RESUMEN
PURPOSE: The present studies assessed the drug-drug interaction of molidustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, with iron and calcium supplements, which are common medications in patients with anaemia due to chronic kidney disease (CKD). METHODS: Forty-two healthy men received molidustat alone (fasted or fed) or combined with oral iron(II) or calcium(II), given immediately before or between 4 h before and 1 h after molidustat in three randomized, open-label, crossover studies (12-15 participants per study). Molidustat AUC and Cmax were assessed as the main pharmacokinetic parameters, and endogenous erythropoietin (EPO) was measured to evaluate pharmacodynamics. RESULTS: Depending on prandial state, concomitant intake of iron(II) reduced molidustat AUC and Cmax by 50-75% and 46-84%, respectively, and EPO AUC(0-24) and Cmax by 31-44% and 36-48%, respectively. The influence of iron(II) declined with increasing the time interval to the intake of molidustat, with reductions in molidustat AUC and Cmax of 9% and 10%, respectively, when iron(II) intake occurred 4 h before molidustat. Accordingly, effects on endogenous EPO were less pronounced with increased time separation between oral iron(II) and molidustat intake. Calcium(II) reduced molidustat AUC and Cmax by 15% and 47%, respectively, without influence on EPO response. All treatments were well tolerated. CONCLUSIONS: In contrast to concomitant oral intake of calcium, the effect of oral iron supplements on molidustat pharmacokinetics and pharmacodynamics should be considered, and the two agents should be administered with an appropriate time separation.
Asunto(s)
Calcio/administración & dosificación , Hierro/administración & dosificación , Pirazoles/administración & dosificación , Triazoles/administración & dosificación , Administración Oral , Adulto , Anemia/tratamiento farmacológico , Área Bajo la Curva , Calcio/farmacología , Estudios Cruzados , Suplementos Dietéticos , Esquema de Medicación , Interacciones Farmacológicas , Eritropoyetina/metabolismo , Humanos , Prolina Dioxigenasas del Factor Inducible por Hipoxia/antagonistas & inhibidores , Hierro/farmacología , Masculino , Persona de Mediana Edad , Pirazoles/farmacocinética , Pirazoles/farmacología , Factores de Tiempo , Triazoles/farmacocinética , Triazoles/farmacología , Adulto JovenRESUMEN
Molidustat is an oral inhibitor of hypoxia-inducible factor (HIF) prolyl-hydroxylase enhancing the erythropoietin (EPO) response to HIF; it is in clinical development for the treatment of anaemia related to chronic kidney disease. The predominant role of glucuronidation for molidustat clearance (formation of N-glucuronide metabolite M1) and subsequent renal excretion was confirmed in a human mass balance study, with about 85% of the drug being excreted as M1 in urine. The inhibitory effects of 176 drugs and xenobiotics from various compound classes on the UGT-mediated glucuronidation of molidustat in human liver microsomes (HLMs) were investigated. Based on preclinical findings, glucuronidation of molidustat was predominantly mediated by the 5'-diphospho-glucuronosyltransferase (UGT) isoform UGT1A1. Therefore, atazanavir, which is a potent inhibitor of UGT1A1, was chosen for the evaluation of pharmacokinetics and EPO release following a single oral dose of 25 mg molidustat. Molidustat exposure increased about twofold upon coadministration with atazanavir when considering area under plasma concentration-time curve from zero to infinity (AUC) and maximum plasma concentration (Cmax ). Baseline-corrected increase of EPO was 14% and 34% for Cmax and AUC (calculated over 24 hours), respectively. Coadministration of molidustat and atazanavir was well tolerated.
