RESUMEN
BNT162b2, a nucleoside-modified mRNA formulated in lipid nanoparticles that encodes the SARS-CoV-2 spike glycoprotein (S) stabilized in its prefusion conformation, has demonstrated 95% efficacy in preventing COVID-191. Here we extend a previous phase-I/II trial report2 by presenting data on the immune response induced by BNT162b2 prime-boost vaccination from an additional phase-I/II trial in healthy adults (18-55 years old). BNT162b2 elicited strong antibody responses: at one week after the boost, SARS-CoV-2 serum geometric mean 50% neutralizing titres were up to 3.3-fold above those observed in samples from individuals who had recovered from COVID-19. Sera elicited by BNT162b2 neutralized 22 pseudoviruses bearing the S of different SARS-CoV-2 variants. Most participants had a strong response of IFNγ+ or IL-2+ CD8+ and CD4+ T helper type 1 cells, which was detectable throughout the full observation period of nine weeks following the boost. Using peptide-MHC multimer technology, we identified several BNT162b2-induced epitopes that were presented by frequent MHC alleles and conserved in mutant strains. One week after the boost, epitope-specific CD8+ T cells of the early-differentiated effector-memory phenotype comprised 0.02-2.92% of total circulating CD8+ T cells and were detectable (0.01-0.28%) eight weeks later. In summary, BNT162b2 elicits an adaptive humoral and poly-specific cellular immune response against epitopes that are conserved in a broad range of variants, at well-tolerated doses.
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Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/inmunología , SARS-CoV-2/inmunología , Linfocitos T/inmunología , Adolescente , Adulto , Vacuna BNT162 , Linfocitos T CD8-positivos/inmunología , COVID-19/virología , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/efectos adversos , Epítopos de Linfocito T/inmunología , Femenino , Humanos , Inmunoglobulina G/inmunología , Memoria Inmunológica , Interferón gamma/inmunología , Interleucina-2/inmunología , Masculino , Persona de Mediana Edad , SARS-CoV-2/química , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/inmunología , Células TH1/inmunología , Adulto JovenRESUMEN
An effective vaccine is needed to halt the spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. Recently, we reported safety, tolerability and antibody response data from an ongoing placebo-controlled, observer-blinded phase I/II coronavirus disease 2019 (COVID-19) vaccine trial with BNT162b1, a lipid nanoparticle-formulated nucleoside-modified mRNA that encodes the receptor binding domain (RBD) of the SARS-CoV-2 spike protein1. Here we present antibody and T cell responses after vaccination with BNT162b1 from a second, non-randomized open-label phase I/II trial in healthy adults, 18-55 years of age. Two doses of 1-50 µg of BNT162b1 elicited robust CD4+ and CD8+ T cell responses and strong antibody responses, with RBD-binding IgG concentrations clearly above those seen in serum from a cohort of individuals who had recovered from COVID-19. Geometric mean titres of SARS-CoV-2 serum-neutralizing antibodies on day 43 were 0.7-fold (1-µg dose) to 3.5-fold (50-µg dose) those of the recovered individuals. Immune sera broadly neutralized pseudoviruses with diverse SARS-CoV-2 spike variants. Most participants had T helper type 1 (TH1)-skewed T cell immune responses with RBD-specific CD8+ and CD4+ T cell expansion. Interferon-γ was produced by a large fraction of RBD-specific CD8+ and CD4+ T cells. The robust RBD-specific antibody, T cell and favourable cytokine responses induced by the BNT162b1 mRNA vaccine suggest that it has the potential to protect against COVID-19 through multiple beneficial mechanisms.
