper airway viral loads, compared with placebo for treating patients with mild to moderate SARS-CoV-2 infection with or without symptoms. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04657497. Japan Registry for Clinical Trials, jRCT2031200198.

The µ-opioid receptor gene polymorphism 118A>G weakens the pharmacological action of buprenorphine.

AIMS: Opioids are commonly used analgesics for moderate to severe pain, but levels of drug effect vary among individuals. As for the mechanisms underlying these individual differences, there have been reports suggesting effects of polymorphisms in the gene encoding µ-opioid receptor (OPRM1). However, whether these polymorphisms affect the actions of µ-opioid receptor partial agonists has yet to be determined. This study aimed to assess differences in the pharmacological actions of buprenorphine, a µ-opioid receptor partial agonist, due to a polymorphism (A118G, rs1799971) in the OPRM1 gene in humans. MATERIALS AND METHODS: Ten healthy adult men (5 with OPRM1 c.118AA and 5 with OPRM1 c.118GG) received a single intravenous dose of buprenorphine hydrochloride at 0.001 mg/kg. Blood samples were collected up to 360 minutes after drug administration to assess the pharmacokinetics of buprenorphine. Nociceptive thresholds (temperature), digital symbol substitution test (DSST), and visual analog self-rating scale (VAS) for subjective symptoms were also evaluated over time to assess the pharmacodynamics. RESULTS: Nociceptive thresholds were significantly increased in the AA as compared to the GG group after buprenorphine administration (p = 0.025), while the DSST scores were significantly lower in the AA group (p < 0.001). The VAS scores for drowsiness (p < 0.001), malaise (p < 0.001), nausea (p < 0.001), and euphoria (p = 0.004) were higher in the AA than in the GG group. CONCLUSION: Levels of pharmacological actions of a µ-opioid receptor partial agonist vary in accordance with a polymorphism in the OPRM1 gene (A118G).

Effects of Anticholinergic Drugs Used for the Therapy of Overactive Bladder on P-Glycoprotein Activity.

We evaluated the effects of anticholinergic drugs principally used for the therapy of overactive bladder (OAB) on the activity of P-glycoprotein, an efflux transport protein, in Caco-2 cells. The time-dependent changes in the fluorescence of residual rhodamine 123, a P-glycoprotein activity marker, in the apical region of Caco-2 cells were measured in the presence of anticholinergic drugs using time-lapse confocal laser scanning microscopy. The effect of anticholinergic drugs on human P-glycoprotein ATPase activity was also measured. The fluorescence of residual rhodamine 123 in untreated Caco-2 cells decreased over time. The gradual decrease in the fluorescence was significantly inhibited by treatment with cyclosporine A, darifenacin, and trospium. In contrast, oxybutynin, N-desethyl-oxybutynin (DEOB), propiverine, and its active metabolites (M-1, M-2), imidafenacin, solifenacin, or tolterodine had little effect on the efflux of rhodamine 123. P-Glycoprotein ATPase activity was increased by darifenacin. Darifenacin and trospium reduced the rhodamine 123 transfer across the apical cell membrane. These data suggest that darifenacin and trospium interact with P-glycoprotein. Additionally, darifenacin influenced P-glycoprotein ATPase activity. These results suggest that darifenacin may be a substrate of P-glycoprotein. This study is the first paper to test simultaneously the effects of 10 anticholinergic drugs used currently for the therapy of OAB, on the P-glycoprotein.

Effect of Hepatic Impairment on the Pharmacokinetics of Grazoprevir, a Hepatitis C Virus Protease Inhibitor.

