Comparison of pediatric lens scattered dose measurements between axial 40-mm and helical 160-mm detector width computed tomography scan modes.

BACKGROUND: Reports comparing field lens doses between helical scans with a 40-mm detector width and axial scans with a 160-mm detector width using different computed tomography (CT) scanners are currently scarce. OBJECTIVE: To compare scatter doses for lenses between a helical scan with a 40-mm detector width and an axial scan with a 160-mm detector width when using different CT scanners in the context of pediatric chest examinations. MATERIALS AND METHODS: Two different CT machines were used: Revolution CT (GE Healthcare, Waukesha, WI) with a 256-row, 0.625-mm multidetector; and Aquilion ONE GENESIS Edition (Canon Medical Systems, Otawara, Japan) with a 320-row, 0.5-mm multidetector. Three pediatric anthropomorphic phantoms were used, with optically stimulated luminescence dosimeters (OSLDs) placed on the left and right lenses. The scatter dose values measured by the OSLDs were compared between a helical scan with a 40-mm detector width and an axial scan with a 160-mm detector width during pediatric chest CT examinations. RESULTS: Median equivalent doses for the helical and axial scans were 0.12 and 0.12 mSv/mGy for the newborn, 0.17 and 0.16 mSv/mGy for the 1-year-old, and 0.18 and 0.15 mSv/mGy for the 5-year-old, respectively, when using the Revolution CT. With the Revolution CT, no significant differences were observed in the scatter doses between helical and axial scans in the newborn and 1-year-old phantoms. However, the lens scatter dose for the helical scan was approximately 20-35% higher than that for the axial scan in the 5-year-old phantom (P<0.01). The median equivalent doses of eye lenses for the helical and axial scans were 0.12 and 0.07 mSv/mGy for the newborn, 0.07 and 0.05 mSv/mGy for the 1-year-old, and 0.14 and 0.12 mSv/mGy for the 5-year-old, respectively, when using the Aquilion ONE. With the Aquilion ONE, lens scatter doses for the helical scan were approximately 70%, 40%, and 30% higher in the newborn, 1-year-old, and 5-year-old phantoms, respectively, than those for the axial scan (P<0.01). CONCLUSIONS: When using the Aquilion ONE, lens scatter doses for the helical scan were significantly higher in all three phantoms than those for the axial scan. In contrast, when using the Revolution CT, the lens scatter dose for the helical scan was significantly higher in the 5-year-old phantom than that for the axial scan. These results suggest that although scattered doses may vary with respect to the CT scanner and body size, they are generally lower in the case of axial scans.

Impact of beam collimation of z-overscanning on dose to the lens and thyroid gland in paediatric thoracic computed tomography imaging.

BACKGROUND: Adaptive collimation reduces the dose deposited outside the imaged volume along the z-axis. An increase in the dose deposited outside the imaged volume (to the lens and thyroid) in the z-axis direction is a concern in paediatric computed tomography (CT). OBJECTIVE: To compare the dose deposited outside the imaged volume (to the lens and thyroid) between 40-mm and 80-mm collimation during thoracic paediatric helical CT. MATERIALS AND METHODS: We used anthropomorphic phantoms of newborns and 5-year-olds with 40-mm and 80-mm collimation during helical CT. We compared the measured dose deposited outside the imaged volume using optically stimulated luminescence dosimeters (OSLD) at the surfaces of the lens and thyroid and the image noise between the 40-mm and 80-mm collimations. RESULTS: There were significant differences in the dose deposited outside the imaged volume (to the lens and thyroid) between the 40-mm and 80-mm collimations for both phantoms (P < 0.01). CONCLUSION: Compared with that observed for 80-mm collimation in helical CT scans of the paediatric thorax, the dose deposited outside the imaged volume (to the lens and thyroid) was significantly lower in newborns and 5-year-olds with 40-mm collimation.

Pharmacokinetic and pharmacodynamic analysis of baloxavir marboxil, a novel cap-dependent endonuclease inhibitor, in a murine model of influenza virus infection.