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Anticuerpos Antivirales/inmunología , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , Células TH1/inmunología , Vacunas Virales/inmunología , Adulto , Anticuerpos Neutralizantes/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , COVID-19 , Vacunas contra la COVID-19 , Infecciones por Coronavirus/prevención & control , Citocinas/inmunología , Femenino , Alemania , Humanos , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Pandemias , Células TH1/citología , Vacunas Virales/administración & dosificación , Vacunas Virales/efectos adversos , Adulto JovenRESUMEN
AIMS: We aimed to incorporate a pharmacologically inactive midazolam microdose into early clinical studies for the assessment of CYP3A drug-drug interaction liability. METHODS: Three early clinical studies were conducted with substances (Compounds A, B and C) which gave positive CYP3A perpetrator signals in vitro. A 75 µg dose of midazolam was administered alone (baseline CYP3A activity) followed by administration with the highest dose groups tested for each compound on Day 1/3 and Day 14 or Day 17. Midazolam exposure (AUC0-∞ , Cmax ) during administration with the test substances was compared to baseline data via an analysis of variance on log-transformed data. Partial AUC2-4 ratios were also compared to AUC0-∞ ratios using linear regression on log-transformed data. RESULTS: Test compound Cmax values exceeded relevant thresholds for drug-drug interaction liability. Midazolam concentrations were quantifiable over the full profiles for all subjects in all studies. Point estimates of the midazolam AUC0-∞ gMean ratios ranged from 108.3 to 127.1% for Compound A, from 93.3 to 114.5% for Compound B, and from 92.0 to 96.7% for the two highest dose groups of Compound C. Cmax gMean ratios were in the same range. Thus, no relevant drug-drug interactions were evident, based on the results of midazolam microdosing. AUC2-4 ratios from these studies were comparable to the AUC0-∞ ratios. CONCLUSION: Midazolam microdosing incorporated into early clinical studies is a feasible tool for reducing dedicated drug-drug interaction studies, meaning reduced subject burden. Limited sampling could further reduce subject burden, costs and needed resources.
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Midazolam , Preparaciones Farmacéuticas , Área Bajo la Curva , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , HumanosRESUMEN
AIMS: To evaluate the safety, pharmacokinetics and pharmacodynamics of single- and multiple-rising doses (MRDs) of BI 705564 and establish proof of mechanism. METHODS: BI 705564 was studied in 2 placebo-controlled, Phase I clinical trials testing single-rising doses (1-160 mg) and MRDs (1-80 mg) of BI 705564 over 14 days in healthy male volunteers. Blood samples were analysed for BI 705564 plasma concentration, Bruton's tyrosine kinase (BTK) target occupancy (TO) and CD69 expression in B cells stimulated ex vivo. A substudy was conducted in allergic, otherwise healthy, MRD participants. Safety was assessed in both studies. RESULTS: All doses of BI 705564 were well tolerated. Geometric mean BI 705564 plasma terminal half-life ranged from 10.1 to 16.9 hours across tested doses, with no relevant accumulation after multiple dosing. Doses ≥20 mg resulted in ≥85% average TO that was maintained for ≥48 hours after single-dose administration. Functional effects of BTK signalling were demonstrated by dose-dependent inhibition of CD69 expression. In allergic participants, BI 705564 treatment showed a trend in wheal size reduction in a skin prick test and complete inhibition of basophil activation. Mild bleeding-related adverse events were observed with BI 705564; bleeding time increased in 1/12 participants (8.3%) who received placebo vs 26/48 (54.2%) treated with BI 705564. CONCLUSION: BI 705564 showed efficient target engagement through durable TO and inhibition of ex vivo B-cell activation, and proof of mechanism through effects on allergic skin responses. Mild bleeding-related adverse events were probably related to inhibition of platelet aggregation by BTK inhibition.
