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AIMS: Filgotinib is a potent, oral, JAK1-preferential inhibitor for the treatment of rheumatoid arthritis (RA). This report describes exposure-response (ER) analyses of filgotinib for dose confirmation based on three phase 3 and two phase 2 studies in moderate to severe RA patients. METHODS: The pharmacokinetic exposures used in ER analyses were derived from population pharmacokinetic analysis. The exposure-efficacy relationships were assessed for efficacy endpoints (ACR20/50/70 and DAS28) over effective area under curve (AUCeff ), the combined exposures of filgotinib and GS-829845 (major, active metabolite), with nonlinear logistic regression models developed. Also, a t-test was performed to compare the exposure between subjects who achieved response and those who did not. For the ER analyses of safety, exposures were examined between subjects who experienced and who did not experience the evaluated safety events, which was conducted separately for filgotinib and GS-829845. RESULTS: The nonlinear logistic regression showed increasing response with increasing exposure, with exposures at 200 mg dose primarily residing on the curve plateau. Also, AUCeff was significantly higher in the subjects who achieved responses compared to those who did not (10 900 vs 9900 h*ng/mL for ACR20, P value < .0001). For exposure-safety analyses, filgotinib and GS-829845 exposures were similar irrespective of the presence/absence of the evaluated safety endpoints, indicating no exposure-safety relationship for common treatment-emergent adverse events (TEAEs)/laboratory abnormalities and serious TEAEs/infections. CONCLUSIONS: ER analyses confirmed that filgotinib produced more robust therapeutic effects across the exposure range observed at 200 mg once daily compared to lower doses, and collectively with the lack of exposure-safety relationship, the 200 mg once daily dose was supported for commercialization.
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Artritis Reumatoide , Piridinas , Triazoles , Antirreumáticos/efectos adversos , Artritis Reumatoide/tratamiento farmacológico , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Humanos , Inhibidores de las Cinasas Janus/efectos adversos , Piridinas/efectos adversos , Resultado del Tratamiento , Triazoles/efectos adversosRESUMEN
Warming-induced mountain pine beetle (Dendroctonus ponderosae; MPB) outbreaks have caused extensive mortality of whitebark pine (Pinus albicaulis; WBP) throughout the species' range. In the highest mountains where WBP occur, they cross alpine treeline ecotones (ATEs) where growth forms transition from trees to shrub-like krummholz, some of which survived recent MPB outbreaks. This observation motivated the hypothesis that ATEs are refugia for WBP because krummholz growth forms escape MPB attack and have the potential to produce viable seed. To test this hypothesis, we surveyed WBP mortality along transects from the ATE edge (locally highest krummholz WBP) downslope into the forest and, to distinguish if survival mechanisms are unique to ATEs, across other forest ecotones (OFEs) from the edge of WBP occurrence into the forest. We replicated this design at 10 randomly selected sites in the U.S. Northern Rocky Mountains. We also surveyed reproduction in a subset of ATE sites. Mortality was nearly absent in upper ATEs (mean ± SE percent dead across all sites of 0.03% ± 0.03% 0-100 m from the edge and 14.1% ± 1.7% 100-500 m from the edge) but was above 20% along OFEs (21.4 ± 5.2% 0-100 m and 32.4 ± 2.7% 100-500 m from the edge). We observed lower reproduction in upper ATEs (16 ± 9.9 cones/ha and 12.9 ± 5.3 viable seeds/cone 0-100 m from the edge) compared to forests below (317.1 ± 64.4 cones/ha and 32.5 ± 2.5 viable seeds/cone 100-500 m from the edge). Uniquely high WBP survival supports the hypothesis that ATEs serve as refugia because krummholz growth forms escape MPB attack. However, low reproduction suggests ATE refugia function over longer time periods. Beyond our WBP system, we propose that plant populations in marginal environments are candidate refugia if distinct phenotypes result in reduced disturbance impacts.