Grazoprevir (GZR) plus elbasvir is an approved treatment for chronic infection with hepatitis C virus (HCV) genotype 1 or 4. HCV infection complications include liver cirrhosis, end-stage liver disease, and hepatocellular carcinoma. The objective of this study was to evaluate the pharmacokinetics and safety of multiple-dose GZR (200, 100, or 50 mg) in non-HCV participants with mild, moderate, or severe hepatic impairment (HI), respectively, and in healthy matched controls (protocol MK-5172_p013; Merck & Co., Inc., Kenilworth, NJ). Participants with mild, moderate, or severe HI and controls (aged 18 to 65 years) matched for race, age, sex, and body mass index were enrolled in a 3-part, open-label, sequential-panel pharmacokinetic study. Participants received oral doses of GZR 200 mg (two 100-mg tablets), 100 mg (one 100-mg tablet), or 50 mg (two 25-mg tablets) once daily for 10 days. A total of 50 participants were enrolled: 8 with mild HI, 9 with moderate HI, 8 with severe HI, and a corresponding number of healthy matched controls for each hepatic cohort. Participants with HI demonstrated higher GZR exposure than healthy matched controls and showed an increase in exposure with increasing HI severity. The steady-state GZR AUC0-24 (area under the concentration-time curve from 0 to 24 h) for participants with mild, moderate, or severe HI was ≈2-, ≈5-, or ≈12-fold higher, respectively, than that for healthy matched controls. GZR was generally well tolerated in participants with HI. No dose adjustment is required for GZR in people with HCV with mild HI. GZR is contraindicated for those with moderate or severe HI (Child-Pugh class B or C), since they may have significantly increased GZR exposures that may lead to an increased risk of transaminase elevation.

Assessing Immunogenicity in Drug Reviews and Prescribing Information in Japan.

Anti-drug antibodies (ADAs) generated in response to biopharmaceuticals can significantly impact pharmacokinetics (PK) and overall drug efficacy. Thus, the ICH M4 guidelines mandate summarizing immunogenicity data from clinical trials in drug approval applications. However, following the approval of the first antibody drug in Japan in 2001, no cross-sectional investigation has focused on immunogenicity during the regulatory review process. Therefore, this study aims to examine the review reports and prescribing information of antibody drugs approved in Japan to identify key points related to immunogenicity evaluation. We conducted a cross-sectional analysis of review reports for antibody drugs approved between June 2001 and July 2022 by the Japanese regulatory authority. Specifically, we evaluated the ADA positivity rate, presence of neutralizing antibodies, antibody titers, and effects of ADA on PK, efficacy, and safety. We also compared this information with that provided in the prescribing information. Our analysis revealed that the ADA positivity rate and its effects on PK, efficacy, and safety were critical aspects of the review process. The emphasis on these factors varied depending on the number of applications and disease area. The information presented in the prescribing information was largely consistent with that discussed in the review reports. Overall, this study provides the first cross-sectional evaluation of immunogenicity considerations in the regulatory review of antibody drugs in Japan. Our findings can contribute to the efficiency of clinical trial planning and preparation of approval applications, to potentially improve the overall drug development process and address the drug loss problem in Japan.

An Explanation of Why Dose-Corrected Area Under the Curve for Alternate Administration Routes Can Be Greater than for Intravenous Dosing.

It is generally believed that bioavailability (F) calculated based on systemic concentration area under the curve (AUC) measurements cannot exceed 1.0, yet some published studies report this inconsistency. We teach and believe, based on differential equation derivations, that rate of absorption has no influence on measured systemic clearance following an oral dose, i.e., determined as available dose divided by AUC. Previously, it was thought that any difference in calculating F from urine data versus that from systemic concentration AUC data was due to the inability to accurately measure urine data. A PubMed literature search for drugs exhibiting F > 1.0 and studies for which F was measured using both AUC and urinary excretion dose-corrected analyses yielded data for 35 drugs. We show and explain, using Kirchhoff's Laws, that these universally held concepts concerning bioavailability may not be valid in all situations. Bioavailability, determined using systemic concentration measurements, for many drugs may be overestimated since AUC reflects not only systemic elimination but also absorption rate characteristics, which is most easily seen for renal clearance measures. Clearance of drug from the absorption site must be significantly greater than clearance following an iv bolus dose for F(AUC) to correctly correspond with F(urine). The primary purpose of this paper is to demonstrate that studies resulting in F > 1.0 and/or greater systemic vs urine bioavailability predictions may be accurate. Importantly, these explications have no significant impact on current regulatory guidance for bioequivalence testing, nor on the use of exposure (AUC) measures in making drug dosing decisions.

Flecainide Toxicity From Clinical Pharmacology Perspectives.

