RESUMO
AIMS: Our aim was to determine the absolute bioavailability, mass balance, metabolism and excretion of soticlestat (TAK-935). METHODS: An open-label, two-period, single-site, phase 1 study was conducted in six healthy men. In Period 1, a single 300 mg dose of soticlestat was administered orally, followed by a 15-min intravenous infusion of [14 C]soticlestat 50 µg (~1 µCi) 10 min later. In Period 2, a single 300 mg dose (~100 µCi) of [14 C]soticlestat in solution was administered orally. Samples were collected, analysed for radioactivity or unchanged soticlestat, and profiled for metabolites. RESULTS: In Period 1, soticlestat had an absolute bioavailability of 12.6% (90% confidence interval, 7.81-20.23%). In Period 2, there was near-complete recovery of total radioactivity (TRA) following a 300 mg dose of [14 C]soticlestat: urine, 94.8% (standard deviation [SD], 1.35%); faeces, 2.7% (SD, 1.67%). Of TRA, 0.1% (SD, 0.09%) and 0.6% (SD, 0.21%) were recovered as soticlestat and metabolite M-I in urine, respectively. In plasma, soticlestat and M-I reached geometric mean maximum observed concentrations of 1352 ng/mL (geometric percent coefficient of variation [gCV%], 61.3) and 253.2 ng/mL (gCV%, 44.1) after 25 min and declined with mean terminal half-lives (SD) of 5.7 (2.90) and 2.0 (0.15) h, respectively. Soticlestat represented 4.9% of TRA in plasma. Soticlestat was rapidly eliminated primarily via O-glucuronidation to metabolite M3, which was the dominant species in plasma (92.6%) and urine (86%). CONCLUSIONS: This study indicates that soticlestat and its metabolites are rapidly cleared and eliminated, lowering the risk of dose accumulation from repeated dosing and supporting further investigation of soticlestat.
Assuntos
Piperidinas , Piridinas , Humanos , Masculino , Administração Oral , Disponibilidade Biológica , Colesterol 24-Hidroxilase , Voluntários SaudáveisRESUMO
BACKGROUND: Nasal congestion could affect the absorption of an epinephrine nasal spray (ENS). OBJECTIVE: To compare the pharmacokinetics of 13.2 mg ENS with nasal congestion vs without congestion and vs intramuscular (IM) treatments. METHODS: This phase I, open-label, 4-period randomized crossover study enrolled 51 healthy adults with seasonal allergies into cohorts that received a single dose of 13.2 mg ENS (NDS1C; Bryn Pharma, Lebanon, New Jersey) administered as 2 consecutive sprays in either opposite nostrils (cohort 1) or the same nostril (cohort 2). Both cohorts received 13.2 mg ENS with and without nasal allergen challenge (NAC), 0.3 mg IM epinephrine by autoinjector, and 0.5 mg IM epinephrine by manual syringe (MS). RESULTS: The ENS after NAC resulted in higher extent and peak exposures and more rapid time to maximum plasma concentration vs ENS without NAC and IM treatments. In cohort 1, the maximum observed baseline-adjusted epinephrine plasma concentration (pg/mL) of ENS with NAC, IM autoinjector, IM MS, or ENS without NAC was 458.0, 279.0, 364.2, and 270.1, respectively, and in cohort 2 was 436.3, 228.2, 322.3, and 250.8, respectively. The maximum observed baseline-adjusted epinephrine plasma concentration geometric mean ratio (90% CI) for ENS with NAC vs without NAC in cohort 1 was 170% (123%-234%), and in cohort 2 was 174% (115%-263%). In cohort 1, the time to maximum plasma concentration was 15, 21, 45, and 25 minutes, respectively, and in cohort 2 was 18, 20, 45, and 20 minutes, respectively (P < .01 for ENS with NAC vs IM MS). The postdose mean heart rate and blood pressure remained stable and relatively similar to predose values regardless of plasma epinephrine concentration. Mild nausea and headache were the most common adverse events with ENS. CONCLUSION: The 13.2 mg ENS with congestion exhibited enhanced absorption vs IM treatments and ENS without congestion and seemed to be well tolerated. There was no clinically impactful relationship between pharmacodynamic effects and plasma epinephrine concentration.