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Sulfato de Atazanavir/farmacología , Glucurónidos/metabolismo , Glucuronosiltransferasa/fisiología , Pirazoles/farmacocinética , Triazoles/farmacocinética , Adulto , Interacciones Farmacológicas , Eritropoyetina/farmacocinética , Glucuronosiltransferasa/antagonistas & inhibidores , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The absorption, distribution, metabolism and excretion of molidustat were investigated in healthy male participants. In study 1, a mass balance study, radiolabelled molidustat 25 mg (3.57 MBq) was administered as an oral solution (n = 4). Following rapid absorption, molidustat-related radioactivity was predominantly distributed in plasma rather than in red blood cells. The total recovery of the administered radioactivity was 97.0%, which was mainly excreted renally (90.7%). Metabolite M-1, produced by N-glucuronidation, was the dominant component in plasma (80.2% of the area under the concentration-time curve for total radioactivity) and was primarily excreted via urine (~85% of dose). Only minor amounts of unchanged molidustat were excreted in urine (~4%) and faeces (~6%). Study 2 investigated the absolute bioavailability and pharmacodynamics of molidustat (part 1, n = 12; part 2, n = 16). Orally administered molidustat immediate release tablets had an absolute bioavailability of 59%. Following intravenous administration (1, 5 and 25 mg), total body clearance of molidustat was 28.7-34.5 L/h and volume of distribution at steady state was 39.3-50.0 L. All doses of molidustat transiently elevated endogenous erythropoietin levels, irrespective of the route of administration. Molidustat was considered safe and well tolerated at the administered doses.
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Pirazoles/metabolismo , Pirazoles/farmacocinética , Triazoles/metabolismo , Triazoles/farmacocinética , Administración Oral , Adulto , Disponibilidad Biológica , Evaluación Preclínica de Medicamentos , Voluntarios Sanos , Humanos , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Pirazoles/sangre , Pirazoles/orina , Distribución Tisular , Triazoles/sangre , Triazoles/orinaRESUMEN
The diagnosis and management of drug-induced liver injury (DILI) remains a challenge in clinical trials in drug development. The qualification of emerging biomarkers capable of predicting DILI soon after the initiation of treatment, differentiating DILI from underlying liver disease, identifying the causal entity, and assigning appropriate treatment options after DILI is diagnosed are needed. Qualification efforts have been hindered by lack of properly stored and consented biospecimens that are linked to clinical data relevant to a specific context of use. Recommendations are made for biospecimen collection procedures, with the focus on clinical trials, and for specific emerging biomarkers to focus qualification efforts.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Desarrollo de Medicamentos/métodos , Desarrollo de Medicamentos/normas , Manejo de Especímenes/métodos , Manejo de Especímenes/normas , Biomarcadores , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Ensayos Clínicos como Asunto/normas , Humanos , Consentimiento Informado , Pruebas de Función Hepática , FenotipoRESUMEN
STUDY OBJECTIVES: To evaluate the impact of obstructive sleep apnea syndrome (OSAS) on serum creatine phosphokinase (CK) levels. DESIGN: Single-center prospective cross-sectional study. SETTING: Academic sleep disorder center. PATIENTS: Two hundred one consecutive patients (mean [+/- SD] age, 54.9 +/- 11.0 years; 155 men and 46 women; mean body mass index, 31.3 +/- 6.9 kg/m(2)) with suspected sleep-disordered breathing. MEASUREMENTS AND RESULTS: OSAS was confirmed in182 patients (apnea-hypopnea index [AHI], > 5 events per hour) and was ruled out in 19 patients (control subjects) by standard polysomnography. Sixty-six OSAS patients and 1 control patient showed an unexplained CK elevation. The mean baseline CK level was significantly higher in patients with severe OSAS (AHI, > 30 event per hour; n = 89) compared to those with mild-to-moderate OSAS (AHI, 5 to 30 events per hour; n = 93) and control subjects (191.4 +/- 12.9 vs 134.3 +/- 7.5 vs 107.1 +/- 7.9 U/L, respectively; p < 0.01). Receiver operating curve analysis identified an optimal cutoff value of > 148 U/L (r = 0.660) for CK, which yielded a positive predictive value of 99%, a sensitivity of 43%, and a specificity of 95% for the diagnosis of OSAS. The mean nocturnal oxyhemoglobin saturation was the main predictor of CK level (r = 0.47; p < 0.001). Continuous positive airway pressure (CPAP) treatment resulted in a significant decline of CK levels both in patients with mild-to-moderate OSAS (n = 38; 129.7 +/- 13.4 vs 96.7 +/- 7.6 U/L, respectively; p < 0.001) and in patients with severe OSAS (n = 39; 187.7 +/- 18.9 vs 132.2 +/- 12.9 U/L, respectively; p < 0.001). CONCLUSIONS: One third of our study population showed a mild-to-moderate elevation in CK level, which was highly predictive of OSAS. The application of CPAP therapy in OSAS patients resulted in a significant decrease in CK level. We speculate that OSAS may account for a substantial number of cases of unexplained CK elevation (ie, hyperCKemia). Further studies should address the prevalence of OSAS in patients with mild-to-moderate hyperCKemia.