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Linfocitos B , Agregación Plaquetaria , Agammaglobulinemia Tirosina Quinasa , Voluntarios Sanos , Humanos , Masculino , Inhibidores de Proteínas Quinasas/efectos adversos , Transducción de SeñalRESUMEN
AIMS: To demonstrate the bioequivalence of macitentan/tadalafil fixed-dose combination (FDC) tablets with single-component tablets of macitentan and tadalafil in healthy subjects. METHODS: Studies AC-077-101 and AC-077-103 were single-centre, open-label, single-dose, 2-period, randomized, crossover Phase 1 studies conducted in healthy subjects. Two FDCs were investigated: FDC-1 and FDC-2 in Study AC-077-101 and FDC-2 in Study AC-077-103. Both FDCs contained 10 mg/40 mg of macitentan/tadalafil and differed in excipients and coating materials used. In both studies, pharmacokinetic sampling over 216 hours was conducted, and pharmacokinetic parameters were derived using noncompartmental methods. RESULTS: Bioequivalence of macitentan, its active metabolite ACT-132577, and tadalafil was established for FDC-2 in both studies AC-077-101 and AC-077-103 in which tadalafil as a single component was sourced from the USA and EU, respectively, to fulfil regional regulatory requirements. The area under the plasma concentration-time curve and maximum plasma concentration with 90% confidence intervals of all components were entirely within the bioequivalence limits (0.8000-1.2500). No subject died and no serious adverse events were reported in either studies. CONCLUSION: The FDC-2 tablet containing 10 mg/40 mg of macitentan/tadalafil was bioequivalent to the free combination of 10 mg macitentan and 40 mg tadalafil (both US and EU sourced). Macitentan and tadalafil were well tolerated when administered as FDC or as a free combination.
Asunto(s)
Hipoglucemiantes , Metformina , Pirimidinas , Sulfonamidas , Tadalafilo , Adolescente , Adulto , Área Bajo la Curva , Estudios Cruzados , Preparaciones de Acción Retardada , Combinación de Medicamentos , Femenino , Voluntarios Sanos , Humanos , Hipoglucemiantes/farmacología , Masculino , Persona de Mediana Edad , Pirimidinas/farmacología , Sulfonamidas/farmacología , Comprimidos , Tadalafilo/farmacología , Equivalencia Terapéutica , Adulto JovenRESUMEN
Introduction: BI 1015550 is a phosphodiesterase 4 (PDE4) inhibitor that has antifibrotic properties. Phase I and Ic studies were conducted to investigate the safety, tolerability and pharmacokinetics of BI 1015550 in healthy male subjects and patients with idiopathic pulmonary fibrosis (IPF). Methods: In the phase I study, 42 subjects were partially randomised to receive placebo or BI 1015550 in single rising doses of 36â mg and 48â mg, or multiple rising doses of 6â mg and 12â mg twice daily over 14â days. In the phase Ic study, 15 patients with IPF were randomised to receive 18â mg BI 1015550 or placebo twice daily for up to 12â weeks. For both studies, the primary endpoint was the number of subjects with drug-related adverse events (AEs). Results: In the Phase I study, drug-related AEs were reported for 50.0% of healthy male subjects treated with a single dose of BI 1015550, compared with 16.7% receiving placebo. For those receiving multiple doses, drug-related AEs were reported for 37.5% of those treated with BI 1015550 and 12.5% receiving placebo. The most frequently reported AEs by organ class were nervous system disorders, which were largely driven by headache. In the Phase Ic study, drug-related AEs were reported in 90.0% of patients treated with BI 1015550, compared with 60.0% of those receiving placebo. The most frequent AEs by organ class were gastrointestinal AEs. Conclusions: BI 1015550 had an acceptable safety profile in healthy male subjects and male and female patients with IPF, supporting further development in larger trials.
RESUMEN
Oral NEPA is the fixed-combination antiemetic comprising netupitant (neurokinin-1 receptor antagonist [NK1 RA]) and palonosetron (5-hydroxytryptamine-3 receptor antagonist [5-HT3 RA]). Intravenous (IV) NEPA, containing fosnetupitant, a water-soluble N-phosphoryloxymethyl prodrug of netupitant, has been developed. Fosnetupitant does not require excipients or solubility enhancers often used to increase IV NK1 RA water solubility, preventing the occurrence of hypersensitivity and infusion-site reactions associated with these products. In this phase 1 study, subjects received a 30-minute placebo or fosnetupitant (17.6-353 mg) infusion and an oral NEPA or placebo capsule, with 2-sequence crossover treatment for fosnetupitant 118- to 353-mg dose cohorts. IV fosnetupitant safety and pharmacokinetics were evaluated, and its equivalence to an oral netupitant 300-mg dose was defined. Overall, 158 healthy volunteers were enrolled. All adverse events (AEs) were mild or moderate in intensity. Doppler-identified infusion-site asymptomatic thrombosis occurred in 5.4% (fosnetupitant) and 1.2% (oral NEPA) of subjects. The frequency or number of treatment-related AEs did not increase with ascending fosnetupitant doses. The most common treatment-related AEs were headache (fosnetupitant, 8.1%; oral NEPA, 12.7%) and constipation (fosnetupitant, 1.4%; oral NEPA, 7.5%). A fosnetupitant 235-mg dose was equivalent, in terms of netupitant exposure, to 300-mg oral netupitant. The safety profile of a single fosnetupitant 235-mg infusion was similar to that of single-dose oral NEPA.
