RESUMEN
CRS3123 is a novel small molecule that potently inhibits methionyl-tRNA synthetase of Clostridioides difficile, inhibiting C. difficile toxin production and spore formation. CRS3123 has been evaluated in a multiple-ascending-dose placebo-controlled phase 1 trial. Thirty healthy subjects, ages 18 to 45 years, were randomized into three cohorts of 10 subjects each, receiving either 200, 400, or 600 mg of CRS3123 (8 subjects per cohort) or placebo (2 subjects per cohort) by oral administration twice daily for 10 days. CRS3123 was generally safe and well tolerated, with no serious adverse events (SAEs) or severe treatment-emergent adverse events (TEAEs) reported. All subjects completed their assigned treatment and follow-up visits, and there were no trends in systemic, vital sign, or laboratory TEAEs. There were no QTcF interval changes or any clinically significant changes in other electrocardiogram (ECG) intervals or morphology. CRS3123 showed limited but detectable systemic uptake; although absorption increased with increasing dose, the increase was less than dose proportional. Importantly, the bulk of the oral dose was not absorbed, and fecal concentrations were substantially above the MIC90 value of 1 µg/ml at all dosages tested. Subjects receiving either of the two lower doses of CRS3123 exhibited minimal disruption of normal gut microbiota after 10 days of twice-daily dosing. CRS3123 was inactive against important commensal anaerobes, including Bacteroides, bifidobacteria, and commensal clostridia. Microbiome data showed favorable differentiation compared to other CDI therapeutics. These results support further development of CRS3123 as an oral agent for the treatment of CDI. (This study has been registered at Clinicaltrials.gov under identifier NCT02106338.).
Asunto(s)
Antibacterianos/administración & dosificación , Benzopiranos/administración & dosificación , Clostridioides difficile/efectos de los fármacos , Microbioma Gastrointestinal/efectos de los fármacos , Tiofenos/administración & dosificación , Administración Oral , Adolescente , Adulto , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Benzopiranos/efectos adversos , Benzopiranos/farmacocinética , Clostridioides difficile/enzimología , Clostridioides difficile/genética , Infecciones por Clostridium/tratamiento farmacológico , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Esquema de Medicación , Electrocardiografía , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Voluntarios Sanos , Humanos , Masculino , Metionina-ARNt Ligasa/antagonistas & inhibidores , Metionina-ARNt Ligasa/genética , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Tiofenos/efectos adversos , Tiofenos/farmacocinética , Adulto JovenRESUMEN
PURPOSE: Eltrombopag is indicated in patients with severe aplastic anemia (SAA) refractory to prior immunosuppressive therapy. The combination of eltrombopag and immunosuppressive therapy (such as cyclosporine) is currently being evaluated in patients with treatment-naive SAA. Cyclosporine is a human breast cancer resistance protein (BCRP) inhibitor, and can potentially alter plasma exposure to eltrombopag, a BCRP substrate. This phase 1, open-label, randomized, 3-period, crossover study evaluated the effect of cyclosporine on the pharmacokinetics of eltrombopag in healthy adults. METHODS: Thirty-nine subjects were randomized to either single dose of eltrombopag 50 mg, cyclosporine 200 mg + eltrombopag 50 mg or cyclosporine 600 mg + eltrombopag 50 mg treatment groups. Eltrombopag pharmacokinetic parameters (Cmax, tmax, AUClast, AUCinf, %AUCex, t1/2, and CL/F) were determined using noncompartmental methods. RESULTS: Geometric mean AUCinf, AUClast, and Cmax, were decreased by 18, 20, and 25%, respectively, for cyclosporine 200 mg + eltrombopag and by 24, 22, and 39%, respectively, for cyclosporine 600 mg + eltrombopag groups compared to the eltrombopag alone group. The median tmax was prolonged by ~ 1 h in both coadministration treatments. The geometric mean t1/2 was ≈ 21, ≈ 24, and ≈ 26 h, respectively, in cyclosporine 200 mg + eltrombopag, cyclosporine 600 mg + eltrombopag and eltrombopag alone groups. All the treatments were safe and well-tolerated. No serious adverse event or death was reported during the study. CONCLUSION: These changes in exposure were not considered clinically meaningful as the dose of eltrombopag is adjusted using within-patient dose titration based on platelet counts.
Asunto(s)
Benzoatos/administración & dosificación , Benzoatos/sangre , Ciclosporina/administración & dosificación , Hidrazinas/administración & dosificación , Hidrazinas/sangre , Inmunosupresores/administración & dosificación , Pirazoles/administración & dosificación , Pirazoles/sangre , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Adolescente , Adulto , Área Bajo la Curva , Benzoatos/efectos adversos , Estudios Cruzados , Ciclosporina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Hidrazinas/efectos adversos , Inmunosupresores/farmacología , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Proteínas de Neoplasias/metabolismo , Pirazoles/efectos adversos , Receptores de Trombopoyetina/agonistas , Especificidad por Sustrato , Adulto JovenRESUMEN
BACKGROUND: The oral factor Xa inhibitor edoxaban has demonstrated safety and efficacy in stroke prevention in patients with atrial fibrillation and in the treatment and secondary prevention of venous thromboembolism. This study investigated the reversal of edoxaban's effects on bleeding measures and biomarkers by using a 4-factor prothrombin complex concentrate (4F-PCC). METHODS AND RESULTS: This was a phase 1 study conducted at a single site. This was a double-blind, randomized, placebo-controlled, 2-way crossover study to determine the reversal effect of descending doses of 4F-PCC on bleeding duration and bleeding volume following edoxaban treatment. A total of 110 subjects (17 in part 1, 93 in part 2) were treated. Intravenous administration of 4F-PCC 50, 25, or 10 IU/kg following administration of edoxaban (60 mg) dose-dependently reversed edoxaban's effects on bleeding duration and endogenous thrombin potential, with complete reversal at 50 IU/kg. Effects on prothrombin time were partially reversed at 50 IU/kg. A similar trend was seen for bleeding volume. CONCLUSIONS: The 4F-PCC dose-dependently reversed the effects of edoxaban (60 mg), with complete reversal of bleeding duration and endogenous thrombin potential and partial reversal of prothrombin time following 50 IU/kg. Edoxaban alone and in combination with 4F-PCC was safe and well tolerated in these healthy subjects. A dose of 50 IU/kg 4F-PCC may be suitable for reversing edoxaban anticoagulation. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT02047565.