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Background: Current treatments for progressive neurodegenerative disorders characterized by cognitive impairment either have limited efficacy or are lacking altogether. SDI-118 is a small molecule which modulates the activity of synaptic vesicle glycoprotein 2A (SV2A) in the brain and shows cognitive enhancing effects in a range of animal models of cognitive deficit. Methods: This first-in-human study evaluated safety, tolerability, and pharmacokinetics/pharmacodynamics of SDI-118 in single ascending oral doses up to 80 mg administered to 32 healthy male subjects. Brain target occupancy was measured in eight subjects using positron emission tomography with PET-ligand [11C]-UCB-J. Food effect was assessed in seven subjects. Mood state was regularly evaluated using standardized questionnaires, and resting state fMRI data were analyzed as exploratory objectives. Key Results: At all doses tested, SDI-118 was well tolerated and appeared safe. Adverse events were mainly dizziness, hypersomnia, and somnolence. All were mild in intensity and increased in frequency with increasing administered dose. No dose-limiting adverse reactions were observed at any dose. SDI-118 displayed a linear pharmacokinetic profile with no significant food effect. Brain penetration and target engagement were demonstrated by a dose-proportional SV2A occupancy. Conclusion: Single oral doses of SDI-118 up to 80 mg were very well tolerated in healthy male subjects. Dose-proportional SV2A occupancy in the brain was demonstrated with brain imaging. Adverse effects in humans mainly occurred in higher dose ranges, with high occupancy levels, and were all mild and self-limiting. These data support further clinical exploration of the compound in patients with cognitive disorders. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT05486195.
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CONTEXT: Polycystic ovary syndrome (PCOS), a highly prevalent endocrine disorder characterized by hyperandrogenism, is the leading cause of anovulatory infertility. OBJECTIVE: This proof-of-concept study evaluated clinical efficacy and safety of the neurokinin 3 (NK3) receptor antagonist fezolinetant in PCOS. METHODS: This was a phase 2a, randomized, double-blind, placebo-controlled, multicenter study (EudraCT 2014-004409-34). The study was conducted at 5 European clinical centers. Women with PCOS participated in the study. Interventions included fezolinetant 60 or 180 mg/day or placebo for 12 weeks. The primary efficacy end point was change in total testosterone. Gonadotropins, ovarian hormones, safety and tolerability were also assessed. RESULTS: Seventy-three women were randomly assigned, and 64 participants completed the study. Adjusted mean (SE) changes in total testosterone from baseline to week 12 for fezolinetant 180 and 60 mg/day were -0.80 (0.13) and -0.39 (0.12) nmol/L vs -0.05 (0.10) nmol/L with placebo (Pâ <â .001 and Pâ <â .05, respectively). Adjusted mean (SE) changes from baseline in luteinizing hormone (LH) for fezolinetant 180 and 60 mg/d were -10.17 (1.28) and -8.21 (1.18) vs -3.16 (1.04) IU/L with placebo (Pâ <â .001 and Pâ =â .002); corresponding changes in follicle-stimulating hormone (FSH) were -1.46 (0.32) and -0.92 (0.30) vs -0.57 (0.26) IU/L (Pâ =â .03 and Pâ =â .38), underpinning a dose-dependent decrease in the LH-to-FSH ratio vs placebo (Pâ <â .001). Circulating levels of progesterone and estradiol did not change significantly vs placebo (Pâ >â .10). Fezolinetant was well tolerated. CONCLUSION: Fezolinetant had a sustained effect to suppress hyperandrogenism and reduce the LH-to-FSH ratio in women with PCOS.
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Compuestos Heterocíclicos con 2 Anillos/uso terapéutico , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Receptores de Neuroquinina-3/antagonistas & inhibidores , Tiadiazoles/uso terapéutico , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Hormona Folículo Estimulante/sangre , Gonadotropinas/sangre , Compuestos Heterocíclicos con 2 Anillos/efectos adversos , Humanos , Hiperandrogenismo/tratamiento farmacológico , Hormona Luteinizante/sangre , Persona de Mediana Edad , Pruebas de Función Ovárica , Testosterona/sangre , Tiadiazoles/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: In the primary analysis of the phase 2b VESTA study, oral fezolinetant reduced frequency and severity of menopausal vasomotor symptoms (VMS) compared with placebo. This secondary analysis evaluates effects of fezolinetant on responder rates and patient-reported outcomes (PROs). METHODS: In this 12-week, double-blind study, postmenopausal women with moderate/severe VMS were randomized to fezolinetant 15, 30, 60, or 90âmg BID or 30, 60, or 120âmg QD or placebo. Proportion of responders was based on reductions in VMS from daily diary records. P values for comparisons between active treatment and placebo were calculated using logistic regression. Changes from baseline in PROs (Menopause-Specific Quality of Life questionnaire, Hot Flash-Related Daily Interference Scale, Greene Climacteric Scale) were conducted using a mixed model for repeated measurements and compared post hoc with published minimally important differences (MIDs). RESULTS: Of 356 women randomized, 352 were treated and analyzed. A greater proportion of women receiving fezolinetant versus placebo met definitions of response at week 12. For all doses, mean changes from baseline in Menopause-Specific Quality of Life questionnaire VMS scores exceeded the MID (1.2) at weeks 4 (placebo: -1.8; fezolinetant: range, -1.9 to -3.6) and 12 (placebo: -2.3; fezolinetant: range, -2.9 to -4.4). Mean changes in Hot Flash-Related Daily Interference Scale at weeks 4 (placebo: -2.2; fezolinetant: range, -2.5 to -3.8) and 12 (placebo: -2.9; fezolinetant: range, -3.3 to -4.3) exceeded the MID (1.76). Greene Climacteric Scale-VMS domain scores improved for most fezolinetant doses versus placebo (week 4, placebo: -1.7; fezolinetant: range, -2.1 to -3.3; week 12, placebo: -2.1; fezolinetant: range, -2.7 to -3.6). CONCLUSIONS: Oral fezolinetant was associated with higher responder rates than placebo and larger improvements in QoL and other PRO measures, including a reduction in VMS-related interference with daily life.