BACKGROUND: Baloxavir acid, the active form of the orally available prodrug baloxavir marboxil, is a novel cap-dependent endonuclease inhibitor of influenza virus. Baloxavir marboxil has been shown to rapidly reduce virus titres compared with oseltamivir in clinical studies. OBJECTIVES: We investigated the relationship between pharmacokinetic (PK) parameters and antiviral activity of baloxavir acid based on virus titre reduction in lungs of infected mice. METHODS: BALB/c mice infected with a sub-lethal dose of influenza A(H1N1), A(H1N1)pdm09, A(H3N2) or type B virus were treated on day 5 with oral baloxavir marboxil (0.5-50 mg/kg q12h), subcutaneous baloxavir acid (0.25-8 mg/kg/day), oseltamivir phosphate (5 or 50 eq mg/kg q12h) or other antivirals for 1 day. Lung virus titres were assessed 24 h after initial antiviral dosing. PK testing was performed at up to 24 h post-dosing of baloxavir marboxil or baloxavir acid in A/WSN/33-infected mice and the PK/pharmacodynamic (PD) relationship was evaluated for baloxavir acid. RESULTS: Oral baloxavir marboxil administration showed dose-dependent virus titre reductions in lungs of mice infected with the different types/subtypes of influenza viruses 24 h post-dosing. Baloxavir marboxil at 15 mg/kg q12h resulted in ≥100-fold and ≥10-fold reductions in influenza A and B virus titres, respectively, compared with oseltamivir phosphate. PK/PD analysis showed that the plasma concentration at the end of the dosing interval (Cτ) or the plasma concentration at 24 h after initial dosing (C24) was the PK parameter predicting the virus titres at 24 h post-dosing of baloxavir acid. CONCLUSIONS: PK/PD analysis of baloxavir acid based on virus titre reduction in this mouse model could be helpful in predicting and maximizing virological outcomes in clinical settings.

Baloxavir Marboxil in Japanese Pediatric Patients With Influenza: Safety and Clinical and Virologic Outcomes.

BACKGROUND: We assessed the safety and effectiveness of baloxavir marboxil administration in Japanese children with influenza. METHODS: This open-label study administered 1 weight-adjusted dose of baloxavir to 107 children aged 1-11 years with laboratory-confirmed, febrile influenza virus infection of ≤48 hours duration. RESULTS: Adverse events (AEs) were reported in 34.6% of patients, most commonly vomiting (7.5%); no serious AEs or AEs causing discontinuation occurred. The median time to alleviation of influenza illness was 44.6 hours (95% confidence interval, 38.9-62.5 hours), to resolution of fever was 21.4 hours, and to sustained cessation of infectious viral shedding was 24.0 hours. However, viruses with amino acid substitutions in the viral polymerase acidic protein at position I38 (PA/I38T/M) emerged in 18 of 77 (23.4%) patients. Emergence was associated with longer infectious virus detectability (median time, 180.0 hours) and time to illness alleviation (median, 79.6 vs 42.8 hours in patients without PA/I38T/M-substituted viruses). Among patients with PA/I38T/M-substituted virus emergence, those with baseline hemagglutinin inhibition (HAI) antibody titer <40 experienced delay in time to illness alleviation (median, 85.4 vs 56.0 hours in patients with higher baseline HAI antibody titer). CONCLUSIONS: A single, oral dose of baloxavir marboxil was well tolerated and rapidly reduced viral titers, but the common emergence of PA/I38T/M-substituted viruses warrants consideration of alternative dosing regimens in young children. CLINICAL TRIALS REGISTRATION: Japan Pharmaceutical Information Center Clinical Trials Information (Japic CTI-163417).

Population Pharmacokinetics and Exposure-Response Relationships of Baloxavir Marboxil in Influenza Patients at High Risk of Complications.