Asunto(s)
Náusea , Antagonistas del Receptor de Neuroquinina-1 , Humanos , Náusea/inducido químicamente , Antagonistas del Receptor de Neuroquinina-1/efectos adversos , Vómitos/inducido químicamente , AguaRESUMEN
The α2C -adrenoreceptor antagonist BAY 1193397 is in development for the oral treatment of diabetic foot ulcers. Safety, tolerability, and pharmacokinetics of BAY 1193397 were investigated in 3 randomized, single-center phase 1 studies in healthy male subjects: a first-in-human study (single oral doses of 0.5-50 mg), a relative bioavailability and food effect study (single doses of 1 and 10 mg), and a multiple-dose escalation study (using 2 and 5 mg twice daily and 10 and 20 mg once daily for 9 consecutive days). BAY 1193397 was rapidly absorbed in the fasted state, peak concentrations were reached between 0.6 and 2 hours. The mean terminal half-life was in the range of 17 to 20 hours. Area under the plasma concentration-time curve and maximum concentration appeared to be dose proportional, with a negligible food effect. There were no high-accumulation effects of BAY 1193397 after repeated dosing. BAY 1193397 was safe and well tolerated. At supratherapeutic plasma concentrations, there were slight transient increases in norepinephrine levels, heart rate, and blood pressure that were more pronounced after a single dose compared to steady state and appeared to be maximum concentration dependent. The results of the presented studies support the conduct of subsequent clinical trials with BAY 1193397 in patients with diabetes and compromised microcirculation.
Asunto(s)
Relación Dosis-Respuesta a Droga , Administración Oral , Área Bajo la Curva , Disponibilidad Biológica , Ensayos Clínicos Fase I como Asunto , Voluntarios Sanos , Humanos , Masculino , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
1. The low molecular weight heparin (LMWH) dalteparin is used, for example, to prevent primary venous thromboembolism in patients undergoing surgery or in medically ill patients. The anticoagulant activity of dalteparin can be monitored by measuring anti-factor Xa levels and activated partial thromboplastin time (aPTT); however, aPTT is an unreliable parameter in this case. The aim of the present in vitro study was to evaluate the thrombelastograph ROTEM(®) (Tem International, Munich, Germany) with respect to determining the anticoagulant activity of dalteparin at therapeutic and supratherapeutic plasma concentrations. 2. The ROTEM(®) parameters, namely coagulation time (CT), clot formation time (CFT) and maximum clot firmness (MCF), were measured using the reagents EXTEM and INTEM (Pentapharm, Munich, Germany) at increasing concentrations of dalteparin (0.01-10 µg/mL, which corresponded to anti-factor Xa levels of 1-1000 U/mL, respectively). 3. The mean CT measured using EXTEM was found to increase from 65.4 ± 27.9 s at baseline to 173.3 ± 112.2 s and 332.2 ± 200.7 s at drug concentrations of 1 and 10 µg/mL, respectively (P < 0.0001 for both). Moreover, the mean CFT value (EXTEM) increased from 97.7 ± 21.5 s at baseline to 187.6 ± 115.2 s (P = 0.0001) at a drug concentration of 10 µg/mL, which is greater than the therapeutic anti-factor Xa concentrations for LMWH. The results obtained when INTEM was used as the reagent were similar to those obtained using EXTEM. 4. In conclusion, the results indicate that the thrombelastograph ROTEM(®) can detect the anticoagulant effects of dalteparin only at supratherapeutic levels of anti-factor Xa.