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Escarabajos , Pinus , Animales , Brotes de Enfermedades , Corteza de la Planta , Refugio de FaunaRESUMEN
There has been much recent interest in the concept of rewilding as a tool for nature conservation, but also confusion over the idea, which has limited its utility. We developed a unifying definition and 10 guiding principles for rewilding through a survey of 59 rewilding experts, a summary of key organizations' rewilding visions, and workshops involving over 100 participants from around the world. The guiding principles convey that rewilding exits on a continuum of scale, connectivity, and level of human influence and aims to restore ecosystem structure and functions to achieve a self-sustaining autonomous nature. These principles clarify the concept of rewilding and improve its effectiveness as a tool to achieve global conservation targets, including those of the UN Decade on Ecosystem Restoration and post-2020 Global Biodiversity Framework. Finally, we suggest differences in rewilding perspectives lie largely in the extent to which it is seen as achievable and in specific interventions. An understanding of the context of rewilding projects is the key to success, and careful site-specific interpretations will help achieve the aims of rewilding.
Recientemente ha habido mucho interés por el concepto de retorno a la vida silvestre como herramienta para la conservación de la naturaleza, pero también ha habido confusión por la idea que ha limitado su utilidad. Desarrollamos una definición unificadora y diez principios básicos para el retorno a la vida silvestre por medio de encuestas a 59 expertos en retorno a la vida silvestre, un resumen de las visiones de las organizaciones más importantes para el retorno a la vida silvestre y talleres que involucraron a más de 100 participantes de todo el mundo. Los principios básicos transmiten que el retorno a la vida silvestre existe en un continuo de escala, conectividad y nivel de influencia humana y que su objetivo es restaurar la estructura y las funciones del ecosistema para lograr una naturaleza autónoma autosustentable. Estos principios aclaran el concepto del retorno a la vida silvestre e incrementan su efectividad como herramienta para lograr los objetivos mundiales de conservación, incluyendo aquellos de la Década de la ONU para la Restauración de Ecosistemas y el Marco de Trabajo de la Biodiversidad Global post 2020. Finalmente, sugerimos que las diferencias en las perspectivas del retorno a la vida silvestre yacen principalmente en el grado al que es visto como factible y en intervenciones específicas. Un entendimiento del contexto de los proyectos de retorno a la vida silvestre es importante para el éxito, y las interpretaciones específicas de sitio ayudarán a lograr las metas del retorno a la vida silvestre. Principios Básicos para el Retorno a la Vida Silvestre.
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Conservación de los Recursos Naturales , Ecosistema , Biodiversidad , HumanosRESUMEN
Resilience has become a common goal for science-based natural resource management, particularly in the context of changing climate and disturbance regimes. Integrating varying perspectives and definitions of resilience is a complex and often unrecognized challenge to applying resilience concepts to social-ecological systems (SESs) management. Using wildfire as an example, we develop a framework to expose and separate two important dimensions of resilience: the inherent properties that maintain structure, function, or states of an SES and the human perceptions of desirable or valued components of an SES. In doing so, the framework distinguishes between value-free and human-derived, value-explicit dimensions of resilience. Four archetypal scenarios highlight that ecological resilience and human values do not always align and that recognizing and anticipating potential misalignment is critical for developing effective management goals. Our framework clarifies existing resilience theory, connects literature across disciplines, and facilitates use of the resilience concept in research and land-management applications.
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Seed transfer zones, which define the geographical relationship between adaptive traits and environmental factors, are increasingly used to determine the source populations that can be combined in restoration and revegetation. Climatic variables have been the most commonly used environmental data in transfer zone development, even though soils are also a primary selective force on plants. We assessed the importance of including soils in seed transfer zones using Bromus marginatus, a native grass used for restoration and revegetation in the western United States, as an example. Seeds were collected from 64 populations across Montana and Idaho and grown in a common garden for two years. We assessed among-population variation based on 11 traits related to germination rate, plant size, vigor, inflorescence number, survival, and carbon isotope discrimination (∆13 ), and used this variation to develop seed transfer zone maps using two approaches: (1) a conventional approach, using only climatic variables (climate only) and (2) an expanded approach that included soils and climatic variables (soils + climate). The most influential drivers of trait variation were factors related to soil water availability: soil order, available water content (AWC), and organic carbon levels. Populations from areas with andic soils, which have high soil AWC and soil organic carbon, had low germination, limited first-year survival, low ∆13 , and small seeds. Growing season length and winter temperatures were also predictive of trait variation. In comparison to climate-only models, soils + climate models explained 11% more variance (120% relative increase) for ∆13 and an average of 4.5% more (27% relative increase) for growth traits and survival. The transfer zone map developed using soils + climate differed from the climate-only map in both spatial pattern of ecotypic variation and number of transfer zones; the soils + climate map had more zones and a higher proportion of small (<4 km2 ) transfer zone patches, while the climate-only map had more large patches >37 km2 . Including soils in transfer zone development may identify adaptive trait variation that is obscured by large-scale differences in climate and could improve plant materials used for ecosystem management.