Baloxavir marboxil, a prodrug of cap-dependent endonuclease inhibitor baloxavir acid, reduces the time to improvement of influenza symptoms in patients infected with type A or B influenza virus. To characterize its pharmacokinetics, a population pharmacokinetic model for baloxavir acid was developed using 11,846 plasma concentration data items from 1,827 subjects, including 2,341 plasma concentration data items from 664 patients at high risk of influenza complications. A three-compartment model with first-order elimination and first-order absorption with lag time well described the plasma concentration data. Body weight and race were found to be the most important factors influencing clearance and volume of distribution. The exposures in high-risk patients were similar to those in otherwise healthy patients, and no pharmacokinetic difference was identified regarding any risk factors for influenza complications. Exposure-response analyses were performed regarding the time to improvement of symptoms and the reduction in the influenza virus titer in high-risk patients. The analyses suggested that body weight-based dosage, 40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg, can shorten the time to improvement of influenza symptoms and reduce virus titer for both type A and B influenza virus regardless of the exposure levels of the high-risk patients as well as for the otherwise healthy influenza patients. The results of our population pharmacokinetic and exposure-response analyses in patients with risk factors of influenza complications should provide useful information on the pharmacokinetic and pharmacodynamic characteristics of baloxavir marboxil and also for the optimization of dose regimens.

Molecular hydrogen suppresses superoxide generation in the mitochondrial complex I and reduced mitochondrial membrane potential.

Molecular hydrogen (H2) is recognized as a medical gas applicable to numerous diseases including neurodegenerative diseases, metabolic disorders, and rheumatoid arthritis. Although the efficacy of H2 is reportedly attributed to its scavenging capability against the hydroxyl radical, the mechanisms underlying its therapeutic efficacy are not fully understood. Herein, we estimated the role of H2 in the energy converting system of the mitochondria, the source of reactive oxygen species. To investigate the effects of H2 on mitochondrial function, direction of electron flow, superoxide generation, and mitochondrial membrane potential were investigated. Forward electron transport (FET) or reverse electron transport (RET) was assessed by monitoring the decrease or increase of ß-nicotinamide adenine dinucleotide hydrate (NADH, - or +, µM, respectively) in the presence of ß-nicotinamide adenine dinucleotide (NAD+) and/or succinate in the isolated mitochondria. H2O2 converted from superoxide by superoxide dismutase (SOD) was measured to estimate electron leakage in the mitochondria. The effects of H2 on mitochondrial membrane potential were observed by staining cells with the fluorescence probe, teramethylrhodamine ethyl ester (TMRE). Despite the absence of succinate, a distinct RET was observed (from +0.0313 ± 0.0106 µM to +1.20 ± 0.302 µM) by adding 25 µM H2. In the presence of 5 µM NADH, RET by succinate inverted to FET from +1.62 ± 0.358 µM to -1.83 ± 0.191 µM, accompanied by a suppression of superoxide generated predominantly from complex I by 51.1%. H2 solely reduced mitochondrial membrane potential of the cultured cells by 11.3% as assessed by TMRE. The direction of electron flow was altered by H2 depending on the NAD+/NADH ratio, accompanied by suppression of superoxide generation H2 could suppress superoxide generation in complex I in vitro and reduce membrane potential in vivo. H2 may also neutralize semiquinone radicals to reduce superoxide produced in complex III. H2 may function as a rectifier of the electron flow affecting the mitochondrial membrane potential to suppress oxidative damage in mitochondria.

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of Cefiderocol, a Parenteral Siderophore Cephalosporin, for Dose Adjustment Based on Renal Function.

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria, including carbapenem-resistant strains. Since cefiderocol is excreted primarily via the kidneys, this study was conducted to develop a population pharmacokinetics (PK) model to determine dose adjustment based on renal function. Population PK models were developed based on data for cefiderocol concentrations in plasma, urine, and dialysate with a nonlinear mixed-effects model approach. Monte-Carlo simulations were conducted to calculate the probability of target attainment (PTA) of fraction of time during the dosing interval where the free drug concentration in plasma exceeds the MIC (Tf>MIC) for an MIC range of 0.25 to 16 µg/ml. For the simulations, dose regimens were selected to compare cefiderocol exposure among groups with different levels of renal function. The developed models well described the PK of cefiderocol for each renal function group. A dose of 2 g every 8 h with 3-h infusions provided >90% PTA for 75% Tf>MIC for an MIC of ≤4 µg/ml for patients with normal renal function, while a more frequent dose (every 6 h) could be used for patients with augmented renal function. A reduced dose and/or extended dosing interval was selected for patients with impaired renal function. A supplemental dose immediately after intermittent hemodialysis was proposed for patients requiring intermittent hemodialysis. The PK of cefiderocol could be adequately modeled, and the modeling-and-simulation approach suggested dose regimens based on renal function, ensuring drug exposure with adequate bactericidal effect.

