RESUMEN
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
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.
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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
BACKGROUND: There are only limited treatment options for patients with non-cystic fibrosis bronchiectasis (non-CF BE). Human neutrophil elastase (HNE) is a mediator of tissue destruction in non-CF BE. BAY 85-8501, a selective and reversible HNE inhibitor, could represent a new treatment option for this disease. METHODS: This was a phase 2a, randomized, placebo-controlled, double-blind, parallel-group study. The primary objective was to assess the safety and tolerability of 1â¯mg BAY 85-8501 once daily (OD) for 28 days compared with placebo in patients with non-CF BE. Secondary objectives were to investigate the effects of 4 weeks of treatment with BAY 85-8501 on health-related quality of life, pulmonary function, and inflammatory and tissue damage biomarkers in sputum, blood and/or urine, and to evaluate the pharmacokinetics of BAY 85-8501. RESULTS: Overall, 94 patients (mean age, 66 years; 53% male) were randomized (nâ¯=â¯47 per group), and 82 completed the study (BAY 85-8501, nâ¯=â¯37; placebo, nâ¯=â¯45). Treatment-emergent adverse events (TEAEs) occurred in 31 patients (66%) taking BAY 85-8501 and in 36 patients (77%) taking placebo, and were mostly mild or moderate. The serious TEAEs (BAY 85-8501, nâ¯=â¯3; placebo, nâ¯=â¯1) were not considered to be study-drug related. There were no changes in pulmonary function parameters from baseline to end of treatment, and health-related quality of life did not improve in any group. HNE activity in blood after zymosan challenge decreased significantly with BAY 85-8501 treatment (Pâ¯=â¯0.0250 versus placebo). There were no significant differences in other biomarkers between treatment groups, with the exception of a small increase in interleukin-8 levels in sputum in the BAY 85-8501 group. Trough plasma concentrations of BAY 85-8501 plateaued after 2 weeks. CONCLUSIONS: 1â¯mg BAY 85-8501 OD had a favourable safety and tolerability profile when administered for 28 days to patients with non-CF BE. Further studies with a longer treatment duration are needed to evaluate the potential clinical efficacy in this study population.
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Bronquiectasia/tratamiento farmacológico , Elastasa de Leucocito/antagonistas & inhibidores , Proteínas Inhibidoras de Proteinasas Secretoras/uso terapéutico , Pirimidinonas/uso terapéutico , Sulfonas/uso terapéutico , Anciano , Bronquiectasia/fisiopatología , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Inhibidoras de Proteinasas Secretoras/efectos adversos , Proteínas Inhibidoras de Proteinasas Secretoras/farmacocinética , Pirimidinonas/efectos adversos , Pirimidinonas/farmacocinética , Calidad de Vida , Esputo/metabolismo , Sulfonas/efectos adversos , Sulfonas/farmacocinética , Resultado del TratamientoRESUMEN
PURPOSE: To determine the pharmacokinetics of radiolabeled copanlisib (BAY 80-6946) in healthy male volunteers and to investigate the disposition and biotransformation of copanlisib. METHODS: A single dose of 12 mg copanlisib containing 2.76 MBq [14C]copanlisib was administered as a 1-h intravenous infusion to 6 volunteers with subsequent sampling up to 34 days. Blood, plasma, urine and feces were collected to monitor total radioactivity, parent compound and metabolites. RESULTS: Copanlisib treatment was well tolerated. Copanlisib was rapidly distributed throughout the body with a volume distribution of 1870 L and an elimination half-life of 52.1-h (range 40.4-67.5-h). Copanlisib was the predominant component in human plasma (84% of total radioactivity AUC) and the morpholinone metabolite M1 was the only circulating metabolite (about 5%). Excretion of drug-derived radioactivity based on all 6 subjects was 86% of the dose within a collection interval of 20-34 days with 64% excreted into feces as major route of elimination and 22% into urine. Unchanged copanlisib was the main component excreted into urine (15% of dose) and feces (30% of dose). Excreted metabolites (41% of dose) of copanlisib resulted from oxidative biotransformation. CONCLUSIONS: Copanlisib was eliminated predominantly in the feces compared to urine as well as by hepatic biotransformation, suggesting that the clearance of copanlisib would more likely be affected by hepatic impairment than by renal dysfunction. The dual mode of elimination via unchanged excretion of copanlisib and oxidative metabolism decreases the risk of clinically relevant PK-related drug-drug interactions.