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Bromus , Suelo , Ecosistema , Montana , SemillasRESUMEN
All-trans retinoic acid (atRA) is a front-line treatment of acute promyelocytic leukemia (APL). Due to its activity in regulating the cell cycle, it has also been evaluated for the treatment of other cancers. However, the efficacy of atRA has been limited by atRA inducing its own metabolism during therapy, resulting in a decrease of atRA exposure during continuous dosing. Frequent relapse occurs in patients receiving atRA monotherapy. In an attempt to combat therapy resistance, inhibitors of atRA metabolism have been developed. Of these, ketoconazole and liarozole have shown some benefits, but their usage is limited by side effects and low potency toward the cytochrome P450 26A1 isoform (CYP26A1), the main atRA hydroxylase. We determined the pharmacokinetic basis of therapy resistance to atRA and tested whether the complex disposition kinetics of atRA could be predicted in healthy subjects and in cancer patients in the presence and absence of inhibitors of atRA metabolism using physiologically based pharmacokinetic (PBPK) modeling. A PBPK model of atRA disposition was developed and verified in healthy individuals and in cancer patients. The population-based PBPK model of atRA disposition incorporated saturable metabolic clearance of atRA, induction of CYP26A1 by atRA, and the absorption and distribution kinetics of atRA. It accurately predicted the changes in atRA exposure after continuous dosing and when coadministered with ketoconazole and liarozole. The developed model will be useful in interpretation of atRA disposition and efficacy, design of novel dosing strategies, and development of next-generation atRA metabolism inhibitors.
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Neoplasias , Ácido Retinoico 4-Hidroxilasa/metabolismo , Tretinoina , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Biofarmacia/métodos , Diseño de Fármacos , Interacciones Farmacológicas , Humanos , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Distribución Tisular , Tretinoina/metabolismo , Tretinoina/farmacocinéticaRESUMEN
Collaborative approaches to natural resource management are becoming increasingly common on public lands. Negotiating a shared vision for desired conditions is a fundamental task of collaboration and serves as a foundation for developing management objectives and monitoring strategies. We explore the complex socio-ecological processes involved in developing a shared vision for collaborative restoration of fire-adapted forest landscapes. To understand participant perspectives and experiences, we analyzed interviews with 86 respondents from six collaboratives in the western U.S., part of the Collaborative Forest Landscape Restoration Program established to encourage collaborative, science-based restoration on U.S. Forest Service lands. Although forest landscapes and group characteristics vary considerably, collaboratives faced common challenges to developing a shared vision for desired conditions. Three broad categories of challenges emerged: meeting multiple objectives, collaborative capacity and trust, and integrating ecological science and social values in decision-making. Collaborative groups also used common strategies to address these challenges, including some that addressed multiple challenges. These included use of issue-based recommendations, field visits, and landscape-level analysis; obtaining support from local agency leadership, engaging facilitators, and working in smaller groups (sub-groups); and science engagement. Increased understanding of the challenges to, and strategies for, developing a shared vision of desired conditions is critical if other collaboratives are to learn from these efforts.
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Conservación de los Recursos Naturales/métodos , Incendios , Agricultura Forestal/métodos , Bosques , Árboles , Conducta Cooperativa , Toma de Decisiones , Ecología , Estados UnidosRESUMEN
Theory suggests that natural fire regimes can result in landscapes that are both self-regulating and resilient to fire. For example, because fires consume fuel, they may create barriers to the spread of future fires, thereby regulating fire size. Top-down controls such as weather, however, can weaken this effect. While empirical examples demonstrating this pattern-process feedback between vegetation and fire exist, they have been geographically limited or did not consider the influence of time between fires and weather. The availability of remotely sensed data identifying fire activity over the last four decades provides an opportunity to explicitly quantify-the ability of wildland fire to limit the progression of subsequent fire. Furthermore, advances in fire progression mapping now allow an evaluation of how daily weather as a top-down control modifies this effect. In this study, we evaluated the ability of wildland fire to create barriers that limit the spread of subsequent fire along a gradient representing time between fires in four large study areas in the western United States. Using fire progression maps in conjunction with weather station data, we also evaluated the influence of daily weather. Results indicate that wildland fire does limit subsequent fire spread in all four study areas, but this effect decays over time; wildland fire no longer limits subsequent fire spread 6-18 years after fire, depending on the study area. We also found that the ability of fire to regulate, subsequent fire progression was substantially reduced under extreme conditions compared to moderate weather conditions in all four study areas. This study increases understanding of the spatial feedbacks that can lead to self-regulating landscapes as well as the effects of top-down controls, such as weather, on these feedbacks. Our results will be useful to managers who seek to restore natural fire regimes or to exploit recent burns when managing fire.