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. Age and body weight were also found to be covariates for clearance and the volume of distribution, respectively. No difference in pharmacokinetics was found between genders or between Japanese and U.S. SUBJECTS: Small differences in pharmacokinetics were observed between uninfected subjects and influenza patients (clearance was 18% higher and the volume of distribution was 6% lower in influenza patients). Monte Carlo simulations indicated that single adjusted doses of 1/3- and 1/6-fold for patients with moderate and severe renal impairment, respectively, would give areas under the curve comparable to those for patients with normal renal function. The population pharmacokinetic model developed for peramivir should be useful for understanding its pharmacokinetic characteristics and for dose adjustment on the basis of renal function.

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. The two-compartment model could well describe the plasma concentration profile of doripenem after intravenous infusion. Creatinine clearance and age were found to be covariates of doripenem clearance, and creatinine clearance was the most important factor influencing the pharmacokinetics of doripenem, which is consistent with the fact that doripenem is mainly excreted via the urine. Simulations suggest that exposures (AUC) to 1 g every 8 h for patients with normal renal function would be similar to those expected at 1 g every 12 h, 0.5 g every 8 h and 0.25 g every 8 h for patients with mild, moderate and severe renal impairment, respectively. These dosing regimens also provide sufficient exposure to doripenem from the viewpoint of the percentage of time above the minimum inhibitory concentration.

Cardiac computed tomography angiography with and without bolus tracking methods in infants with congenital heart disease.

The study investigated radiation dose, vascular computed tomography (CT) enhancement and image quality of cardiac computed tomography angiography (CCTA) with and without bolus tracking (BT) methods in infants with congenital heart disease (CHD). The volume CT dose index (CTDIvol) and dose length product (DLP) were recorded for all CT scans, and the effective dose was obtained using a conversion factors. The CT number for the ascending aorta (AO) and pulmonary artery (PA), image noise of muscle tissue and contrast-to-noise ratio (CNR) were measured and calculated. The median values in the groups with and without BT were 2.20 mGy versus 0.44 mGy for CTDIvol, 8.10 mGy·cm versus 6.20 mGy·cm for DLP, and 0.66 mSv versus 0.51 mSv for effective dose (p < 0.001). There were no statistical differences in vascular CT enhancement, image noise, and CNR. CCTA without BT methods can reduce the radiation dose while maintaining vascular CT enhancement and image quality compared to CCTA with BT methods.

Effectiveness of low tube voltage scan in the exposure dose for lenses during paediatric thoracic CT examination: anthropomorphic phantoms study.

To determine whether using lower-tube voltage reduces the scattered dose for the lens during paediatric thoracic computed tomography (CT). Two paediatric anthropomorphic phantoms (ATOM Phantom, CIRS, Norfolk, Virginia, USA) representing a newborn and 5-year-old were placed on the gantry of CT scanner, and optically stimulated luminescence dosemeters were placed on the left and right lenses, in front of the left and right thyroid glands, in front of the left and right mammary glands, and in front of and behind the mammary gland level and we measured scattered dose of the optically stimulated luminescence dosemeter was compared for each phantom between 80 and 120 kVp. Significant differences were observed in the scatter doses for the lens between 80 and 120 kVp (p < 0.01). Compared with the 120 kVp scan, the scatter doses for the lens were ~15-40% lower in newborn and 5-year-olds using the 80 kVp scan during paediatric CT.

Comparison of the equivalent doses of the eye lenses, thyroid, and mammary gland among three pediatric and one adult anthropomorphic phantom during the chest CT examinations using a 40 mm volume helical scan.

Equivalent doses for the eye lenses, thyroid, and mammary glands were measured and compared between one adult and three pediatric anthropomorphic phantoms during chest computed tomography (CT) using 40 mm volume helical scan on the Aquilion ONE GENESIS Edition CT equipment. Placing an optically stimulated luminescence dosemeter (OSLD) on the eye lenses, thyroid, and mammary gland, we measured and compared the equivalent dose of OSLD among different phantoms during chest CT using a helical scan. Compared with adults, the equivalent doses to the eye lens, thyroid, and mammary glands were ~81%, 77%, and 63% lower in newborns, 1-year-olds, and 5-year-olds using comparable image noise during chest CT.