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Anticoagulantes/uso terapéutico , Dalteparina/uso terapéutico , Inhibidores del Factor Xa , Heparina de Bajo-Peso-Molecular/uso terapéutico , Tromboelastografía/métodos , Adulto , Anticoagulantes/sangre , Coagulación Sanguínea/efectos de los fármacos , Pruebas de Coagulación Sanguínea/métodos , Plaquetas/efectos de los fármacos , Dalteparina/sangre , Relación Dosis-Respuesta a Droga , Factor Xa/metabolismo , Alemania , Humanos , Masculino , Tiempo de Tromboplastina Parcial/métodosRESUMEN
The orally available chymase inhibitor BAY 1142524 is currently being developed as a first-in-class treatment for left-ventricular dysfunction after myocardial infarction. Results from 3 randomized, single-center, phase 1 studies in healthy male volunteers examining the safety, tolerability, and pharmacokinetics of BAY 1142524 are summarized. In this first-in-human study, single oral doses of 1-200 mg were administered in fasted state as liquid service formulation or immediate release (IR) tablets. The relative bioavailability and the effect of a high-fat/high-calorie meal were investigated at the 5-mg dose. In a multiple-dose escalation study, doses of 5-50 mg twice daily and 100 mg once daily were given for 5 consecutive days. BAY 1142524 was safe and well tolerated and had no effects on heart rate or blood pressure compared with placebo. BAY 1142524 was absorbed with peak concentration 1-3 hours after administration for IR tablets; it was eliminated from plasma with a terminal half-life of 6.84-12.0 hours after administration of liquid service formulation or IR tablets. Plasma exposures appeared to be dose-linear, with a negligible food effect. There was only low accumulation of BAY 1142524 after multiple dosing. BAY 1142524 exhibited a pharmacokinetic profile allowing for once-daily dosing. The absence of blood pressure effects after administration of BAY 1142524 supports the combination of this novel anti-remodeling drug with existing standard of care in patients with left-ventricular dysfunction after acute myocardial infarction.
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Ácidos Carboxílicos/administración & dosificación , Ácidos Carboxílicos/farmacocinética , Quimasas/antagonistas & inhibidores , Ayuno/sangre , Indenos/administración & dosificación , Indenos/farmacocinética , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Disponibilidad Biológica , Ácidos Carboxílicos/efectos adversos , Preparaciones de Acción Retardada , Esquema de Medicación , Semivida , Voluntarios Sanos , Humanos , Indenos/efectos adversos , Masculino , Pirimidinas/efectos adversos , Soluciones , Comprimidos , Adulto JovenRESUMEN
BACKGROUND: Macitentan is a clinically approved endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). Increasing use of combination drug therapy in PAH means that it is important to recognize potential drug-drug interactions (DDIs) that could affect the efficacy and safety of macitentan in patients with PAH. OBJECTIVE: Two Phase 1 studies were conducted to investigate the effect of macitentan at steady-state on the pharmacokinetics of the breast cancer resistance protein (BCRP) substrates, rosuvastatin and riociguat in healthy male subjects. Another objective was to determine the safety and tolerability of concomitant administration of rosuvastatin or riociguat with macitentan. METHODS: Healthy male subjects received a single oral dose of rosuvastatin 10 mg (n = 20) or riociguat 1 mg (n = 20) on Day 1 (reference treatment). A loading oral dose of macitentan 30 mg was administered on Day 5 followed by macitentan 10 mg once-daily from Day 6 to Day 15 (riociguat study) or Day 6 to Day 16 (rosuvastatin study). A concomitant oral dose of rosuvastatin 10 mg or riociguat 1 mg was administered on Day 10 (test treatment). Pharmacokinetics were evaluated for 96 h after treatment on Day 1 and for 144 h (riociguat study) or 168 h (rosuvastatin study) after treatment on Day 10. To compare the reference and test treatments, the geometric mean ratio was calculated for the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC) from zero (pre-dose) to time of the last measured concentration above the limit of quantification (AUC0-t), the AUC from zero to infinity (AUC0-∞) and the terminal elimination half-life (t½) of rosuvastatin, riociguat and riociguat's metabolite, M1. The difference in the time to reach maximum plasma concentration (tmax) was determined by the Wilcoxon test. Trough levels of macitentan and its metabolite, ACT-132577, were measured and safety was monitored throughout. RESULTS: Ninety percent confidence intervals of the geometric mean ratios were within the bioequivalence criteria of 0.80-1.25. There was no significant difference between test and reference tmax. Rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan and ACT-132577. The adverse event profile was consistent with the known safety profiles of the drugs. CONCLUSIONS: Macitentan 10 mg did not affect the pharmacokinetics of BCRP substrates, rosuvastatin or riociguat in healthy male subjects. EudraCT numbers: 2017-003095-31 and 2017-003502-41.