We report a case comparing the measured half-life of flecainide with the half-life stated on the label. An 84-year-old woman presented with symptoms of anorexia and exertional dyspnea. She had undergone mitral and aortic valve replacements and excision of the membranous septum in the atrium for mitral and aortic stenosis and cor triatriatum. She was regularly administered 100 mg/day flecainide for paroxysmal atrial fibrillation. A previous electrocardiogram (ECG) showed a regular sinus rhythm. However, upon admission, the ECG revealed a heart rate of 94 bpm and an accelerated idioventricular rhythm originating from the left ventricle. Flecainide toxicity was suspected, leading to the discontinuation of flecainide treatment. The following day, the serum flecainide concentration was 1,348 ng/mL, exceeding the therapeutic window of 200-1,000 ng/mL. After discontinuing flecainide, the accelerated idioventricular rhythm ceased, and a regular sinus rhythm temporarily returned. We measured blood drug concentrations several times; our calculated half-life was 56.8 h, approximately five times longer than the half-life of 11.0 h stated on the package insert. To ensure safe and effective therapy with antiarrhythmic drugs, prioritizing therapeutic drug monitoring and carefully monitoring pharmacokinetics is important, particularly during the elimination phase.

Cadence-Based Pedometer App With Financial Incentives to Enhance Moderate-to-Vigorous Physical Activity: Development and Single-Arm Feasibility Study.

BACKGROUND: High levels of physical activity are key to improving health outcomes, yet many people fail to take action. Using pedometers to target steps per day and providing financial incentives is a simple and scalable approach to promoting public health. However, conventional pedometers do not account for "intensity" and "duration," making it challenging to efficiently increase people's moderate-to-vigorous physical activity (MVPA), which is expected to improve health outcomes. Based on these rationales, we developed a smartphone app that sets step cadence as a goal (defined as a daily challenge of walking more than 1500 steps in 15 minutes twice a day, which is a heuristic threshold for moderate physical activity) and provides financial incentive when the challenge is met. OBJECTIVE: This study aimed to evaluate the feasibility of our novel app and explore whether its use can increase users' daily MVPA. METHODS: A single-arm pre-post study evaluated the feasibility and efficacy of the app. A total of 15 participants used app 1 (an app without financial incentives) for the first period (4 weeks) and then switched to app 2 (an app with financial incentives) for the second period (4 weeks). The primary outcome was the difference between the first and second periods in the number of successful challenge attempts per week. Secondary outcomes were differences between the first and second periods in daily steps and distance walked. Exploratory outcomes included the difference between the first and second periods in daily "heart points" as measured by Google Fit, a publicly available app that measures users' daily MVPA. RESULTS: The number of successful challenge attempts per week increased significantly compared to the first period (5.6 times per week vs 0.7 times per week; P<.001). Although not statistically significant, there was a trend toward an increase in the mean steps per day and distance walked per day (6586 steps per day vs 5950 steps per day; P=.19; and 4.69 km per day vs 3.85 km per day; P=.09, respectively). An exploratory end point examining daily MVPA by "heart points" collected from Google Fit also showed a significant increase compared to the first period (22.7 points per day vs 12.8 points per day; P=.02). CONCLUSIONS: Our app using step cadence as a goal and providing financial incentives seemed feasible and could be an effective app to increase users' daily MVPA. Based on the results of this study, we are motivated to conduct a confirmatory study with a broader and larger number of participants. TRIAL REGISTRATION: UMIN 000050518; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000057420.

Safety, pharmacokinetics, and pharmacodynamics of ART-648, a PDE4 inhibitor in healthy subjects: A randomized, placebo-controlled phase I study.

Phosphodiesterase 4 (PDE4) inhibitor is associated with a broad-spectrum anti-inflammatory mechanism. However, securing clinically efficacious doses with sufficient safety margins remains challenging due to class specific adverse events that are often unavoidable in the clinic. ART-648 is an orally available PDE4 inhibitor being developed for the treatment of inflammatory diseases. According to the estimated clinical doses based on an in vitro whole-blood assay, a phase I study was designed. The purpose of this phase I study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) following single and multiple administration of ART-648 in healthy subjects. PD was assessed by suppression of lipopolysaccharide-induced TNFα release in ex vivo whole-blood assay. In the single rising dose study, ART-648 was safe and well tolerated with a dose-proportional increase in exposures up to 4 mg. Single doses of ART-648 demonstrated dose-dependent PD response, indicating target engagement at 2-8 mg doses. In the multiple rising dose study, doses up to 4 mg BID after careful titration were well tolerated, while doses up to 6 mg BID were tolerated not in all but the majority of subjects. In conclusion, ART-648 exhibits a favorable PK profile with robust target engagement at clinically safe and tolerated doses identified in healthy subjects.