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Calidad de Vida , Receptores de Neuroquinina-3 , Método Doble Ciego , Femenino , Compuestos Heterocíclicos con 2 Anillos , Sofocos/tratamiento farmacológico , Humanos , Menopausia , Medición de Resultados Informados por el Paciente , Posmenopausia , Tiadiazoles , Resultado del TratamientoRESUMEN
OBJECTIVE: Menopausal vasomotor symptoms (VMS) may result from altered thermoregulatory control in brain regions innervated by neurokinin 3 receptor-expressing neurons. This phase 2b study evaluated seven dosing regimens of fezolinetant, a selective neurokinin 3 receptor antagonist, as a nonhormone approach for the treatment of VMS. METHODS: Menopausal women aged >40-65 years with moderate/severe VMS (≥50âepisodes/wk) were randomized (double-blind) to fezolinetant 15, 30, 60, 90âmg BID or 30, 60, 120âmg QD, or placebo for 12 weeks. Primary outcomes were reduction in moderate/severe VMS frequency and severity ([number of moderate VMS ×â2] + [number of severe VMS ×â3]/total daily moderate/severe VMS) at weeks 4 and 12. Response (≥50% reduction in moderate/severe VMS frequency) was a key secondary outcome. RESULTS: Of 352 treated participants, 287 completed the study. Fezolinetant reduced moderate/severe VMS frequency by -1.9 to -3.5/day at week 4 and -1.8 to -2.6/day at week 12 (all Pâ<â0.05 vs placebo). Mean difference from placebo in VMS severity score was -0.4 to -1 at week 4 (all doses Pâ<â0.05) and -0.2 to -0.6 at week 12 (Pâ<â0.05 for 60 and 90âmg BID and 60âmg QD). Response (50% reduction) relative to placebo was achieved by 81.4% to 94.7% versus 58.5% of participants at end of treatment (all doses Pâ<â0.05). Treatment-emergent adverse events were largely mild/moderate; no serious treatment-related treatment-emergent adverse events occurred. CONCLUSIONS: Fezolinetant is a well-tolerated, effective nonhormone therapy that rapidly reduces moderate/severe menopausal VMS. : Video Summary:http://links.lww.com/MENO/A572; video script available at http://links.lww.com/MENO/A573.
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Compuestos Heterocíclicos con 2 Anillos/administración & dosificación , Sofocos/tratamiento farmacológico , Menopausia , Receptores de Neuroquinina-3/administración & dosificación , Tiadiazoles/administración & dosificación , Método Doble Ciego , Femenino , Compuestos Heterocíclicos con 2 Anillos/efectos adversos , Humanos , Persona de Mediana Edad , Receptores de Neuroquinina-3/agonistas , Tiadiazoles/efectos adversosRESUMEN
CONTEXT: The thermoregulatory center in the hypothalamus is stimulated by neurokinin 3 receptor (NK3R) activation and inhibited by estrogen-negative feedback. This balance is disrupted in menopause, producing vasomotor symptoms (VMSs). OBJECTIVE: To evaluate safety and efficacy of the NK3R antagonist fezolinetant in menopausal VMSs. DESIGN: Twelve-week, double-blind, randomized, placebo-controlled study. SETTING: Eight Belgian centers from September 2015 to October 2016. PARTICIPANTS: Generally healthy menopausal women aged 40 to 65 years with moderate/severe VMSs. INTERVENTIONS: Subjects were randomized (1:1) to 90 mg of fezolinetant twice daily or placebo for 12 weeks. MAIN OUTCOME MEASURES: Subjects captured VMS severity and frequency using an electronic diary. The primary outcome was change from baseline to week 12 in total VMS score with fezolinetant vs placebo. Secondary outcomes included timing of changes in frequency and severity of moderate/severe VMSs and quality-of-life assessments at weeks 4, 8, and 12. Pharmacodynamic and pharmacokinetic effects were assessed, as were safety and tolerability. RESULTS: Of 122 subjects screened, 87 were randomized and 80 (92%) completed the study. At week 12, fezolinetant significantly reduced total VMS score vs placebo (-26.5 vs -12.2, P < 0.001) and decreased mean frequency of moderate/severe VMSs by five episodes per day vs placebo. Severity and frequency of moderate/severe VMSs were reduced from the first day of treatment. Improvements were achieved in all quality-of-life measures. Fezolinetant was well tolerated. The most common fezolinetant-related adverse event was gastrointestinal disorder (n = 6). CONCLUSIONS: Fezolinetant rapidly and significantly reduced moderate/severe VMSs, supporting its potential as an effective nonhormonal treatment option for menopausal women.