Assuntos
Administração Intranasal , Estudos Cross-Over , Epinefrina , Humanos , Epinefrina/farmacocinética , Epinefrina/administração & dosagem , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Adulto Jovem , Sprays Nasais , Rinite Alérgica Sazonal/tratamento farmacológico , Obstrução Nasal/tratamento farmacológico , Adolescente , Alérgenos/imunologia , Alérgenos/administração & dosagem , Alérgenos/farmacocinética , Injeções IntramuscularesRESUMO
Background: Recent acute anaphylaxis guideline updates have identified remaining unmet needs based on currently available therapeutic options as a critical focus. Objective: We compared the pharmacokinetic, pharmacodynamic, safety, and tolerability profiles of intranasal epinephrine with intramuscular epinephrine administered by autoinjector and manual syringe. Methods: An open-label, 3-period crossover study was conducted in 116 healthy adult volunteers to assess the bioavailability of a single 13.2 mg intranasal dose of epinephrine compared to a 0.3 mg intramuscular autoinjector and a 0.5 mg manual syringe. Patients with epinephrine concentrations of 50, 100, and 200 pg/mL at 10, 20, 30, and 60 minutes after dosing were also evaluated. Results: Pharmacokinetic parameters for the 13.2 mg intranasal dose exceeded those of the 0.3 mg autoinjector with a rapid and higher maximum observed concentration (intranasal, 429.4 pg/mL; autoinjector, 328.6 pg/mL) and greater systemic exposure (AUC0-360; intranasal, 39,060 pgâmin/mL; autoinjector, 17,440 pgâmin/mL). Similar results were observed compared to the 0.5 mg manual syringe. Pharmacokinetic parameters for opposite-nostril and same-nostril dosing were higher than both intramuscular doses, except time to reach maximum observed concentration, which was bracketed between the 2 intramuscular doses (intranasal opposite and same nostril, 20 minutes; autoinjector, 14.9 minutes; manual syringe, 45 minutes). Similar effects on blood pressure and heart rate were observed for intranasal and autoinjector administration. Intranasal epinephrine was safe and well tolerated. No serious or unexpected adverse events were reported, confirming results from earlier clinical studies. Conclusions: Bidose epinephrine spray addresses the unmet medical and patient needs for a needle-free, convenient, and effective dose-delivery system for self-administration of epinephrine that is as good as or better than the 0.3 mg autoinjector.
RESUMO
Futibatinib, an oral, irreversible fibroblast growth factor receptor (FGFR) 1-4 inhibitor, is being evaluated for FGFR-aberrant tumors. Two open-label phase 1 studies evaluated the effects of high-fat, high-calorie food and concomitant proton pump inhibitors (PPIs; lansoprazole) on single-dose futibatinib (20 mg) pharmacokinetics and safety in healthy adults. In the food effect study (N = 17), subjects received futibatinib under fed and fasted conditions, separated by a 7-day washout. In the PPI study (N = 20), subjects received futibatinib alone, underwent a 2-day washout, and then received lansoprazole 60 mg once daily for 5 days, with futibatinib also administered on day 5. Under fed versus fasted conditions, futibatinib bioavailability was 11.2% lower (area under the plasma concentration-time curve from time 0 to infinity geometric mean ratio 88.8%; 90% confidence interval, 79.8%-98.9%), and median time to maximum plasma concentration was significantly delayed (4.0 vs 1.5 hours; P < .0001). There were no significant differences in futibatinib exposure between futibatinib plus lansoprazole and futibatinib alone. No serious adverse events occurred in either study. These findings suggest that food and PPIs are unlikely to have clinically meaningful impacts on futibatinib bioavailability. Thus, futibatinib may be used with or without food and concomitantly with acid-reducing agents.