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Proteínas de Neoplasias/metabolismo , Pirazoles/farmacocinética , Pirimidinas/farmacología , Pirimidinas/farmacocinética , Rosuvastatina Cálcica/farmacocinética , Sulfonamidas/farmacología , Adolescente , Adulto , Interacciones Farmacológicas , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Faldaprevir (FDV) is a potent, orally administered inhibitor of hepatitis C virus. In this single-centre, open-label, fixed-sequence, crossover study of 32 healthy adult male and female volunteers, subjects received either a single dose of cyclosporine (CsA) 50 mg (N = 16) or tacrolimus (TAC) 0.5 mg (N = 16), followed by a washout of at least 14 days. Each subject then received a loading dose of FDV 240 mg followed by 120 mg FDV once daily for 6 days. FDV 120 mg was then co-administered with an additional single dose of CsA (50 mg) or TAC (0.5 mg), followed by an additional 6 days of FDV 120 mg once daily. Intensive blood sampling was performed to assess the PK interaction potential. Assessment of relative BA indicated that exposure to CsA co-administered with FDV was similar to CsA alone. However, the AUCτ,ss and Cmax,ss of FDV were increased by 23% and 41%, respectively, when FDV was co-administered with CsA. Exposure to TAC was slightly increased (AUC0-∞ increased by 27%, no change in Cmax ) when TAC was co-administered with FDV. In contrast, exposure to FDV co-administered with TAC was similar to FDV alone. No unexpected safety findings arose from the trial. The limitations of the study (use of single, low dose of TAC and CsA, and only healthy volunteers in the trial) are discussed.
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Antivirales/farmacocinética , Ciclosporina/farmacocinética , Inmunosupresores/farmacocinética , Oligopéptidos/farmacocinética , Tacrolimus/farmacocinética , Tiazoles/farmacocinética , Adolescente , Adulto , Ácidos Aminoisobutíricos , Antivirales/uso terapéutico , Área Bajo la Curva , Estudios Cruzados , Ciclosporina/uso terapéutico , Interacciones Farmacológicas , Femenino , Rechazo de Injerto/prevención & control , Voluntarios Sanos , Hepatitis C/prevención & control , Humanos , Leucina/análogos & derivados , Trasplante de Hígado/efectos adversos , Masculino , Persona de Mediana Edad , Oligopéptidos/uso terapéutico , Prolina/análogos & derivados , Estudios Prospectivos , Quinolinas , Prevención Secundaria/métodos , Tacrolimus/uso terapéutico , Tiazoles/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: Schizophrenia and Alzheimer's disease are characterised by abnormalities in glutamatergic pathways related to N-methyl-D-aspartate receptor hypofunction. Glycine is an N-methyl-D-aspartate receptor co-agonist; inhibition of glycine transporter 1 may improve N-methyl-D-aspartate receptor function. This phase I, randomised, two-part study evaluated the safety, tolerability and pharmacokinetic profile of BI 425809, a novel glycine transporter 1 inhibitor, in healthy male and female volunteers. METHODS: Part 1 evaluated BI 425809 10, 25, 50 or 75 mg once daily or 75 mg twice daily in young subjects, and 25 mg or 50 mg once daily in elderly subjects. Each dose group comprised 12 subjects who received BI 425809 (n = 9) or placebo (n = 3) for 14 days (day 1: single dose; days 4-14: multiple dosing). Part 2 compared pharmacokinetic profiles in 12 subjects who received a single dose of BI 425809 25 mg in the morning and evening. RESULTS: Pharmacokinetic profiles were similarly shaped for all dose groups. Median time to maximum plasma concentration was 3.0-4.5 h with steady state being reached between days 6 and 10. Pharmacokinetic parameters demonstrated dose linearity at the predicted therapeutic exposure range of BI 425809 ≤ 25 mg once daily, but increased less than dose proportionally for ≥ 50 mg once daily. All reported adverse events were of mild-to-moderate intensity, 51/84 (61%; part 1) subjects had one or more treatment-related adverse event, no serious adverse events occurred and no dose dependency was observed. CONCLUSIONS: Pharmacokinetic properties support both morning and evening dosing. BI 425809 was generally well tolerated at all tested doses. CLINICALTRIALS. GOV IDENTIFIER: NCT02337283.