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Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Pirimidinas/uso terapéutico , Quinazolinas/uso terapéutico , Administración Intravenosa , Fosfatidilinositol 3-Quinasa Clase I/farmacocinética , Fosfatidilinositol 3-Quinasa Clase I/uso terapéutico , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Quinazolinas/administración & dosificación , Quinazolinas/farmacocinéticaRESUMEN
Predicting oral bioavailability (Foral) is of importance for estimating systemic exposure of orally administered drugs. Physiologically-based pharmacokinetic (PBPK) modelling and simulation have been applied extensively in biopharmaceutics recently. The Oral Biopharmaceutical Tools (OrBiTo) project (Innovative Medicines Initiative) aims to develop and improve upon biopharmaceutical tools, including PBPK absorption models. A large-scale evaluation of PBPK models may be considered the first step. Here we characterise the OrBiTo active pharmaceutical ingredient (API) database for use in a large-scale simulation study. The OrBiTo database comprised 83 APIs and 1475 study arms. The database displayed a median logP of 3.60 (2.40-4.58), human blood-to-plasma ratio of 0.62 (0.57-0.71), and fraction unbound in plasma of 0.05 (0.01-0.17). The database mainly consisted of basic compounds (48.19%) and Biopharmaceutics Classification System class II compounds (55.81%). Median human intravenous clearance was 16.9L/h (interquartile range: 11.6-43.6L/h; n=23), volume of distribution was 80.8L (54.5-239L; n=23). The majority of oral formulations were immediate release (IR: 87.6%). Human Foral displayed a median of 0.415 (0.203-0.724; n=22) for IR formulations. The OrBiTo database was found to be largely representative of previously published datasets. 43 of the APIs were found to satisfy the minimum inclusion criteria for the simulation exercise, and many of these have significant gaps of other key parameters, which could potentially impact the interpretability of the simulation outcome. However, the OrBiTo simulation exercise represents a unique opportunity to perform a large-scale evaluation of the PBPK approach to predicting oral biopharmaceutics.
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Biofarmacia/métodos , Bases de Datos Factuales , Modelos Biológicos , Preparaciones Farmacéuticas/metabolismo , Administración Oral , Evaluación Preclínica de Medicamentos/métodos , Predicción , Humanos , Absorción Intestinal/efectos de los fármacos , Absorción Intestinal/fisiología , Preparaciones Farmacéuticas/administración & dosificaciónRESUMEN
The purpose of the study was to experimentally deduce pH-dependent critical volumes to dissolve applied dose (VDAD) that determine whether a drug candidate can be developed as immediate release (IR) tablet containing crystalline API, or if solubilization technology is needed to allow for sufficient oral bioavailability. pH-dependent VDADs of 22 and 83 compounds were plotted vs. the relative oral bioavailability (AUC solid vs. AUC solution formulation, Frel) in humans and rats, respectively. Furthermore, in order to investigate to what extent Frel rat may predict issues with solubility limited absorption in human, Frel rat was plotted vs. Frel human. Additionally, the impact of bile salts and lecithin on in vitro dissolution of poorly soluble compounds was tested and data compared to Frel rat and human. Respective in vitro - in vivo and in vivo - in vivo correlations were generated and used to build developability criteria. As a result, based on pH-dependent VDAD, Frel rat and in vitro dissolution in simulated intestinal fluid the IR formulation strategy within Pharmaceutical Research and Development organizations can be already set at late stage of drug discovery.