Diverse substrate recognition and hydrolysis mechanisms of human NUDT5.

Human NUDT5 (hNUDT5) hydrolyzes various modified nucleoside diphosphates including 8-oxo-dGDP, 8-oxo-dADP and ADP-ribose (ADPR). However, the structural basis of the broad substrate specificity remains unknown. Here, we report the crystal structures of hNUDT5 complexed with 8-oxo-dGDP and 8-oxo-dADP. These structures reveal an unusually different substrate-binding mode. In particular, the positions of two phosphates (α and ß phosphates) of substrate in the 8-oxo-dGDP and 8-oxo-dADP complexes are completely inverted compared with those in the previously reported hNUDT5-ADPR complex structure. This result suggests that the nucleophilic substitution sites of the substrates involved in hydrolysis reactions differ despite the similarities in the chemical structures of the substrates and products. To clarify this hypothesis, we employed the isotope-labeling method and revealed that 8-oxo-dGDP is attacked by nucleophilic water at Pß, whereas ADPR is attacked at Pα. This observation reveals that the broad substrate specificity of hNUDT5 is achieved by a diversity of not only substrate recognition, but also hydrolysis mechanisms and leads to a novel aspect that enzymes do not always catalyze the reaction of substrates with similar chemical structures by using the chemically equivalent reaction site.

[Usefulness of subtraction computed tomography angiography employing orbital synchronized helical scanning for diagnosis of lower extremity arteries with vessel wall calcification].

PURPOSE: Massive calcification complicates the diagnosis of the blood vessel lumen in computed tomography angiography (CTA) of the arteries of the lower extremities. The purpose of this study was to evaluate subtraction CTA with the use of orbital synchronized helical scanning (OS-SCTA). METHOD: Phantom study: We performed OS-SCTA and non-OSCTA of a calcified vessel phantom (ψ2.5 mm), and compared them with a non-calcified vessel phantom as the reference by full width at half maximum (FWHM) and full width at tenth maximum (FWTM) of maximum intensity projection (MIP) images. Clinical study: 58 patients with peripheral artery disease who were referred for angiography also underwent OS-SCTA. OS-SCTA was produced using MIP images. Findings were graded according to three categories: (1) stenosis greater than 50% or occluded; (2) stenosis less than 50%; (3) not detected due to insufficient image quality. OS-SCTA findings were compared with the angiographic findings for each arterial segment. RESULTS: In the phantom study, FWHM showed no significant difference between OS-SCTA and the reference (P=0.135), whereas FWTM showed a significant difference (P<0.001). FWHM and FWTM showed a significant difference between non-OS-SCTA and the reference (P<0.001), due to misregistration with helical artifacts. In a clinical study comparing OS-SCTA with angiography, the sensitivity and specificity were 93.3% and 95.1% in calcified segments, 91.8% and 93.9% in non-calcified segments, and 92.2% and 94.6% in all segments. There was no significant difference between calcified segments and non-calcified segments (sensitivity: P=0.568, specificity: P=0.549). CONCLUSION: OS-SCTA is beneficial for the diagnosis of lower extremity arteries with vessel wall calcification, since it shows detection accuracy comparable to that of angiography.

PATIENT DOSIMETRY SURVEY OF PEDIATRIC DIAGNOSTIC AND THERAPEUTIC CARDIAC CATHETERISATION IN JAPAN.

To propose reference values for air-kerma at the reference point (Ka,r), air-kerma area product (PKA), fluoroscopy time (FT) and number of cine images (CI) for four age groups in Japan, a nationwide questionnaire was posted to 132 pediatric catheterisation of certified facility in Japan, using the conventional post system, to which 43 facilities responded. For diagnostic cardiac angiography, reference values were as follows: Ka,r: 86, 102, 165 and 264 mGy; PKA: 9.3, 9.5, 16 and 34 Gy.cm2; FT: 33, 29, 26 and 30 min and CI: 1904, 1966, 2405 and 1871 images. For therapeutic cardiac angiography, reference values were as follows: Ka,r: 107, 163, 103 and 202 mGy; PKA: 7.5, 18, 7 and 24 Gy.cm2; FT: 56, 52, 42 and 30 min and CI: 3886, 3232, 2212 and 4316 images for less than 1, 1-5, 6-10 and 11-15 y, respectively. To optimal patient exposure from diagnostic and therapeutic cardiac catheterisation, it is therefore necessary to establish reference values for pediatric cardiac catheterisation examinations for four age groups.