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Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Administración Oral , Adulto , Anciano , Área Bajo la Curva , Biomarcadores Farmacológicos/metabolismo , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
In addition to cellular responses that are elicited by steroids involving the modulation of transcription in the nucleus, it is now generally accepted that additional phenomena occur that do not depend on the genome. However, there is a puzzling variety of candidate receptors described in the literature.
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Receptores de Esteroides/fisiología , Esteroides/fisiología , Animales , Sitios de Unión/fisiología , HumanosRESUMEN
Estrogens, like other steroids, elicit a variety of rapid effects in many tissues in addition to their delayed action on gene expression in the cell nucleus. The rapid responses occur without participation of the genome, and are therefore termed nongenomic. Some of the estrogen induced effects acutely modulate vascular function and may contribute to the gender difference in cardiovascular susceptibility. While some actions may be mediated by novel, nonclassic receptors, the classic estrogen receptor has been shown to also act on signalling cascades. There are sparse examples for compounds structurally related to the endogenous hormone estradiol that bind to the estrogen receptor but may selectively elicit nongenomic responses. The further development of such selectively acting drugs holds much promise for better therapies with fewer side effects, e.g. for vascular malfunction, but also for estrogen-dependent cancer.
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Estrógenos/fisiología , Estrógenos/farmacología , Femenino , Humanos , Receptores de Estrógenos/fisiología , Transducción de Señal/fisiologíaRESUMEN
Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor and an inhibitor of UDP-glucuronosyltransferase-1A1 (UGT1A1), which is involved in raltegravir clearance. Raltegravir, an HIV integrase inhibitor, may be used in combination with HCV treatment in HCV/HIV co-infected patients. In this open-label, 2-period, fixed-sequence study, 24 healthy volunteers (12 males) received faldaprevir 240 mg and raltegravir 400 mg in 2 treatment schedules (A and B) separated by a washout phase of ≥7 days: (A) twice-daily raltegravir (Days 1-3), once-daily raltegravir (Day 4); (B) twice-daily raltegravir and twice-daily faldaprevir (loading dose, Day 1), twice-daily raltegravir and once-daily faldaprevir (Days 2-5), once-daily raltegravir and once-daily faldaprevir (Day 6). Pharmacokinetics and safety were assessed over 132 hours post-dosing. Compared with raltegravir alone, co-administration with faldaprevir led to 2.7-fold and 2.5-fold increases in raltegravir geometric mean AUC(τ,ss) and C(max,ss), respectively, and a similar increase in raltegravir glucuronide metabolite exposure. No serious adverse events (AEs) were reported and no subject discontinued due to AEs. Faldaprevir and raltegravir co-administration was well tolerated and resulted in a moderate increase in raltegravir exposure.