Assuntos
Interações Alimento-Droga , Inibidores da Bomba de Prótons , Adulto , Humanos , Voluntários Saudáveis , Lansoprazol/efeitos adversosRESUMO
The relationship between carbon cycle and water demand is key to understanding global climate change, vegetation productivity, and predicting the future of water resources. The water balance, which enumerates the relative fractions of precipitation P that run off, Q, or are returned to the atmosphere through evapotranspiration, ET, links drawdown of atmospheric carbon with the water cycle through plant transpiration. Our theoretical description based on percolation theory proposes that dominant ecosystems tend to maximize drawdown of atmospheric carbon in the process of growth and reproduction, thus providing a link between carbon and water cycles. In this framework, the only parameter is the fractal dimensionality df of the root system. Values of df appear to relate to the relative roles of nutrient and water accessibility. Larger values of df lead to higher ET values. Known ranges of grassland root fractal dimensions predict reasonably the range of ET(P) in such ecosystems as a function of aridity index. Forests with shallower root systems, should be characterized by a smaller df and, therefore, ET that is a smaller fraction of P. The prediction of ET/P using the 3D percolation value of df matches rather closely results deemed typical for forests based on a phenomenology already in common use. We test predictions of Q with P against data and data summaries for sclerophyll forests in southeastern Australia and the southeastern USA. Applying PET data from a nearby site constrains the data from the USA to lie between our ET predictions for 2D and 3D root systems. For the Australian site, equating cited "losses" with PET underpredicts ET. This discrepancy is mostly removed by referring to mapped values of PET in that region. Missing in both cases is local PET variability, more important for reducing data scatter in southeastern Australia, due to the greater relief.
RESUMO
Futibatinib, a selective, irreversible fibroblast growth factor receptor 1-4 inhibitor, was recently approved for FGFR2 rearrangement-positive cholangiocarcinoma. This Phase I study evaluated the mass balance and metabolic profile of 14 C-futibatinib single oral 20-mg dose in healthy participants (n = 6). Futibatinib was rapidly absorbed; median time to peak drug concentration was 1.0 hours. The mean elimination half-life in plasma was 2.3 hours for futibatinib, and 11.9 hours for total radioactivity. Mean recovery of total radioactivity was 70% of the dose, with 64% recovered in feces and 6% in urine. The major excretion route was fecal; negligible levels were excreted as parent futibatinib. Futibatinib was the most abundant plasma component, comprising 59% of circulating radioactivity (CRA). The most abundant metabolites were cysteinylglycine-conjugated futibatinib in plasma (13% CRA) and reduction of desmethyl futibatinib in feces (17% of dose). In human hepatocytes, 14 C-futibatinib metabolites included glucuronide and sulfate of desmethyl futibatinib, whose formation was inhibited by 1-aminobenzotriazole (a pan-cytochrome P450 inhibitor), and glutathione- and cysteine-conjugated futibatinib. These data indicate the primary metabolic pathways of futibatinib are O-desmethylation and glutathione conjugation, with cytochrome P450 enzyme-mediated desmethylation as the main oxidation pathway. 14 C-futibatinib was well tolerated in this Phase 1 study.
Assuntos
Inibidores de Proteínas Quinases , Pirazóis , Humanos , Voluntários Saudáveis , Pirazóis/efeitos adversos , Sistema Enzimático do Citocromo P-450 , MetabolomaRESUMO
Futibatinib, a selective, irreversible fibroblast growth factor receptor 1-4 inhibitor, is being investigated for tumors harboring FGFR aberrations and was recently approved for the treatment of FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma. In vitro studies identified cytochrome P450 (CYP) 3A as the major CYP isoform in futibatinib metabolism and indicated that futibatinib is likely a P-glycoprotein (P-gp) substrate and inhibitor. Futibatinib also showed time-dependent inhibition of CYP3A in vitro. Phase I studies investigated the drug-drug interactions of futibatinib with itraconazole (a dual P-gp and strong CYP3A inhibitor), rifampin (a dual P-gp and strong CYP3A inducer), or midazolam (a sensitive CYP3A substrate) in healthy adult participants. Compared with futibatinib alone, coadministration of futibatinib with itraconazole increased futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 51% and 41%, respectively, and coadministration of futibatinib with rifampin lowered futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 53% and 64%, respectively. Coadministration of midazolam with futibatinib had no effect on midazolam pharmacokinetics compared with midazolam administered alone. These findings suggest that concomitant use of dual P-gp and strong CYP3A inhibitors/inducers with futibatinib should be avoided, but futibatinib can be concomitantly administered with other drugs metabolized by CYP3A. Drug-drug interaction studies with P-gp-specific substrates and inhibitors are planned.