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Enfermedades del Sistema Nervioso Autónomo/tratamiento farmacológico , Compuestos Heterocíclicos con 2 Anillos/uso terapéutico , Menopausia/fisiología , Receptores de Neuroquinina-3/antagonistas & inhibidores , Tiadiazoles/uso terapéutico , Sistema Vasomotor/efectos de los fármacos , Adulto , Anciano , Enfermedades del Sistema Nervioso Autónomo/etiología , Bélgica , Método Doble Ciego , Femenino , Sofocos/tratamiento farmacológico , Sofocos/etiología , Humanos , Persona de Mediana Edad , Calidad de Vida , Resultado del TratamientoRESUMEN
BI 425809 is a potent and selective glycine transporter 1 (GlyT1) inhibitor being developed for the treatment of cognitive impairment in Alzheimer disease and schizophrenia. Translational studies evaluated the effects of BI 425809 on glycine levels in rat and human cerebrospinal fluid (CSF). Oral administration of BI 425809 in rats induced a dose-dependent increase of glycine CSF levels from 30% (0.2 mg/kg, not significant) to 78% (2 mg/kg, P < 0.01), relative to vehicle. Similarly, oral administration of BI 425809 in healthy volunteers resulted in a dose-dependent increase in glycine CSF levels at steady state, with a mean 50% increase at doses as low as 10 mg. The peak plasma concentration (Cmax ) of BI 425809 was achieved earlier in plasma than in CSF (tmax 3-5 vs. 5-8 hours, respectively). Generally, BI 425809 was safe and well tolerated. These data provide evidence of functional target engagement of GlyT1 by BI 425809.
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Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Glicina/líquido cefalorraquídeo , Nootrópicos/farmacología , Compuestos Orgánicos/farmacología , Administración Oral , Adulto , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Área Bajo la Curva , Línea Celular , Relación Dosis-Respuesta a Droga , Glicina/metabolismo , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Neuronas , Nootrópicos/farmacocinética , Nootrópicos/uso terapéutico , Compuestos Orgánicos/administración & dosificación , Compuestos Orgánicos/farmacocinética , Cultivo Primario de Células , Ratas , Ratas Wistar , Esquizofrenia/tratamiento farmacológico , Adulto JovenRESUMEN
INTRODUCTION: BI 695501 has shown similar efficacy, safety, and immunogenicity to the adalimumab reference product, Humira®. We present two phase 1 studies comparing the pharmacokinetics, safety, and immunogenicity of BI 695501 delivered via autoinjector (AI) vs. prefilled syringe (PFS). METHODS: Both trials were randomized, open-label, parallel-group studies undertaken in subjects aged ≥ 18-65 years. VOLTAIRE®-AI (NCT02606903) recruited healthy, Caucasian, male, non-athletic volunteers with BMI ≥ 18 to ≤ 30 kg/m2. VOLTAIRE®-TAI (NCT02899338) recruited healthy men and women with BMI > 17.5 to < 35 kg/m2. In both studies, a single dose of BI 695501 40 mg was administered via AI or PFS to the abdomen (VOLTAIRE®-AI) or thigh (VOLTAIRE®-TAI). The observation period was 43/57 days and the safety follow-up was 70 days. Co-primary endpoints were AUC0-1032 or AUC0-1368, Cmax, and AUC0-∞. Safety and immunogenicity were assessed. RESULTS: Subjects (VOLTAIRE®-AI: N = 71; VOLTAIRE®-TAI: N = 162) were randomized to AI (n = 35; n = 81) or PFS (n = 36; n = 81). Baseline characteristics were balanced between treatment groups in each study. Total exposure of BI 695501 was similar for both groups; adjusted geometric mean ratios for AUC0-∞, AUC0-1032, and Cmax were 106.17, 104.09, and 114.83%, respectively, for VOLTAIRE®-AI; 103.19, 101.71 (AUC0-1368), and 100.11% for VOLTAIRE®-TAI. In both studies, similar immunogenicity was observed between groups in terms of frequency of binding and neutralizing anti-drug antibody-positive subjects. Incidence of adverse events was similar for both groups. CONCLUSIONS: Pharmacokinetics and immunogenicity of BI 695501 delivered via AI were similar to administration using a PFS, independent of injection site. No differences are expected between AI and PFS use in clinical practice. FUNDING: Boehringer Ingelheim.
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BACKGROUND AND OBJECTIVES: Suvorexant (MK-4305) is an orexin receptor antagonist approved for the treatment of insomnia in the USA and other regions. This randomized, double-blind, placebo-controlled, sequential-panel, Phase 1 trial assessed the safety, tolerability, and pharmacokinetic data following single and multiple dosing of suvorexant in healthy men (aged 18-45 years). METHODS: Within allocated panels, subjects (n = 8) were randomized to receive nightly doses of suvorexant (10, 20, 40, 80, and 100 mg) administered orally for 14 days, or placebo. Safety assessments included daily adverse event (AE) monitoring; pharmacokinetic data were obtained through periodic sampling. RESULTS: Of 40 subjects randomized, 39 completed the trial. The incidence of any AEs in the 10 and 20 mg groups was 67 and 83%, respectively, while 100% of subjects reported AEs in the dose groups of 40, 80, and 100 mg and the placebo group. The most frequently reported AEs were somnolence (n = 19 subjects), fatigue (n = 17), and headache (n = 15). Following single and multiple dosing, median time to reach maximum observed concentration ranged from 1.5 to 4.0 h and the apparent terminal half-life ranged from 7.7 to 14.5 h. Across the investigated doses, accumulation ratios for the area under the concentration-time curve and the maximum observed concentration were independent of dose and ranged from 1.21 to 1.60 and 1.00 to 1.46, respectively. CONCLUSIONS: Suvorexant was generally well tolerated after single and multiple dosing for 14 days. The findings support the once-nightly dosing regimen.