The Prospective Natural History Study of Patients with Intractable Venous Malformation and Klippel-Trenaunay Syndrome to Guide Designing a Proof-of-Concept Clinical Trial for Novel Therapeutic Intervention.

Background: The natural history of venous malformation (VM) and Klippel-Trenaunay Syndrome (KTS) has not been quantitatively studied. To obtain benchmarks to guide designing clinical trials to assess safety and efficacy of novel drug candidates, the clinical course of the patients was followed for 6 months. Methods and Results: This is a multicenter prospective observational study evaluating the change rate in lesion volume from baseline with magnetic resonance images, as the primary endpoint. In addition, disease severities, performance status (PS), pain visual analog scale (VAS) score, quality of life (QoL), infections, and coagulation markers were also evaluated. Thirty-four patients (VM = 17, KTS = 17, 1-53 of age; median 15.9 years) with measurable lesion volume were analyzed. There was no statistically significant difference in the lesion volume between baseline and day 180, and the mean change rate (standard deviation) was 1.06 (0.28). There were no baseline characteristics that affected the change in lesion volume over 6 months. However, there were patients who showed more than 20% volume change and it was suggested that the lesion volume was largely impacted by local infection. There were no statistically significant changes in pain VAS score, severity, PS, QoL score, D-dimer, and platelet count over 6 months within all patients analyzed. Conclusion: The results showed the representative natural course of VM and KTS for a 6-month period with objective change of lesion volume and other factors, suggesting that it is scientifically reasonable to conduct a Phase 2 proof-of-concept study without a placebo arm, using the results of this study as the control. Clinical Trial Registration: NCT04285723, NCT04589650.

The effect of carboxylesterase 1 (CES1) polymorphisms on the pharmacokinetics of oseltamivir in humans.

PURPOSE: The aim of this study was to examine whether carboxylesterase 1 (CES1A) genetic polymorphisms affect the pharmacokinetics of oseltamivir. METHODS: Thirty healthy Japanese male and female subjects ranging in age from 20 to 36 years voluntarily participated in this study. These subjects were administered a single 75-mg dose of oseltamivir (Tamiflu®), and blood samples were collected predose and up to 24 h after oseltamivir administration. Oseltamivir and its active metabolite, oseltamivir carboxylate, were measured by liquid chromatography-time of flight/mass spectrometry with solid-phase extraction. The CES1A diplotypes [a combination of haplotypes A (CES1A3-CES1A1), B (CES1A2-CES1A1), C (CES1A3-CES1A1variant), and D (CES1A2-CES1A1variant)] were determined by PCR-restriction fragment length polymorphism analysis and direct sequencing. RESULTS: All subjects completed the study according to the protocol, and no clinically meaningful adverse events were attributable to the administration of oseltamivir. No significant differences in the pharmacokinetic parameters of oseltamivir and oseltamivir carboxylate were observed according to CES1A genotype. In one subject, the peak concentration and area under the concentration-time curve (AUC) of oseltamivir were approximately tenfold higher than the mean values of the other subjects. CONCLUSIONS: In our study, the known interindividual variability in oseltamivir metabolism was not explained by CES1A genetic polymorphisms, but are likely the result of other factors. While one subject was found to exhibit an approximate tenfold higher AUC than the other subjects, no abnormal behaviors were associated with the increased oseltamivir plasma concentrations. Further studies are required to reveal the cause of individual differences in CES1A metabolism and the abnormal behavioral effects of oseltamivir.

A randomized, placebo-controlled study to evaluate safety and pharmacokinetics of ART-001 with a novel oral pediatric formulation in healthy subjects.