Assuntos
Citocromo P-450 CYP3A , Rifampina , Adulto , Humanos , Citocromo P-450 CYP3A/metabolismo , Rifampina/farmacocinética , Itraconazol/farmacologia , Midazolam/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Indutores do Citocromo P-450 CYP3A/farmacologia , Interações MedicamentosasRESUMO
Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infection and related morbidity and mortality in infants. Passive immunization with an RSV-neutralizing antibody can provide rapid protection to this vulnerable population. Proof-of-concept for this approach has been demonstrated by palivizumab; however, the use of this antibody is generally restricted to the highest-risk infants due to monthly dosing requirements and its cost. To address the large unmet medical need for most infants, we are evaluating MK-1654, a fully human RSV-neutralizing antibody with half-life extending mutations targeting site IV of the fusion protein. In this 2-part, placebo-controlled, double-blind, first-in-human study, 152 healthy adults were randomized 3:1 to receive a single dose of MK-1654 or placebo in 5 cohorts (100 or 300 mg as an intramuscular dose or 300, 1000, or 3000 mg as an intravenous dose). Safety, pharmacokinetics, antidrug antibodies, and RSV serum-neutralizing antibody titers were evaluated through 1 year. MK-1654 serum concentrations increased proportionally with dose and resulted in corresponding elevations in RSV serum-neutralizing antibody titers. The antibody displayed a half-life of 73 to 88 days and an estimated bioavailability of 69% at the 300-mg dose. The overall safety profile of MK-1654 was similar to placebo, and treatment-emergent antidrug antibodies were low (2.6%) with no associated adverse events. These data support the continued development of MK-1654 for the prevention of RSV disease in infants.
Assuntos
Anticorpos Monoclonais , Anticorpos Neutralizantes , Antivirais , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Neutralizantes/administração & dosagem , Anticorpos Neutralizantes/efeitos adversos , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacocinética , Disponibilidade Biológica , Estudos de Coortes , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Vírus Sinciciais Respiratórios/imunologia , Adulto JovemRESUMO
The fate of water and water-soluble toxic wastes in the subsurface is of high importance for many scientific and practical applications. Although solute transport is proportional to water flow rates, theoretical and experimental studies show that heavy-tailed (power-law) solute transport distribution can cause chemical transport retardation, prolonging clean-up time-scales greatly. However, no consensus exists as to the physical basis of such transport laws. In percolation theory, the scaling behavior of such transport rarely relates to specific medium characteristics, but strongly to the dimensionality of the connectivity of the flow paths (for example, two- or three-dimensional, as in fractured-porous media or heterogeneous sediments), as well as to the saturation characteristics (i.e., wetting, drying, and entrapped air). In accordance with the proposed relevance of percolation models of solute transport to environmental clean-up, these predictions also prove relevant to transport-limited chemical weathering and soil formation, where the heavy-tailed distributions slow chemical weathering over time. The predictions of percolation theory have been tested in laboratory and field experiments on reactive solute transport, chemical weathering, and soil formation and found accurate. Recently, this theoretical framework has also been applied to the water partitioning at the Earth's surface between evapotranspiration, ET, and run-off, Q, known as the water balance. A well-known phenomenological model by Budyko addressed the relationship between the ratio of the actual evapotranspiration (ET) and precipitation, ET/P, versus the aridity index, ET0/P, with P being the precipitation and ET0 being the potential evapotranspiration. Existing work was able to predict the global fractions of P represented by Q and ET through an optimization of plant productivity, in which downward water fluxes affect soil depth, and upward fluxes plant growth. In the present work, based likewise on the concepts of percolation theory, we extend Budyko's model, and address the partitioning of run-off Q into its surface and subsurface components, as well as the contribution of interception to ET. Using various published data sources on the magnitudes of interception and information regarding the partitioning of Q, we address the variability in ET resulting from these processes. The global success of this prediction demonstrated here provides additional support for the universal applicability of percolation theory for solute transport as well as guidance in predicting the component of subsurface run-off, important for predicting natural flow rates through contaminated aquifers.