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Creatina Quinasa/sangre , Apnea Obstructiva del Sueño/enzimología , Biomarcadores , Presión de las Vías Aéreas Positiva Contínua , Estudios Transversales , Progresión de la Enfermedad , Electroforesis en Gel de Agar , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Polisomnografía , Pronóstico , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Apnea Obstructiva del Sueño/fisiopatología , Apnea Obstructiva del Sueño/terapiaRESUMEN
The safety, tolerability and pharmacokinetics of the selective nonsteroidal mineralocorticoid receptor antagonist finerenone were evaluated in healthy male volunteers in two randomized, single-centre studies. Study 1 was a first-in-man, single-blinded, placebo-controlled, parallel-group, dose-escalation study. Fasted participants (n = 45) received single oral doses of finerenone 1-40 mg polyethylene glycol (PEG) solution or placebo. Study 2 was a relative bioavailability study comparing a finerenone 10 mg immediate-release (IR) tablet with finerenone 10 mg PEG solution in the fasted state, investigating the effect of a high-fat/high-calorie meal on the pharmacokinetics of the IR tablet and assessing a further dose escalation to finerenone 80 mg (eight × finerenone 10 mg IR tablets), in an open-label, fourfold crossover design (n = 15). Finerenone was rapidly absorbed from PEG solution (median time to maximum plasma concentration [tmax ]: 0.500-1.00 h), exhibited dose-linear pharmacokinetics and was rapidly eliminated from plasma (geometric mean terminal half-life [t½ ]: 1.70-2.83 h). Finerenone IR tablets demonstrated similar pharmacokinetics (median tmax : 0.750-2.50 h; geometric mean t½ : 1.89-4.29 h) with, however, enhanced bioavailability versus PEG solution (least-squares mean tablet/solution ratio of 187% for area under the plasma-concentration curve [AUC] and maximum plasma concentration [Cmax ]). High-fat/high-calorie food affected the rate but not the extent of finerenone absorption. Finerenone was well tolerated and did not influence clinical laboratory parameters, blood pressure, heart rate, urinary electrolytes or neurohormones, including serum aldosterone and angiotensin II. In conclusion, finerenone has favourable pharmacokinetics and tolerability in healthy men, and is suitable for dosing independent of food intake.
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Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Naftiridinas/efectos adversos , Naftiridinas/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Ingestión de Alimentos/fisiología , Ayuno , Interacciones Alimento-Droga/fisiología , Semivida , Humanos , Masculino , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Naftiridinas/uso terapéutico , Soluciones Farmacéuticas/efectos adversos , Soluciones Farmacéuticas/farmacocinética , Soluciones Farmacéuticas/uso terapéutico , Comprimidos/efectos adversos , Comprimidos/farmacocinética , Comprimidos/uso terapéutico , Adulto JovenRESUMEN
Finerenone (BAY 94-8862) is a nonsteroidal mineralocorticoid receptor antagonist in development for the treatment of diabetic kidney disease. This observational trial compared the pharmacokinetics of a single oral dose of finerenone 10 mg (immediate-release tablet) in adults with mild (creatinine clearance [CLCR ] 50-80 mL/min; n = 8), moderate (CLCR 30 to < 50 mL/min; n = 8), or severe (CLCR < 30 mL/min; n = 9) renal impairment with those in adults with normal renal function (CLCR > 80 mL/min; n = 8) over 96 hours postdose. Exposure to finerenone was not affected by mild renal impairment. In participants with moderate or severe renal impairment, exposure to finerenone was increased compared with those with normal renal function (increase in area under the curve for unbound finerenone, 57.1% [outlier excluded] and 46.5%, respectively), with moderate to high interindividual variability. Renal impairment had no consistent effect on the maximum plasma concentration, Cmax (differences in Cmax for unbound finerenone of +12% and -7% with moderate [outlier excluded] and severe impairment vs normal renal function, respectively). Renal elimination of finerenone is minimal. However, changes in exposure may occur because of the effects of renal impairment on nonrenal routes of elimination.