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Azepinas/administración & dosificación , Azepinas/farmacocinética , Antagonistas de los Receptores de Orexina/administración & dosificación , Antagonistas de los Receptores de Orexina/farmacología , Fármacos Inductores del Sueño/administración & dosificación , Fármacos Inductores del Sueño/farmacocinética , Triazoles/administración & dosificación , Triazoles/farmacocinética , Adolescente , Adulto , Área Bajo la Curva , Azepinas/efectos adversos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Fatiga/inducido químicamente , Cefalea/inducido químicamente , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Antagonistas de los Receptores de Orexina/efectos adversos , Fármacos Inductores del Sueño/efectos adversos , Triazoles/efectos adversos , Adulto JovenRESUMEN
AIMS: Idarucizumab, a humanized monoclonal anti-dabigatran antibody fragment, is effective in emergency reversal of dabigatran anticoagulation. Pre-existing and treatment-emergent anti-idarucizumab antibodies (antidrug antibodies; ADA) may affect the safety and efficacy of idarucizumab. This analysis characterized the pre-existing and treatment-emergent ADA and assessed their impact on the pharmacokinetics and pharmacodynamics (PK/PD) of idarucizumab. METHODS: Data were pooled from three Phase I, randomized, double-blind idarucizumab studies in healthy Caucasian subjects; elderly, renally impaired subjects; and healthy Japanese subjects. In plasma sampled before and after idarucizumab dosing, ADA were detected and titrated using a validated electrochemiluminescence method. ADA epitope specificities were examined using idarucizumab and two structurally related molecules. Idarucizumab PK/PD data were compared for subjects with and without pre-existing ADA. RESULTS: Pre-existing ADA were found in 33 out of 283 individuals (11.7%), seven of whom had intermittent ADA. Titres of pre-existing and treatment-emergent ADA were low, estimated equivalent to <0.3% of circulating idarucizumab after a 5 g dose. Pre-existing ADA had no impact on dose-normalized idarucizumab maximum plasma levels and exposure and, although data were limited, no impact on the reversal of dabigatran-induced anticoagulation by idarucizumab. Treatment-emergent ADA were detected in 20 individuals (19 out of 224 treated [8.5%]; 1 out of 59 received placebo [1.7%]) and were transient in ten. The majority had specificity primarily toward the C-terminus of idarucizumab. There were no adverse events indicative of immunogenic reactions. CONCLUSION: Pre-existing and treatment-emergent ADA were present at extremely low levels relative to the idarucizumab dosage under evaluation. The PK/PD of idarucizumab appeared to be unaffected by the presence of pre-existing ADA.
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Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/farmacología , Antitrombinas/efectos adversos , Coagulación Sanguínea/efectos de los fármacos , Dabigatrán/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Neutralizantes/sangre , Método Doble Ciego , Epítopos/inmunología , Voluntarios Sanos , Hemorragia/inducido químicamente , Hemorragia/tratamiento farmacológico , Humanos , Luminiscencia , Persona de Mediana Edad , Insuficiencia Renal/sangre , Resultado del Tratamiento , Adulto JovenRESUMEN
Idarucizumab, a humanised monoclonal antibody fragment, binds dabigatran with high affinity and immediately, completely and sustainably reverses dabigatran-induced changes on blood coagulation. The present analysis focuses on the evaluation of potential procoagulant properties of idarucizumab when administered in the absence of dabigatran. As part of two Phase I studies conducted in healthy Caucasian and Japanese male volunteers, the effect of idarucizumab (8 g as a 1-hour [h] infusion and 4 g as a 5-minute [min] infusion) and placebo on calibrated automated thrombography (CAT) was assessed using platelet-poor plasma samples. Measures were made before and 15 min after the end of infusion in Caucasian subjects, as well as pre-dose, 15 min, 4 h and 8 h in Japanese subjects. The levels of the thrombosis markers D-dimer and prothrombin fragment 1 + 2 (F1.2) were assessed over time in plasma samples up to 72 h after the end of infusion of idarucizumab and placebo. Idarucizumab had no apparent effect on endogenous thrombin formation as measured by CAT. D-dimer and F1.2 levels were highly variable in all dose groups but did not increase when compared with placebo or pre-dose levels. In conclusion, idarucizumab had no effect on endogenous thrombin generation. Additional markers of thrombosis, F1.2 and D-dimer, did not differ between placebo and idarucizumab, indicating a lack of procoagulant properties of idarucizumab.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Coagulación Sanguínea/efectos de los fármacos , Trombosis/inducido químicamente , Adolescente , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Pueblo Asiatico , Biomarcadores/sangre , Pruebas de Coagulación Sanguínea , Método Doble Ciego , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Voluntarios Sanos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/sangre , Protrombina , Medición de Riesgo , Factores de Riesgo , Trombina/metabolismo , Trombosis/sangre , Trombosis/diagnóstico , Trombosis/etnología , Factores de Tiempo , Población Blanca , Adulto JovenRESUMEN
FR104 is a monovalent pegylated Fab' Ab, antagonist of CD28, under development for treatment of transplant rejection and autoimmune diseases. In contrast to CD80/86 antagonists (CTLA4-Ig), FR104 selectively blunts CD28 costimulation while sparing CTLA-4 and PD-L1 coinhibitory signals. In the present work, FR104 has been evaluated in a first-in-human study to evaluate the safety, pharmacokinetics, pharmacodynamics, and potency of i.v. administrations in healthy subjects. Sixty-four subjects were randomly assigned to four single ascending dose groups, two double dose groups and four single ascending dose groups challenged with keyhole limpet hemocyanin. Subjects were followed up over a maximum of 113 d. Overall, the pharmacokinetics of FR104 after a single and double infusions was approximately linear at doses ≥0.200 mg/kg. CD28 receptor occupancy by FR104 was saturated at the first sampling time point (0.5 h) at doses above 0.02 mg/kg and returned to 50% in a dose-dependent manner, by day 15 (0.020 mg/kg) to 85 (1.500 mg/kg). FR104 was well tolerated, with no evidence of cytokine-release syndrome and no impact on blood lymphocyte subsets. Inhibition of anti-keyhole limpet hemocyanin Ab response was dose-dependent in FR104 recipients and was already apparent at a dose of 0.02 mg/kg. Abs to FR104 were detected in 22/46 (48%) of FR104 recipients and only 1/46 (2.2%) was detected during drug exposure. In conclusion, selective blockade of CD28 with FR104 was safe and well tolerated at the doses tested. The observed immunosuppressive activity indicated that FR104 has potential to show clinical activity in the treatment of immune-mediated diseases.