ART-001 is an orally available selective PI3Kα inhibitor currently being developed for the treatment of slow-flow vascular malformations (SFVMs). ART-001 used to be developed for advanced solid tumors, but was suspended largely due to significant pharmacokinetic (PK) variability in its phase I studies. This phase I, randomized, double-blinded, placebo-controlled study evaluated safety, tolerability and PK of ART-001 with a newly developed dry syrup formulation, which was designed to optimize PK properties of ART-001 and to be compliant with the pediatric population. Single and multiple doses of ART-001 were administered to healthy male adults. ART-001 was rapidly absorbed after the single and repeated doses, and the exposure of ART-001 increased with increased dose. The dry syrup formulation substantially improved the intersubject PK variability. Food decreased area under the concentration-time curve (AUC) and maximum plasma concentration by 12% and 36%, respectively. The plasma concentration had reached a steady-state on day 5 of the repeated doses of 100 mg and AUC accumulation ratio was 1.9. There were no deaths or serious adverse events. The most frequent adverse event was hyperglycemia. All cases of hyperglycemia were mild to moderate and transient, and required no medical interventions. Serum creatinine increase was observed in 300 mg once daily dosing group leading to dose discontinuation on day 5. In conclusion, it was demonstrated that the single doses and repeated doses of the ART-001 dry syrup formulation, at up to 400 and 100 mg, respectively, were safe and tolerated with favorable PK profile, supporting further clinical development for the treatment of SFVMs.

A Heart Failure Smartphone Application That Nudges Patients/Physicians Toward Optimal Medical Therapy　- Development and Usability Study.

Background: The low implementation rate of guideline-directed medical therapy for heart failure (HF) remains a problem worldwide. To address this issue, we hypothesized that a smartphone application (app) based on behavioral economics that nudges physicians and patients towards optimal medical therapy would be a scalable approach. Methods and Results: The app prototype was developed, and its usability was tested with 5 HF patients in the outpatient setting. Adherence to the app was outstanding, with a high usability rating from the patients. Conclusions: It appears feasible to further study our app in a larger cohort to evaluate its efficacy.

Association between psychomotor function and ALDH2 genotype after consuming barley shochu: A randomized crossover trial.

Sustained exposure to acetaldehyde, the major metabolite of ethanol, may influence psychomotor performance even after the breath ethanol level significantly drops several hours following ethanol consumption. We examined the relationship between psychomotor function and changes in exhaled ethanol and acetaldehyde concentrations after consuming a low dose (0.33 g/kg) of barley shochu, a traditional Japanese distilled alcohol beverage, at the point when the exhaled ethanol concentrations dropped below 78,000 parts per billion (0.15 mg/L), the standard threshold for driving under the influence of alcohol in Japan. We assessed how the genetic polymorphisms of rs671 G/G homozygous (*1/*1) and G/A heterozygous (*1/*2) of ALDH2 influenced the kinetics of ethanol and acetaldehyde in exhaled air and psychomotor dynamics using the Digit Symbol Substitution Test (DSST), Critical Flicker Fusion Test (CFFT), and visual analogue scale (VAS) up to 12 h after shochu or water intake. There was no significant difference in DSST and CFFT scores depending on genotype; however, the time required for the DSST to attain the level prior to drinking was longer in the ALDH2 *1/*2 group than in the *1/*1 group. In the VAS test, facial flushing and mood elevation tended to be higher in the *1/*2 group after shochu consumption. VAS scores for mood elevation and facial flushing correlated with acetaldehyde concentration in exhaled breath. These results indicate that DSST recovery tends to be slower and mood elevation higher in the ALDH2 *1/*2 group even when exposed to a low dose of alcohol.

Pharmacokinetics of lanoconazole in human skin after repeated topical application.

Drug disposition after topical application to the skin has not been fully elucidated, especially after repeated application. We conducted a clinical trial to evaluate the pharmacokinetics in the stratum corneum of healthy adults after repeated application of lanoconazole cream as a model drug. We applied 25 mg of 1% lanoconazole cream onto the pre-specified areas on the participants' back once daily for 5 days. The stratum corneum was sampled twice on each study day using a standardized tape-stripping method, and the amount of lanoconazole contained in the samples was quantified using the tandem mass spectrometry method. The obtained data were used to evaluate lanoconazole pharmacokinetics in the stratum corneum. The amount of lanoconazole in the stratum corneum after once daily repeated administration reached a steady state on day 3, and it was eliminated from the stratum corneum with a half-life of approximately 11 h after discontinuing application.

A phase I, randomized, placebo-controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID-19.