Asunto(s)
Inhibidores de Integrasa VIH/farmacocinética , Oligopéptidos/farmacología , Inhibidores de Proteasas/farmacología , Raltegravir Potásico/farmacocinética , Tiazoles/farmacología , Adulto , Ácidos Aminoisobutíricos , Esquema de Medicación , Interacciones Farmacológicas/genética , Femenino , Genotipo , Glucuronosiltransferasa/genética , Inhibidores de Integrasa VIH/administración & dosificación , Inhibidores de Integrasa VIH/efectos adversos , Voluntarios Sanos , Humanos , Leucina/análogos & derivados , Masculino , Oligopéptidos/administración & dosificación , Oligopéptidos/efectos adversos , Prolina/análogos & derivados , Inhibidores de Proteasas/administración & dosificación , Inhibidores de Proteasas/efectos adversos , Quinolinas , Raltegravir Potásico/administración & dosificación , Raltegravir Potásico/efectos adversos , Tiazoles/administración & dosificación , Tiazoles/efectos adversos , Adulto JovenRESUMEN
PURPOSE OF REVIEW: The increasing prevalence of allergic rhinitis, its impact on individual quality of life and social costs, as well as its role as a risk factor for asthma, underline the need for improved treatment options for this disorder. We reviewed the recent literature published in English, dealing with relevant and appropriately controlled clinical trials on the treatment of allergic rhinitis. RECENT FINDINGS: In addition to well established pharmacological therapies with antihistamines, corticosteroids, decongestants and mast cell stabilizers, new therapeutic options become increasingly important, including leukotriene modifiers, anti-immunoglobulin E antibodies, phosphodiesterase inhibitors and intranasal heparin; there also exist new developments in appropriate allergen specific immunotherapy. SUMMARY: Promising results, both with established and novel treatment options, are communicated, but further studies are still necessary to confirm these data.
Asunto(s)
Rinitis Alérgica Perenne/tratamiento farmacológico , Rinitis Alérgica Perenne/terapia , Administración Intranasal , Anticuerpos/uso terapéutico , Desensibilización Inmunológica , Heparina/uso terapéutico , Humanos , Inmunoglobulina E/inmunología , Antagonistas de Leucotrieno/uso terapéutico , Inhibidores de Fosfodiesterasa/uso terapéuticoRESUMEN
Not all of the actions of aldosterone are mediated by the classic genomic pathway involving transcription and translation. Non-genomic or non-classical rapid responses that do not require these steps have been known for some time, but have only attracted significant interest in the last decade. At the cellular level, second messengers and kinase cascades are commonly involved. Most of these non-classical effects are insensitive to inhibitors of the classical cytosolic mineralocorticoid receptor. Non-genomic aldosterone action has been observed in clinical studies particularly in the cardiovascular system, and further research may improve the understanding of their participation in the pathogenesis of aldosterone related diseases and eventually enhance the options for therapy.
Asunto(s)
Aldosterona/fisiología , Receptores de Mineralocorticoides/metabolismo , Sistemas de Mensajero Secundario/fisiología , Sistema Cardiovascular/fisiopatología , Regulación de la Expresión Génica/fisiología , Insuficiencia Cardíaca/fisiopatología , HumanosRESUMEN
To investigate the influence of modifying in vivo cytochrome P450 3A (CYP3A) activity on the pharmacokinetics of etoricoxib, a selective inhibitor of cyclooxygenase-2, and of etoricoxib administration on CYP3A activity, a 3-part, randomized, crossover study was conducted in 3 panels of healthy volunteers. In part I, 8 subjects were administered a single dose of 60 mg etoricoxib alone and following daily doses of 400 mg ketoconazole, a known strong inhibitor of CYP3A. In part II, 8 different subjects were administered a single dose of 60 mg etoricoxib alone and following daily doses of 600 mg rifampin, a known strong inducer of CYP3A. In parts I and II, plasma samples were collected following each etoricoxib dose and analyzed for etoricoxib. In part III, 8 different subjects were administered 120 mg etoricoxib or placebo once daily for 11 days, and the erythromycin breath test was administered on day 11 of each period. Coadministration of etoricoxib with daily doses of ketoconazole resulted in an average 43% increase in etoricoxib AUC; based on previous studies, this increase would not be expected to have any clinically meaningful effect. In contrast, coadministration of etoricoxib with daily doses of rifampin had a potentially clinically important effect on etoricoxib pharmacokinetics (average 65% decrease in etoricoxib AUC). Etoricoxib had no effect on hepatic CYP3A activity, as assessed by the erythromycin breath test.