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Anticuerpos Monoclonales/uso terapéutico , Enfermedades Autoinmunes/terapia , Rechazo de Injerto/prevención & control , Fragmentos Fab de Inmunoglobulinas/uso terapéutico , Inmunoterapia/métodos , Trasplante de Órganos , Administración Intravenosa , Adulto , Anticuerpos Monoclonales/farmacología , Enfermedades Autoinmunes/inmunología , Antígenos CD28/antagonistas & inhibidores , Antígenos CD28/inmunología , Protocolos Clínicos , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Rechazo de Injerto/inmunología , Voluntarios Sanos , Humanos , Inmunidad Humoral/efectos de los fármacos , Inmunosupresores , Recuento de Linfocitos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Cerebrospinal fluid (CSF) amyloid-beta (Aß) peptides are predictive biomarkers for Alzheimer's disease and are proposed as pharmacodynamic markers for amyloid-lowering therapies. However, frequent sampling results in fluctuating CSF Aß levels that have a tendency to increase compared with baseline. The impact of sampling frequency, volume, catheterization procedure, and ibuprofen pretreatment on CSF Aß levels using continuous sampling over 36 h was assessed. METHODS: In this open-label biomarker study, healthy participants (n = 18; either sex, age 55-85 years) were randomized into one of three cohorts (n = 6/cohort; high-frequency sampling). In all cohorts except cohort 2 (sampling started 6 h post catheterization), sampling through lumbar catheterization started immediately post catheterization. Cohort 3 received ibuprofen (800 mg) before catheterization. Following interim data review, an additional cohort 4 (n = 6) with an optimized sampling scheme (low-frequency and lower volume) was included. CSF Aß(1-37), Aß(1-38), Aß(1-40), and Aß(1-42) levels were analyzed. RESULTS: Increases and fluctuations in mean CSF Aß levels occurred in cohorts 1-3 at times of high-frequency sampling. Some outliers were observed (cohorts 2 and 3) with an extreme pronunciation of this effect. Cohort 4 demonstrated minimal fluctuation of CSF Aß both on a group and an individual level. Intersubject variability in CSF Aß profiles over time was observed in all cohorts. CONCLUSIONS: CSF Aß level fluctuation upon catheterization primarily depends on the sampling frequency and volume, but not on the catheterization procedure or inflammatory reaction. An optimized low-frequency sampling protocol minimizes or eliminates fluctuation of CSF Aß levels, which will improve the capability of accurately measuring the pharmacodynamic read-out for amyloid-lowering therapies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01436188 . Registered 15 September 2011.
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Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Cateterismo , Catéteres de Permanencia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Punción Espinal , Proteínas tau/líquido cefalorraquídeoRESUMEN
CONTEXT: Women's health disorders are commonly treated by agents that suppress the hypothalamic-pituitary-gonadal axis. NK3 receptor antagonism modulates this axis with distinct pharmacology compared to existing therapies. OBJECTIVE: The study aim was to evaluate safety, pharmacokinetics, and pharmacodynamics on gonadotropins and sex hormones after single- and multiple-dose administration of an NK3R antagonist to healthy men and women. DESIGN AND SETTING: This was a first-in-human, double-blind, placebo-controlled, combined single and multiple ascending dose trial. PARTICIPANTS: Forty-one men and 24 regularly cycling women participated in the study. INTERVENTION(S): In part 1 of the study, men received single oral doses of 3-180 mg or placebo. In part 2, men received placebo or 20, 60, or 180 mg each day for 10 days. In part 3, women received placebo or 20, 60, or 180 mg each day for 21 days, where dosing was initiated on day 3 ± 2 after menses. MAIN OUTCOME MEASURE(S): Safety, tolerability, pharmacokinetics, and pharmacodynamics on circulating levels of LH, FSH, testosterone, estradiol, and progesterone, in addition to physiological biomarkers of endometrial thickening, follicle growth, and the duration of the menstrual cycle were evaluated. RESULTS: ESN364 was well-tolerated and rapidly bioavailable with linear pharmacokinetics and no drug accumulation with repeated, daily oral administration. Drug treatment dose-dependently decreased basal LH, but not FSH, and consequently decreased estradiol and progesterone (in women) as well as testosterone (in men). The hormonal changes in women corresponded to delayed ovulation, decreased endometrial thickening, impeded follicular maturation, and prolongation of the menstrual cycle. Drug effects were rapidly reversible. CONCLUSIONS: Oral administration of the NK3R antagonist, ESN364, suppressed the hypothalamic-pituitary-gonadal axis in healthy volunteers by selective modulation of gonadotropin secretion, leading to a restrained decrease in ovarian hormone levels in women. These results suggest that ESN364 may offer therapeutic benefit in the treatment of women's health disorders with a mitigated risk of menopausal-like adverse events.