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Conservación de los Recursos Naturales , Monitoreo del Ambiente/estadística & datos numéricos , Incendios , Tiempo (Meteorología) , Monitoreo del Ambiente/métodos , Estados UnidosRESUMEN
Firsocostat is an oral, liver-targeted inhibitor of acetyl-coenzyme A carboxylase in development for the treatment of metabolic dysfunction-associated steatohepatitis. Hepatic organic anion transporting polypeptides play a significant role in the disposition of firsocostat with minimal contributions from uridine diphospho-glucuronosyltransferase and cytochrome P450 3A enzymes. This phase 1 study evaluated the pharmacokinetics and safety of firsocostat in participants with mild, moderate, or severe hepatic impairment. Participants with stable mild, moderate, or severe hepatic impairment (Child-Pugh A, B, or C, respectively [n = 10 per cohort]) and healthy matched controls with normal hepatic function (n = 10 per cohort) received a single oral dose of firsocostat (20 mg for mild and moderate hepatic impairment; 5 mg for severe hepatic impairment) with intensive pharmacokinetic sampling over 96 h. Safety was monitored throughout the study. Firsocostat plasma exposure (AUCinf) was 83%, 8.7-fold, and 30-fold higher in participants with mild, moderate, and severe hepatic impairment, respectively, relative to matched controls. Firsocostat was generally well tolerated, and all reported adverse events were mild in nature. Dose adjustment is not necessary for the administration of firsocostat in patients with mild hepatic impairment. However, based on the observed increases in firsocostat exposure, dose adjustment should be considered for patients with moderate or severe hepatic impairment, and additional safety and efficacy data from future clinical trials will further inform dose adjustment.
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Acetil-CoA Carboxilasa , Humanos , Masculino , Persona de Mediana Edad , Femenino , Acetil-CoA Carboxilasa/antagonistas & inhibidores , Adulto , Anciano , Furanos/farmacocinética , Furanos/efectos adversos , Furanos/administración & dosificación , Hepatopatías , Área Bajo la Curva , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/uso terapéutico , Índice de Severidad de la Enfermedad , Isobutiratos/farmacocinética , Isobutiratos/efectos adversos , Isobutiratos/administración & dosificación , Oxazoles , PirimidinasRESUMEN
Firsocostat, a liver-targeted acetyl-coenzyme A carboxylase inhibitor, and cilofexor, a nonsteroidal farnesoid X receptor agonist, are being developed in combination for treatment of nonalcoholic steatohepatitis. This phase 1 study evaluated firsocostat and cilofexor pharmacokinetics and tolerability in participants with severe renal impairment (SRI) and healthy matched controls (HMCs). Ten participants with SRI (estimated glomerular filtration rate by Modification of Diet in Renal Disease <30 mL/min/1.73 m2 ), and 10 HMCs received single oral doses of firsocostat (20 mg) on day 1 and cilofexor (100 mg) on day 7 in a fasted state. Plasma concentrations of firsocostat (and nonactive metabolite GS-834773) and cilofexor (and nonactive metabolites GS-716070 and GS-1056756) were collected over 96 hours and quantified; plasma exposures (area under the concentration-time curve [AUC] and peak concentration [Cmax ]) and plasma protein binding were characterized. Firsocostat AUC was ≈40% higher in SRI versus HMC, while Cmax was 8% lower. Observed exposures of the firsocostat metabolite were ≈4.6-fold higher in SRI participants versus HMC. Exposures (AUC and Cmax ) of cilofexor and metabolites and percentages of protein binding of all analytes were similar between SRI and HMC groups. Treatment-emergent adverse events were generally mild and not considered related to study drug. A <50% increase in firsocostat exposure was observed among SRI participants but was deemed not clinically relevant. There was no apparent effect of SRI on cilofexor exposure. Based on this trial, firsocostat and cilofexor dosing are not expected to require modification in patients who are renally impaired.