Efficacy, safety, and pharmacokinetics of intravenous peramivir in children with 2009 pandemic H1N1 influenza A virus infection.

Peramivir is a new neuraminidase inhibitor for intravenous administration that was first introduced in clinical practice in Japan. We conducted a multicenter, open-label, uncontrolled study in children with influenza virus infection ranging in age from ≥28 days to <16 years during the 2009 pandemic A (H1N1) influenza epidemic to evaluate the efficacy, safety, and pharmacokinetics of peramivir in children after intravenous infusion of 10 mg/kg (600 mg maximum) once daily. Among the 106 children (125 days to 15 years old) confirmed to have been infected with the pH1N1 virus by the PCR who were treated with peramivir, the median time to alleviation of symptoms was 29.1 h (95% confidence interval = 22.1 to 32.4), and the proportion of the 106 children who were virus positive was 78.2% on day 2 after the start of treatment and had decreased to 7.1% on day 6. The results of the safety evaluation among 117 patients enrolled in this study showed that adverse events and adverse drug reactions were reported in 62.4 and 29.1%, respectively, of the patients. All of the adverse events and adverse drug reactions resolved or improved rapidly. A population pharmacokinetic analysis was performed on the basis of 297 observed plasma concentration data obtained from 115 children with influenza virus infection. Peramivir exposure in children was within the range of levels within which the efficacy and safety was confirmed in adults, and it is considered that peramivir is clinically and virologically effective and safe in children with pH1N1 virus infection.

NATIONWIDE SURVEY OF RADIATION EXPOSURE FOR RADIOFREQUENCY CATHETER ABLATION FOR PULMONARY VEIN ISOLATION AND NONPULMONARY VEIN ISOLATION IN JAPAN.

To propose typical values for the arrhythmia region between pulmonary vein isolation (PVI) and nonpulmonary vein isolation (non-PVI) in Japan. A nationwide questionnaire was posted to 343 facilities, to which 125 facilities (36.4%) responded. Results is the median for PVI and non-PVI were in terms of Ka,r (317 and 196 mGy), PKA (40.8 and 26.3 Gy.cm2), FT (43.0 and 27.3 min), and CI (326 and 102 images). When comparing PVI and non-PVI procedures, there were significant differences in Ka, r, PKA, FT, and CI (p < 0.05). In other words, by classifying into two types, PVI and non-PVI, we contributed to the establishment of typical values in Japan's RFCA.

Baloxavir Treatment in Adolescents With Acute Influenza: Subgroup Analysis From the CAPSTONE-1 Trial.

BACKGROUND: Baloxavir marboxil has demonstrated safety and efficacy in treating adult and adolescent outpatients with acute influenza (CAPSTONE-1 trial). Here, we report a subgroup analysis of outcomes in adolescents from the trial. METHODS: CAPSTONE-1 was a randomized, double-blind, placebo-controlled study. Eligible adolescent outpatients (aged 12-17 years of age) were randomized in a ratio of 2:1 to a single dose of baloxavir 40/80 mg if less than/greater than or equal to 80 kg or placebo. The main outcomes were the time to alleviation of symptoms (TTAS), duration of infectious virus detection, and incidence of adverse events (AEs). RESULTS: Among 117 adolescent patients, 90 (77%) comprised the intent-to-treat infected population (63 baloxavir and 27 placebo; 88.9% A(H3N2)). The median TTAS was 38.6 hours shorter (95% confidence interval: -2.6, 68.4) in the baloxavir group compared with placebo (median TTAS, 54.1 hours vs 92.7 hours, P = .0055). The median time to sustained cessation of infectious virus detection was 72.0 hours for baloxavir compared with 120.0 hours for placebo recipients (P < .0001). Treatment-emergent PA/I38X-substituted viruses were detected in 5 of the 51 (9.8%) baloxavir recipients. In the safety population (76 baloxavir and 41 placebo), AEs were less common in baloxavir than placebo recipients (17.1% vs 34.1%; P = .0421). In the baloxavir group, no AEs except for diarrhea were reported in 2 or more patients. CONCLUSIONS: Baloxavir demonstrated clinical and virologic efficacy in the otherwise healthy adolescents with acute influenza compared with placebo. There were no safety concerns identified. These results were similar to the adult population in CAPSTONE-1 and support baloxavir as a treatment option in adolescents.