Molnupiravir (MK-4482) is an oral prodrug of the antiviral ribonucleoside analog, N-hydroxycytidine (NHC), which has activity against RNA viruses, including severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). We conducted a phase I safety and pharmacokinetic study of molnupiravir in healthy Japanese adult participants. A sample size larger than typically used in pharmacokinetic studies was implemented to collect additional safety data in the Japanese population to support special approval for emergency use in Japan. Single doses of molnupiravir up to 1600 mg and multiple doses of 400 and 800 mg administered every 12 h (q12h) for 5.5 days were generally well-tolerated. NHC appeared rapidly in plasma and reached maximum concentration (Cmax ), with a median time to Cmax (Tmax ) between 1.00 and 2.00 h. Area under the concentration versus time curve from zero to infinity (AUC0-inf ), area under the concentration versus time curve from zero to 12 h (AUC0-12 ), and Cmax of plasma NHC increased approximately dose proportionally. With q12h dosing, the geometric mean (GM) accumulation ratios for NHC AUC0-12 and Cmax were ~1 for 400 and 800 mg. Pharmacokinetics of NHC triphosphate (NHC-TP), the active metabolite of NHC was assessed in peripheral blood mononuclear cells and also demonstrated roughly dose proportional pharmacokinetics. The GM accumulation ratios for NHC-TP AUC0-12 and Cmax were ~2.5 for 400 and 800 mg. Following administration with food, only a modest reduction (24%) in plasma NHC Cmax with comparable AUC0-inf was seen, supporting administration without regard to food.

A phase I study to evaluate safety, pharmacokinetics, and pharmacodynamics of respiratory syncytial virus neutralizing monoclonal antibody MK-1654 in healthy Japanese adults.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among all infants worldwide and remains a significant cause of morbidity and mortality. To address this unmet medical need, MK-1654, a half-life extended RSV neutralizing monoclonal antibody, is in clinical development for the prevention of RSV disease in infants. This was a phase I, randomized, placebo-controlled, single-site, double-blind trial of MK-1654 in 44 healthy Japanese adults. The safety, tolerability, pharmacokinetics, antidrug antibodies (ADAs), and serum neutralizing antibody (SNA) titers against RSV were evaluated for 1 year after a single intramuscular (i.m.) or intravenous (i.v.) dose of MK-1654 or placebo in five groups (100 mg i.m., 300 mg i.m., 300 mg i.v., 1000 mg i.v., or placebo). MK-1654 was generally well-tolerated in Japanese adults. There were no serious drug-related adverse events (AEs) reported in any MK-1654 recipient and no discontinuations due to any AEs in the study. The half-life of MK-1654 ranged from 76 to 91 days across dosing groups. Estimated bioavailability was 86% for 100 mg i.m. and 77% for 300 mg i.m. One participant out of 33 (3.0%) developed detectable ADA with no apparent associated AEs. The RSV SNA titers increased in a dose-dependent manner among participants who received MK-1654. These data support the development of MK-1654 for use in Japanese infants.

A phase I study of high dose camostat mesylate in healthy adults provides a rationale to repurpose the TMPRSS2 inhibitor for the treatment of COVID-19.

Camostat mesylate, an oral serine protease inhibitor, is used to treat chronic pancreatitis and reflux esophagitis. Recently, camostat mesylate and its active metabolite 4-(4-guanidinobenzoyloxy)phenylacetic acid (GBPA) were reported to inhibit the infection of cells by severe acute respiratory syndrome coronavirus 2 by inhibiting type II transmembrane serine protease. We conducted a phase I study to investigate high-dose camostat mesylate as a treatment for coronavirus disease 2019. Camostat mesylate was orally administered to healthy adults at 600 mg 4 times daily under either of the following conditions: fasted state, after a meal, 30 min before a meal, or 1 h before a meal, and the pharmacokinetics and safety profiles were evaluated. In addition, the time of plasma GBPA concentration exceeding the effective concentration was estimated as the time above half-maximal effective concentration (EC50 ) by using pharmacokinetic/pharmacodynamic modeling and simulation. Camostat mesylate was safe and tolerated at all dosages. Compared with the fasted state, the exposure of GBPA after a meal and 30 min before a meal was significantly lower; however, no significant difference was observed at 1 h before a meal. The time above EC50 was 11.5 h when camostat mesylate 600 mg was administered 4 times daily in the fasted state or 1 h before a meal. Based on the results of this phase I study, we are currently conducting a phase III study.