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Hormonas Esteroides Gonadales/antagonistas & inhibidores , Compuestos Heterocíclicos con 2 Anillos/farmacología , Antagonistas de Hormonas/farmacología , Receptores de Neuroquinina-3/antagonistas & inhibidores , Tiadiazoles/farmacología , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Endometrio/efectos de los fármacos , Femenino , Hormonas Esteroides Gonadales/metabolismo , Gonadotropinas/sangre , Gónadas/efectos de los fármacos , Compuestos Heterocíclicos con 2 Anillos/efectos adversos , Compuestos Heterocíclicos con 2 Anillos/farmacocinética , Antagonistas de Hormonas/efectos adversos , Antagonistas de Hormonas/farmacocinética , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Masculino , Ciclo Menstrual/efectos de los fármacos , Folículo Ovárico/efectos de los fármacos , Folículo Ovárico/crecimiento & desarrollo , Ovulación/efectos de los fármacos , Tiadiazoles/efectos adversos , Tiadiazoles/farmacocinética , Adulto JovenRESUMEN
OBJECTIVES: Safety, tolerability, pharmacokinetics, and pharmacodynamics of a novel ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, JNJ-54861911, were assessed after single and multiple dosing in healthy participants. METHODS: Two randomized, placebo-controlled, double-blind studies were performed using single and multiple ascending JNJ-54861911 doses (up to 14 days) in young and elderly healthy participants. Regular blood samples and frequent CSF samples, up to 36 hours after last dose, were collected to assess the pharmacokinetic and pharmacodynamic (Aß, sAPPα,ß,total levels) profiles of JNJ-54861911. RESULTS: JNJ-54861911 was well-tolerated, adverse events were uncommon and unrelated to JNJ-54861911. JNJ-54861911 showed dose-proportional CSF and plasma pharmacokinetic profiles. Plasma- and CSF-Aß and CSF-sAPPß were reduced in a dose-dependent manner. Aß reductions (up to 95%) outlasted exposure to JNJ-54861911. APOE ε4 carrier status and baseline Aß levels did not influence Aß/sAPPß reductions. CONCLUSION: JNJ-54861911, a potent brain-penetrant BACE1 inhibitor, achieved high and stable Aß reductions after single and multiple dosing in healthy participants.
RESUMEN
BACKGROUND: Idarucizumab is a monoclonal antibody fragment that binds dabigatran with high affinity in a 1:1 molar ratio. We investigated the safety, tolerability, and efficacy of increasing doses of idarucizumab for the reversal of anticoagulant effects of dabigatran in a two-part phase 1 study (rising-dose assessment and dose-finding, proof-of-concept investigation). Here we present the results of the proof-of-concept part of the study. METHODS: In this randomised, placebo-controlled, double-blind, proof-of-concept phase 1 study, we enrolled healthy volunteers (aged 18-45 years) with a body-mass index of 18·5-29·9 kg/m(2) into one of four dose groups at SGS Life Sciences Clinical Research Services, Belgium. Participants were randomly assigned within groups in a 3:1 ratio to idarucizumab or placebo using a pseudorandom number generator and a supplied seed number. Participants and care providers were masked to treatment assignment. All participants received oral dabigatran etexilate 220 mg twice daily for 3 days and a final dose on day 4. Idarucizumab (1 g, 2 g, or 4 g 5-min infusion, or 5 g plus 2·5 g in two 5-min infusions given 1 h apart) was administered about 2 h after the final dabigatran etexilate dose. The primary endpoint was incidence of drug-related adverse events, analysed in all randomly assigned participants who received at least one dose of dabigatran etexilate. Reversal of diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT) were secondary endpoints assessed by measuring the area under the effect curve from 2 h to 12 h (AUEC2-12) after dabigatran etexilate ingestion on days 3 and 4. This trial is registered with ClinicalTrials.gov, number NCT01688830. FINDINGS: Between Feb 23, and Nov 29, 2013, 47 men completed this part of the study. 12 were enrolled into each of the 1 g, 2 g, or 5 g plus 2·5 g idarucizumab groups (nine to idarucizumab and three to placebo in each group), and 11 were enrolled into the 4 g idarucizumab group (eight to idarucizumab and three to placebo). Drug-related adverse events were all of mild intensity and reported in seven participants: one in the 1 g idarucizumab group (infusion site erythema and hot flushes), one in the 5 g plus 2·5 g idarucizumab group (epistaxis); one receiving placebo (infusion site haematoma), and four during dabigatran etexilate pretreatment (three haematuria and one epistaxis). Idarucizumab immediately and completely reversed dabigatran-induced anticoagulation in a dose-dependent manner; the mean ratio of day 4 AUEC2-12 to day 3 AUEC2-12 for dTT was 1·01 with placebo, 0·26 with 1 g idarucizumab (74% reduction), 0·06 with 2 g idarucizumab (94% reduction), 0·02 with 4 g idarucizumab (98% reduction), and 0·01 with 5 g plus 2·5 g idarucizumab (99% reduction). No serious or severe adverse events were reported, no adverse event led to discontinuation of treatment, and no clinically relevant difference in incidence of adverse events was noted between treatment groups. INTERPRETATION: These phase 1 results show that idarucizumab was associated with immediate, complete, and sustained reversal of dabigatran-induced anticoagulation in healthy men, and was well tolerated with no unexpected or clinically relevant safety concerns, supporting further testing. Further clinical studies are in progress. FUNDING: Boehringer Ingelheim Pharma GmbH & Co KG.