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Acetil-CoA Carboxilasa , Insuficiencia Renal , Humanos , Acetil-CoA Carboxilasa/metabolismo , Área Bajo la Curva , Coenzima A/metabolismo , Insuficiencia Renal/metabolismoRESUMEN
BACKGROUND AND OBJECTIVE: Cilofexor is a selective farnesoid X receptor (FXR) agonist in development for the treatment of nonalcoholic steatohepatitis and primary sclerosing cholangitis. Our objective was to evaluate potential drug-drug interactions of cilofexor as a victim and as a perpetrator. METHODS: In this Phase 1 study, healthy adult participants (n = 18-24 per each of the 6 cohorts) were administered cilofexor in combination with either perpetrators or substrates of cytochrome P-450 (CYP) enzymes and drug transporters. RESULTS: In total, 131 participants completed the study. As a victim, cilofexor area under the curve (AUC) was 651%, 795%, and 175% when administered following single-dose cyclosporine (600 mg; organic anion transporting polypeptide [OATP]/P-glycoprotein [P-gp]/CYP3A inhibitor), single-dose rifampin (600 mg; OATP1B1/1B3 inhibitor), and multiple-dose gemfibrozil (600 mg twice daily [BID]; CYP2C8 inhibitor), respectively, compared with the administration of cilofexor alone. Cilofexor AUC was 33% when administered following multiple-dose rifampin (600 mg; OATP/CYP/P-gp inducer). Multiple-dose voriconazole (200 mg BID; CYP3A4 inhibitor) and grapefruit juice (16 ounces; intestinal OATP inhibitor) did not affect cilofexor exposure. As a perpetrator, multiple-dose cilofexor did not affect the exposure of midazolam (2 mg; CYP3A substrate), pravastatin (40 mg; OATP substrate), or dabigatran etexilate (75 mg; intestinal P-gp substrate), but atorvastatin (10 mg; OATP/CYP3A4 substrate) AUC was 139% compared with atorvastatin administered alone. CONCLUSION: Cilofexor may be coadministered with inhibitors of P-gp, CYP3A4, or CYP2C8 without the need for dose modification. Cilofexor may be coadministered with OATP, BCRP, P-gp, and/or CYP3A4 substrates-including statins-without dose modification. However, coadministration of cilofexor with strong hepatic OATP inhibitors, or with strong or moderate inducers of OATP/CYP2C8, is not recommended.
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Transportadores de Anión Orgánico , Rifampin , Adulto , Humanos , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP3A/metabolismo , Atorvastatina , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Proteínas de Neoplasias , Preparaciones Farmacéuticas , Interacciones Farmacológicas , Sistema Enzimático del Citocromo P-450 , Proteínas de Transporte de Membrana , Inhibidores del Citocromo P-450 CYP3A/farmacologíaRESUMEN
Cilofexor is a nonsteroidal farnesoid X receptor agonist in clinical development for treatment of nonalcoholic steatohepatitis. This work characterized the pharmacokinetics, pharmacodynamics, safety, and tolerability of cilofexor in participants with normal hepatic function or hepatic impairment (HI). Participants with stable mild, moderate, or severe HI (Child-Pugh [CP] A, B, or C, respectively, [n = 10/group]) and healthy matched controls with normal hepatic function received a single oral dose of cilofexor (30 mg for CP-A or B; 10 mg for CP-C) with a standardized meal. Overall, 56 participants received cilofexor and completed the study. Cilofexor area under the plasma concentration-time curve was 76%, 2.5-fold, and 6.3-fold higher in participants with mild, moderate, or severe HI, respectively, relative to the area under the plasma concentration-time curve in matched participants with normal hepatic function. Cilofexor unbound fraction was 38%, 2-fold, and 3.16-fold higher in participants with mild, moderate, and severe HI, respectively, relative to participants with normal hepatic function. Moderate correlations were identified between cilofexor exposure and CP score or laboratory tests components of CP score. Serum 7α-hydroxy-4-cholesten-3-one and plasma fibroblast growth factor 19 were similar in participants with mild, moderate, or severe HI and participants with normal hepatic function. Cilofexor was generally well tolerated; all cilofexor-related adverse events were mild in severity. Cilofexor can be administered to patients with mild HI without dose adjustment. Caution and dose modification are warranted when administering cilofexor to patients with moderate or severe HI.