Asunto(s)
Antagonistas de Receptores de Mineralocorticoides/farmacocinética , Naftiridinas/farmacocinética , Insuficiencia Renal/metabolismo , Adulto , Anciano , Área Bajo la Curva , Biotransformación , Nefropatías Diabéticas/metabolismo , Femenino , Semivida , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Antagonistas de Receptores de Mineralocorticoides/efectos adversos , Naftiridinas/efectos adversosRESUMEN
BACKGROUND: Miliary tuberculosis is a rare manifestation of tuberculosis with a high mortality rate. Diagnosis may easily be missed when severe neurologic symptoms are the first clinical manifestation. A typical case of miliary tuberculosis is reported, with special regard to the problems of diagnostic work-up. The need for an early empirical therapy for suspected military tuberculosis is emphasized in particular. CASE REPORT: A 32-year-old Moroccan woman was admitted to the hospital with aphasia and a hemiparesis due to an intracerebral hemorrhage caused by a ruptured septic A. cerebri media aneurysm. Despite intensive work-up no septic focus could be found. Chest radiograph and computerized tomography (CT) showed miliary consolidations in the lungs. Skin testing (Tuberkulin Behring GT5) and smears for acid-fast bacilli and polymerase chain reaction (PCR) for tuberculosis of bronchoalveolar lavage (BAL) were negative. A four-drug antituberculous regimen (rifampicin [RMP], isoniazid [INH], pyrazinamide [PZA], ethambutol [EMB]) was initiated, and resulted in normalization of temperature, blood pressure, and C-reactive protein. Subsequently, cultures of BAL yielded Mycobacterium tuberculosis. The patient was discharged, a two-drug regimen was conducted (RMP, INH) after 2 months. Follow-up of the patient showed a significant improvement of the miliary lung consolidations after 5 months in CT of the lung. Only minor neurologic symptoms persisted after cessation of the therapy. CONCLUSION: In developed countries, miliary tuberculosis is a very rare cause of septic infiltrative lung disease. However, due to the nonspecific nature of the presentation and despite improved diagnostic techniques, a high clinical suspicion is essential for successful treatment.
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Aneurisma Roto/complicaciones , Arterias Cerebrales , Aneurisma Intracraneal/complicaciones , Tuberculosis Miliar/complicaciones , Adulto , Hemorragia Cerebral/etiología , Femenino , Estudios de Seguimiento , Humanos , Radiografía Torácica , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Tuberculosis Miliar/diagnóstico , Tuberculosis Miliar/diagnóstico por imagen , Tuberculosis Miliar/tratamiento farmacológicoRESUMEN
Pseudomembranous and obstructive Aspergillus tracheobronchitis (PMATB/OATB) are still considered to be refractory to therapy and to have a fatal outcome. To evaluate the optimal diagnostic strategy and to describe factors affecting the outcome of PMATB and OATB. Retrospective analysis of four new cases of PMATB and OATB combined with 16 previously reported cases over a 10-year period (1995-2004). Among the four new cases reported and the 16 published cases, four patients survived their infection. The mortality rate was significantly higher in the group of ventilated patients [94% (15 of 16 patients)] than in the group of non-ventilated patients [25% (1 of 4 patients), P < 0.05, Fisher's exact test]. In all 20 patients, diagnosis was established by bronchoscopy. Culture examination of mucous plugs was positive in 8 of 10, culture of the tracheobronchial aspirate was positive in 8 of 12, and bronchoalveolar lavage was diagnostic in 7 of 13 patients. All bronchoscopic techniques were complementary in improving the yield of bronchoscopy. However, microscopy of mucous plugs and/or necrotic material was the best diagnostic modality [positive in 94% (17 of 18 patients)]. Prognosis of PMATB and OATB remains poor. Microscopy of respiratory specimens is the most sensitive tool to confirm the diagnosis. The characteristic appearance of the disease makes it possible to start antifungal therapy immediately.