Assuntos
Água Subterrânea , Ciclo Hidrológico , Modelos Teóricos , Porosidade , Solo , Água , Movimentos da ÁguaRESUMO
Contemporary management of chronic wounds focuses on improving natural healing and individualization of treatment. Incorporating multiple therapies has become increasingly common. Of interest are autologous growth factors, which are especially important in chronic wound healing and may contribute to tissue formation and epithelialization. Autologous platelet concentrate or platelet-rich plasma (PRP) is a concentration of at least five autologous growth factors and has been shown to accelerate wound healing and may have infection-fighting properties. Chronic wound healing is complicated by both decreased growth factor availability and infection, making PRP use valuable in these types of wounds. In this report, the use of PRP therapy alone and in combination with a bioengineered skin substitute as a platelet-rich tissue graft in a chronic, non-healing wound is detailed. Over 27 weeks, the patient received multiple therapies in attempts to heal a severe decubitus ulcer of the sacrum. The introduction of PRP therapy at Week 14 led to a 26% reduction in wound depth over 4 weeks. At Week 19, PRP therapy was combined with a powdered skin substitute to create a platelet-rich tissue graft. The combination brought dramatic results, eliminating wound tunneling and reducing the wound dimensions from 6.2 cm long x 6.7 cm wide x 2.7 cm deep to 5.0 cm long x 6.0 cm wide x 1.4 cm deep. The promising observations from this case report indicate that further study on the combining of PRP therapy and skin substitutes is necessary.
Assuntos
Plasma Rico em Plaquetas , Pele Artificial , Cicatrização/fisiologia , Humanos , Região Lombossacral/patologia , Masculino , Pessoa de Meia-Idade , Úlcera Cutânea/patologiaRESUMO
OBJECTIVE: In children, lead can cause serious permanent damage as a neurotoxicant. The objectives of the study were to evaluate potential exposure to lead-based paint in family housing units at a typical U.S. military installation and determine blood lead (PbB) levels in children ages 6 years or younger residing in these housing units. METHODS: The authors conducted a risk assessment of 1,723 housing units and occupants at Fort Devens in Massachusetts. Data from the military dependent cohort was compared to estimates for the U.S. national population as reported from Phase 1 of the Third National Health and Nutrition Examination Survey (NHANES III). RESULTS: A total of 1992 individuals (1,009 males and 983 females) were screened for PbB, stratified into age groups, and separated into racial/ethnic categories. Four (0.3%) dust samples and 59 (11.6%) internal and 298 (77.8%) external paint chip samples contained hazardous levels of lead. The geometric mean PbB concentration for people ages 1 year and older reported by NHANES III was 2.8 micro g/dL, compared with 1.5 microg/dL for the military installation cohort (p<0.0001). PbB levels were higher for males than for females and higher for blacks than whites 6 years of age and older. Hispanics had lower PbB concentrations for all age groups except for those ages 1-2.9 years. Prevalence of PbB levels >10 microg/dL for all age groups was 1.6% in the military cohort, compared with 4.5% for the general population. For ages 1-2.9 years, no blacks or Hispanics and 0.6% of whites had PbB levels >10 micro g/dL, compared with 21.6% of blacks, 10.1% of Hispanics, and 8.5% of whites for the general population. For ages 3-5.99 years, 0.15% of blacks, 0% of Hispanics, and 0.3% of whites had PbB levels > or = 10 microg/dL, compared with 20.0% of blacks, 6.8% of Hispanics, and 3.7% of whites for the general population. CONCLUSION: Lead exposure for occupants of on-post military housing is much less than for those residing in the civilian sector.
Assuntos
Exposição Ambiental/análise , Habitação/normas , Intoxicação por Chumbo/epidemiologia , Militares , Pintura/efeitos adversos , Medição de Risco , Adolescente , Adulto , Distribuição por Idade , Criança , Pré-Escolar , Estudos de Coortes , Poeira/análise , Feminino , Inquéritos Epidemiológicos , Habitação/classificação , Humanos , Lactente , Chumbo/sangue , Intoxicação por Chumbo/sangue , Intoxicação por Chumbo/etnologia , Masculino , Massachusetts/epidemiologia , Pessoa de Meia-Idade , Prevalência , Distribuição por SexoRESUMO
Aedes alboscutellatus was recorded first in Korea. This mosquito was collected near Demilitarized Zone of Korea Penninsula from 1979-1980. Its morphology and taxonomical position was described.