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Hepatopatías , Humanos , Área Bajo la Curva , Hepatopatías/metabolismoRESUMEN
Innovation in ecological restoration is necessary to achieve the ambitious targets established in United Nations conventions and other global restoration initiatives. Innovation is also crucial for navigating uncertainties in repairing and restoring ecosystems, and thus practitioners often develop innovations at project design and implementation stages. However, innovation in ecological restoration can be hindered by many factors (e.g., time and budget constraints, and project complexity). Theory and research on innovation has been formally applied in many fields, yet explicit study of innovation in ecological restoration remains nascent. To assess the use of innovation in restoration projects, including its drivers and inhibitors, we conducted a social survey of restoration practitioners in the United States. Specifically, we assessed relationships between project-based innovation and traits of the individual practitioner (including, for example, age, gender, experience); company (including, for example, company size and company's inclusion of social goals); project (including, for example, complexity and uncertainty); and project outcomes (such as completing the project on time/on budget and personal satisfaction with the work). We found positive relationships between project-based innovation and practitioner traits (age, gender, experience, engagement with research scientists), one company trait (company's inclusion of social goals in their portfolio), and project traits (project complexity and length). In contrast, two practitioner traits, risk aversion and the use of industry-specific information, were negatively related to project-based innovation. Satisfaction with project outcomes was positively correlated with project-based innovation. Collectively, the results provide insights into the drivers and inhibitors of innovation in restoration and suggest opportunities for research and application.
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Ecosistema , Objetivos , Estados Unidos , IncertidumbreRESUMEN
Because of increasing concern about the effects of catastrophic wildland fires throughout the western United States, federal land managers have been engaged in efforts to restore historical fire behavior and mitigate wildfire risk. During the last 5 years (2004-2008), 44,000 fuels treatments were implemented across the western United States under the National Fire Plan (NFP). We assessed the extent to which these treatments were conducted in and near the wildland-urban interface (WUI), where they would have the greatest potential to reduce fire risk in neighboring homes and communities. Although federal policies stipulate that significant resources should be invested in the WUI, we found that only 3% of the area treated was within the WUI, and another 8% was in an additional 2.5-km buffer around the WUI, totaling 11%. Only 17% of this buffered WUI is under federal ownership, which significantly limits the ability of federal agencies to implement fire-risk reduction treatments near communities. Although treatments far from the WUI may have some fire mitigation benefits, our findings suggest that greater priority must be given to locating treatments in and near the WUI, rather than in more remote settings, to satisfy NFP goals of reducing fire risk to communities. However, this may require shifting management and policy emphasis from public to private lands.
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Planificación en Desastres/métodos , Incendios/prevención & control , Gestión de Riesgos/métodos , Agricultura , Ciudades , Conservación de los Recursos Naturales/economía , Conservación de los Recursos Naturales/métodos , Bases de Datos como Asunto , Planificación en Desastres/economía , Ecosistema , Apoyo Financiero , Financiación Gubernamental , Geografía , Factores de Riesgo , Gestión de Riesgos/economía , Estados UnidosRESUMEN
Filgotinib (GS-6034, formerly GLPG0634; Jyseleca®) is an oral, preferential Janus kinase (JAK)-1 inhibitor. Preferential inhibition of JAK1 modulates a subset of proinflammatory cytokines within the JAK-signal transducer and activator of transcription pathway, which differ from those inhibited by JAK2 or JAK3. Filgotinib is absorbed extensively and rapidly after oral dosing and is metabolized by carboxylesterase isoform 2 to form its primary active metabolite, GS-829845. The primary metabolite has a similar JAK1 selectivity profile but reduced activity (by 10-fold) and increased systemic exposure (approximately 16- to 20-fold) compared with the parent compound. Both the parent and the metabolite demonstrate low binding to plasma proteins in humans (< 60%). Systemic exposures of filgotinib and its primary metabolite increase dose proportionally over a 50- to 200-mg once-daily dose range. Food does not affect the pharmacokinetics of filgotinib. Consistent with their terminal elimination half-lives (4.9-10.7 h for filgotinib and 19.6-27.3 h for the primary metabolite), steady state in plasma is reached by day 2 for filgotinib and day 4 for its metabolite. Filgotinib is mainly eliminated in the urine as the metabolite (> 80%). Intrinsic factors such as age, sex, race, mild renal impairment, and mild-to-moderate hepatic impairment have either no or minimal impact on the pharmacokinetics of filgotinib and its primary metabolite. Filgotinib has a low drug-drug interaction potential, without clinically significant interactions with commonly coadministered medications in patients with inflammatory diseases. Both filgotinib and its primary metabolite are substrates of P-glycoprotein (P-gp); however, coadministration with P-gp inhibitors and inducers does not affect filgotinib pharmacokinetics sufficiently to warrant dose adjustment. Neither filgotinib nor its primary metabolite affect the corrected QT interval (calculated using Fridericia's correction formula). Filgotinib is approved for the treatment of rheumatoid arthritis and ulcerative colitis in Europe, the UK, and Japan.