Asunto(s)
Anticuerpos Monoclonales Humanizados/farmacología , Bencimidazoles/farmacología , Coagulación Sanguínea/efectos de los fármacos , Inhibidores del Factor Xa/farmacología , Piridinas/farmacología , Adolescente , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Bencimidazoles/administración & dosificación , Tiempo de Circulación Sanguínea/efectos de los fármacos , Dabigatrán , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Interacciones Farmacológicas , Inhibidores del Factor Xa/administración & dosificación , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Piridinas/administración & dosificación , Adulto JovenRESUMEN
Idarucizumab, a monoclonal antibody fragment that binds dabigatran with high affinity, is in development as a specific antidote for dabigatran. In this first-in-human, single-rising-dose study, we investigated the pharmacokinetics, safety and tolerability of idarucizumab. Healthy male volunteers aged 18-45 years received between 20 mg and 8 g idarucizumab as a 1-hour intravenous infusion in 10 sequential dose groups, or 1, 2 or 4 g idarucizumab as a 5-minute infusion. Subjects within each dose group were randomised 3:1 to idarucizumab or placebo. A total of 110 randomised subjects received study drug (27 placebo, 83 idarucizumab). Peak and total exposure to idarucizumab increased proportionally with dose. Maximum plasma concentrations were achieved near the end of infusion, followed by a rapid decline, with an initial idarucizumab half-life of ~45 minutes. For the 5-minute infusions, this resulted in a reduction of plasma concentrations to less than 5 % of peak within 4 hours. Idarucizumab (in the absence of dabigatran) had no effect on coagulation parameters or endogenous thrombin potential. Overall adverse event (AE) frequency was similar for idarucizumab and placebo, and no relationship with idarucizumab dose was observed. Drug-related AEs (primary endpoint) were rare (occurring in 2 placebo and 3 idarucizumab subjects) and were mostly of mild intensity; none of them resulted in study discontinuation. In conclusion, the pharmacokinetic profile of idarucizumab meets the requirement for rapid peak exposure and rapid elimination, with no effect on pharmacodynamic parameters. Idarucizumab was safe and well tolerated in healthy males.
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Anticuerpos Monoclonales Humanizados/farmacocinética , Anticoagulantes/farmacocinética , Dabigatrán/antagonistas & inhibidores , Adolescente , Adulto , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticoagulantes/administración & dosificación , Área Bajo la Curva , Coagulación Sanguínea , Pruebas de Coagulación Sanguínea , Dabigatrán/química , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Voluntarios Sanos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: We evaluated the potential for QT/corrected QT (QTc) interval prolongation after sugammadex given with propofol or sevoflurane anaesthesia. METHODS: This was a two-factorial, randomized, parallel-group study in 132 healthy subjects. Anaesthesia was maintained with sevoflurane or propofol. At ~20 min following sevoflurane/propofol initiation, sugammadex 4 mg/kg or placebo was administered. Neuromuscular blocking agents were not administered. Electrocardiograms were recorded regularly. The primary variable was the time-matched mean difference in the Fridericia-corrected QT interval (QTcF) change from baseline for sugammadex versus placebo when combined with propofol or sevoflurane. No relevant QTcF prolongation was concluded if the upper one-sided 95 % confidence interval (CI) was below the 10 ms margin of regulatory non-inferiority, up to 30 min post-study drug. Blood samples were taken for pharmacokinetic analysis. An exploratory analysis evaluated potential QT/QTc effects of neostigmine 50 µg/kg/glycopyrrolate 10 µg/kg in combination with propofol. RESULTS: The estimated mean QTcF differences between sugammadex and placebo ranged from -2.4 to 0.6 ms when combined with either anaesthetic. The largest upper one-sided 95 % CI for the mean QTcF difference between sugammadex and placebo was 2 ms, occurring 2 min post-dosing. Propofol and sevoflurane resulted in mean QTcF increases exceeding 10 and 30 ms, respectively. On top of these prolongations, the effect of sugammadex was negligible at all timepoints. The mean peak sugammadex concentration was 66.5 µg/mL, with exposure similar in the sevoflurane/propofol groups. The mean QTcF changes from baseline following neostigmine/glycopyrrolate in 10 healthy subjects ranged between -1.4 and 3.6 ms. CONCLUSION: Sugammadex 4 mg/kg does not cause clinically relevant QTc interval prolongation versus placebo when combined with propofol or sevoflurane.