Clinical Drug-Drug Interaction Studies to Evaluate the Effects of a P-Glycoprotein Inhibitor, CYP3A Inhibitors, and a CYP3A Inducer on the Pharmacokinetics of Naldemedine in Healthy Subjects.

BACKGROUND: Naldemedine is a peripherally acting µ-opioid receptor antagonist that is indicated to treat opioid-induced constipation. OBJECTIVES: To assess the potential for drug-drug interactions between a single oral dose of naldemedine and the oral P-glycoprotein inhibitor cyclosporine, cytochrome P450 (CYP) 3A inhibitors itraconazole and fluconazole, and CYP3A inducer rifampin. METHODS: Three Phase 1, open-label studies were conducted in healthy subjects. In the P-glycoprotein inhibitor study, subjects received naldemedine 0.4 mg alone or coadministered with cyclosporine 600 mg. In the CYP3A inhibitors study, subjects in separate cohorts received naldemedine 0.2 mg alone or with itraconazole or fluconazole. In the CYP3A inducer study, subjects received naldemedine 0.2 mg alone or with rifampin 600 mg. Geometric mean ratios and 90 % confidence intervals were used to evaluate the effects of coadministered drugs on naldemedine maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC). Safety assessments included occurrence of adverse events (AEs), laboratory parameters, vital signs, and electrocardiography results. RESULTS: A total of 56 subjects were enrolled (n = 14 in each cohort). Cyclosporine increased naldemedine AUC0-inf 1.78-fold and Cmax 1.45-fold. Itraconazole and fluconazole increased naldemedine AUC0-inf 2.91-fold and 1.90-fold, and Cmax 1.12-fold and 1.38-fold, respectively. Rifampin decreased naldemedine AUC0-inf by 83% and Cmax by 38%. Across studies, AEs were generally mild. Laboratory, vital sign, or electrocardiogram assessments produced no clinically significant findings. CONCLUSIONS: Coadministration of naldemedine with a P-glycoprotein inhibitor or a strong/moderate CYP3A inhibitor increases naldemedine exposure; coadministration with a strong CYP3A inducer decreases its exposure. Coadministration of naldemedine with cyclosporine, itraconazole, fluconazole, or rifampin was generally safe and well tolerated.

Naldemedine is a targeted medication approved in the USA, Europe, and Japan for the treatment of opioid-induced constipation. Symptoms of constipation may include passing fewer stools than usual, having lumpy or hard stools, and/or straining to have bowel movements. In some cases, these symptoms are side effects of regular opioid use, which is often medically necessary for the management of moderate-to-severe pain. For naldemedine to be prescribed safely, doctors must know what other medications a patient is taking and how these medications may affect one another. This is commonly known as drug-drug interactions. Some drug-drug interactions may decrease how well a medication works, while other drug-drug interactions may increase the side effects experienced by a patient. In this paper, researchers report the results of three Phase 1 studies in healthy subjects examining how naldemedine interacts with other drugs. The drugs chosen for investigation are commonly evaluated in DDI studies and may affect the transport or metabolic pathway of naldemedine, including the P-glycoprotein inhibitor cyclosporine, the CYP3A inhibitors itraconazole and fluconazole, and the CYP3A inducer rifampin. These studies demonstrate that co-administration of naldemedine with each of these drugs impacted the pharmacokinetics of naldemedine. Cyclosporine, itraconazole, or fluconazole all increased naldemedine exposure, while rifampin decreased naldemedine exposure. For all drug combinations, observed side effects were generally mild and well tolerated. Additional testing, including vital signs and heart monitoring, did not reveal any other safety concerns. In conclusion, these findings support the cautious use of naldemedine in combination with cyclosporine, itraconazole or fluconazole. Concomitant use with rifampin should be avoided.