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Artritis Reumatoide , Inhibidores de las Cinasas Janus , Farmacología Clínica , Artritis Reumatoide/tratamiento farmacológico , Humanos , Inhibidores de las Cinasas Janus/uso terapéutico , Piridinas/farmacocinética , Triazoles/farmacocinéticaRESUMEN
Tirabrutinib (TIRA), a potent and nonreversible oral Bruton tyrosine kinase inhibitor, is evaluated for treatment of certain hematological malignancies and inflammatory diseases. A drug-drug interaction study to evaluate the effect of TIRA on the pharmacokinetics of the oral contraceptive levonorgestrel (LEVO)/ethinyl estradiol (EE) was conducted in healthy female participants (N = 26). Participants received a single dose of LEVO (150 mcg)/EE (30 mcg) alone (reference), and on day 12 of a 15-day regimen of TIRA 160 mg once-daily (test). Intensive blood sampling for determination of LEVO, EE, and TIRA plasma concentrations was conducted, and safety was assessed throughout the study. Pharmacokinetic interactions were evaluated using 90% confidence intervals (CIs) of the geometric least squares mean (GLSM) ratios of the test versus reference treatments. The GLSM (90% CI) ratios of area under the concentration-time curve from zero to infinity (AUCinf ; LEVO: 0.95, 95% CI: 0.88-1.03, EE: 1.10, 95% CI: 1.05-1.16) and maximum plasma concentration (Cmax ; LEVO: 0.85, 95% CI: 0.74-0.98, EE: 1.07, 95% CI: 0.98-1.18) were within the prespecified 0.70 to 1.43 no effect bounds; and the AUC ratios met the stricter 0.80 to 1.25 equivalence bounds. Study treatments were generally well-tolerated. In conclusion, co-administration with TIRA did not alter the exposure of LEVO/EE, and accordingly LEVO/EE containing oral contraceptives can serve as a contraception method for participants on TIRA 160 mg (or lower) daily doses.
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Etinilestradiol , Levonorgestrel , Interacciones Farmacológicas , Etinilestradiol/efectos adversos , Femenino , Humanos , Imidazoles , Levonorgestrel/efectos adversos , Pirimidinas , VoluntariosRESUMEN
Filgotinib, an oral Janus kinase-1 preferential inhibitor, is approved in Europe and Japan for adults with rheumatoid arthritis. Patients with rheumatoid arthritis are at higher risk of cardiovascular morbidity/mortality; thus, it is important to understand potential drug-drug interactions of filgotinib with lipid-lowering agents. This open-label, randomized, 2-way crossover study evaluated the pharmacokinetics of atorvastatin, pravastatin, and rosuvastatin with and without filgotinib coadministration. Healthy participants (N = 27) received single doses of atorvastatin (40 mg) and of a pravastatin (40 mg)/rosuvastatin (10 mg) cocktail-alone or with filgotinib (200 mg once daily for 11 days)-on 2 different occasions with washout in between. Serial pharmacokinetic blood samples were collected, and safety was assessed. Pharmacokinetic parameters were evaluated using 90% confidence intervals (CI) of the geometric least-squares mean (GLSM) ratio of the test treatment (statin coadministration with filgotinib) vs statin alone, with prespecified lack-of-interaction bounds of 0.70 to 1.43. Coadministration of filgotinib did not affect atorvastatin area under the plasma concentration-time curve extrapolated to infinity (AUCinf ; [GLSM ratios (90% CI): 0.91 (0.84-0.99)]), but maximum concentration [Cmax ] was slightly lower [0.82 (0.69-0.99)]. The exposure of 2-hydroxy-atorvastatin was unaffected (GLSM ratios [90% CI], 0.98 [0.81-1.19] for Cmax ; 1.11 [1.02-1.22] for AUCinf ). Pravastatin AUCinf was also unaffected (GLSM ratios, 1.22 [1.05-1.41], but Cmax was slightly higher 1.25 [1.01-1.54]). Rosuvastatin exposure was moderately higher with filgotinib coadministration-GLSM ratios (90% CI), 1.68 (1.43-1.97) for Cmax ; 1.42 (1.30-1.57) for AUCinf -but this was not considered clinically relevant. These results indicate that filgotinib has no clinically meaningful effect on exposure of atorvastatin, pravastatin, or rosuvastatin.
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Pravastatina , Adulto , Atorvastatina/efectos adversos , Atorvastatina/farmacocinética , Estudios Cruzados , Interacciones Farmacológicas , Voluntarios Sanos , Humanos , Pravastatina/efectos adversos , Pravastatina/farmacocinética , Piridinas , Rosuvastatina Cálcica , TriazolesRESUMEN
Tirabrutinib is an irreversible, small-molecule Bruton's tyrosine kinase (BTK) inhibitor, which was approved in Japan (VELEXBRU) to treat B-cell malignancies and is in clinical development for inflammatory diseases. As an application of model-informed drug development, a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for irreversible BTK inhibition of tirabrutinib was developed to support dose selection in clinical development, based on clinical PK and BTK occupancy data from two phase I studies with a wide range of PK exposures in healthy volunteers and in subjects with rheumatoid arthritis. The developed model adequately described and predicted the PK and PD data. Overall, the model-based simulation supported a total daily dose of at least 40 mg, either q.d. or b.i.d., with adequate BTK occupancy (> 90%) for further development in inflammatory diseases. Following the PK/PD modeling and simulation, the relationship between model-predicted BTK occupancy and preliminary clinical efficacy data was also explored and a positive trend was identified between the increasing time above adequate BTK occupancy and better efficacy in treatment for RA by linear regression.
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Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Antiinflamatorios/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Imidazoles/administración & dosificación , Modelos Biológicos , Inhibidores de Proteínas Quinasas/administración & dosificación , Pirimidinas/administración & dosificación , Adolescente , Adulto , Agammaglobulinemia Tirosina Quinasa/metabolismo , Antiinflamatorios/farmacocinética , Artritis Reumatoide/enzimología , Ensayos Clínicos Fase I como Asunto , Simulación por Computador , Cálculo de Dosificación de Drogas , Femenino , Humanos , Imidazoles/farmacocinética , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/farmacocinética , Pirimidinas/farmacocinética , Adulto JovenRESUMEN
Accurate estimation of responses of understory plants to disturbance is essential for understanding the efficacy of management activities. However, the ability to assess changes in the abundance of plants may be hampered by inappropriate sampling methodologies. Conventional methods for sampling understory plants may be precise for common species but may fail to adequately characterize abundance of less common species. We tested conventional (modified Whittaker plots and Daubenmire and point-line intercept transects) and novel (strip adaptive cluster sampling [SACS]) approaches to sampling understory plants to determine their efficacy for quantifying abundance on control and thinned-and-burned treatment units in Pinus ponderosa forests in western Montana, USA. For species grouped by growth-form and for common species, all three conventional designs were capable of estimating cover with a 50% relative margin of error with reasonable sample sizes (3-36 replicates for growth-form groups; 8-14 replicates for common species); however, increasing precision to 25% relative margin of error required sample sizes that may be infeasible (11-143 replicates for growth-form groups; 28-54 replicates for common species). All three conventional designs required enormous sample sizes to estimate cover of nonnative species as a group (29-60 replicates) and of individual less common species (62-118 replicates), even with a 50% relative margin of error. SACS was the only design that efficiently sampled less common species, requiring only 6-11% as many replicates relative to conventional designs. Conventional designs may not be effective for estimating abundance of the majority of forest understory plants, which are typically patchily distributed with low abundance, or of newly establishing nonnative plants. Novel methods such as SACS should be considered in investigations when cover of these species is of concern.