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Corazón/efectos de los fármacos , Éteres Metílicos/administración & dosificación , Propofol/administración & dosificación , gamma-Ciclodextrinas/farmacología , Adulto , Anestésicos por Inhalación/administración & dosificación , Anestésicos por Inhalación/sangre , Anestésicos por Inhalación/farmacología , Anestésicos Intravenosos/administración & dosificación , Anestésicos Intravenosos/sangre , Anestésicos Intravenosos/farmacología , Electrocardiografía , Humanos , Éteres Metílicos/sangre , Persona de Mediana Edad , Placebos , Propofol/sangre , Sevoflurano , Sugammadex , gamma-Ciclodextrinas/administración & dosificación , gamma-Ciclodextrinas/sangreRESUMEN
AIMS: To characterize pharmacokinetic parameters of MK-0916 and its safety and tolerability in lean, healthy male subjects following single and multiple oral doses. To assess (by stable-isotope labelling) the in vivo inhibition of cortisone-to-cortisol conversion following oral MK-0916. METHODS: Data are presented from two randomized, controlled, double-blind, rising-dose phase I studies. In the first study, subjects received single oral doses of 0.4-100 mg MK-0916 (n = 16). In the second study, subjects received 0.2-225 mg MK-0916 followed by daily doses of 0.2-100 mg for 13 days beginning on day 2 or day 15 (n = 80). Plasma and urine drug concentrations were measured for pharmacokinetic analysis. For pharmacodynamic analysis, concentrations of plasma [(13)C4]cortisol were measured by high-pressure liquid chromatography and tandem mass spectrometry following a single oral dose of 5 mg [(13)C4]cortisone. RESULTS: Doses ≥3 mg were rapidly absorbed (time at which maximal concentration was achieved in plasma, 1.1-1.8 h). Exposure (measured as the area under the concentration-time curve from 0 to 168 h) increased approximately in proportion to dose. Values for the maximal plasma concentration and the plasma concentration at 24 h increased in excess of dose proportionality at doses <6 mg and roughly in proportion to dose at doses >6 mg. In subjects dosed with 6 mg MK-0916 once daily for 14 days, the mean trough plasma concentration was 240 nm and in vivo cortisone-to-cortisol conversion was inhibited by 84%. The relationship between plasma MK-0916 and hepatic 11ß-hydroxysteroid dehydrogenase type 1 inhibition was well represented by a simple Emax model with an IC50 of 70.4 nm. Exposure to MK-0916 was generally well tolerated. CONCLUSIONS: These findings indicate that 11ß-hydroxysteroid dehydrogenase type 1 is effectively inhibited in human subjects by doses of MK-0916 that are well tolerated.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/farmacocinética , Triazoles/farmacología , Triazoles/farmacocinética , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Triazoles/administración & dosificación , Triazoles/efectos adversos , Adulto JovenRESUMEN
OBJECTIVE: Use of glucocorticoids for anti-inflammatory efficacy is limited by their side effects. This study examined, in the same individuals, prednisone's acute, dose-dependent effects on inflammation as well as biomarkers of glucose regulation and bone homeostasis. DESIGN: In this randomized, double-blind, parallel-design trial of healthy adults demonstrating cutaneous allergen-induced hypersensitivity, patients received placebo or prednisone 10, 25 or 60 mg daily for 7 days. METHODS: Effects on peripheral white blood cell (WBC) count, ex vivo whole blood lipopolysaccharide (LPS)-stimulated TNF-α release and response to cutaneous allergen challenge were assessed concurrently with biomarkers for glucose tolerance and bone turnover. RESULTS: Differential peripheral WBC counts changed significantly within hours of prednisone administration. Ex vivo, LPS-stimulated TNF-α was significantly reduced by all prednisone doses on days 1 and 7. The late phase cutaneous allergen reaction was significantly reduced with prednisone 60 mg vs placebo on days 1 and 7. Oral glucose tolerance tests revealed significant increases in glycaemic excursion on days 1 and 7, whereas increases in insulin and C-peptide excursions were more notable on day 7 with all doses of prednisone. The bone formation markers osteocalcin, and procollagen I N- and C-terminal peptides decreased significantly on days 1 and 7 vs placebo. CONCLUSIONS: In healthy young adults after single doses as low as 10 mg, prednisone treatment has significant effects on glucose tolerance and bone formation markers within hours of treatment, in parallel with anti-inflammatory effects.
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Glucemia/metabolismo , Remodelación Ósea/efectos de los fármacos , Remodelación Ósea/fisiología , Mediadores de Inflamación/administración & dosificación , Prednisona/administración & dosificación , Adolescente , Adulto , Biomarcadores/metabolismo , Método Doble Ciego , Femenino , Prueba de Tolerancia a la Glucosa/métodos , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Mediadores de Inflamación/uso terapéutico , Masculino , Persona de Mediana Edad , Prednisona/uso terapéutico , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Sugammadex, a modified γ-cyclodextrin, facilitates rapid reversal of rocuronium- and vecuronium-induced neuromuscular blockade (NMB). Cyclodextrins are known for their ability to form inclusion complexes with various drugs. Theoretically, molecules with a high affinity for sugammadex could interact and displace sugammadex from the sugammadex-rocuronium or sugammadex-vecuronium complex, potentially resulting in the recurrence of NMB due to recirculation of free rocuronium or vecuronium. OBJECTIVE: This study aimed to evaluate whether the administration of high doses of flucloxacillin or diclofenac can result in recurrence of NMB through displacement of sugammadex from its complex with rocuronium or vecuronium, following successful reversal of NMB by a suboptimal dose of sugammadex 2 mg/kg. Flucloxacillin has previously been identified using a modelling approach as a drug with displacement potential, while diclofenac was assessed due to its common intravenous use in the peri-operative and post-surgery setting. METHODS: This was a randomized, open-label, parallel, single-centre study conducted at SGS Life Services-CPU, Antwerp, Belgium. Twenty-four healthy, propofol-anaesthetized, adult volunteers were randomized to either rocuronium 0.6 mg/kg or vecuronium 0.1 mg/kg, followed by a suboptimal dose of sugammadex 2 mg/kg 15 minutes after induction of NMB. Five minutes after successful sugammadex reversal, subjects received either diclofenac 75 mg (15-minute infusion) or flucloxacillin 2 g (5-minute infusion) according to randomization. The suboptimal dose of sugammadex and relatively high doses of diclofenac and flucloxacillin were applied to create favourable conditions for the potential displacement of sugammadex from the sugammadex-rocuronium or sugammadex-vecuronium complex, and thus possible recurrence of NMB due to recirculation of free rocuronium or vecuronium. Possible recurrence of NMB was assessed by neuromuscular monitoring, performed with acceleromyography, and was continued until â¼90 minutes after the start of diclofenac or flucloxacillin administration. Recurrence of NMB was concluded if three consecutive train-of-four (TOF) ratios were <0.8. RESULTS: Following successful reversal with a suboptimal dose of sugammadex 2 mg/kg administered 15 minutes after NMB induction, subsequent administration of diclofenac or flucloxacillin did not result in recurrence of NMB in any subject based on measurement of TOF ratios during anaesthesia and neuromuscular function tests upon awakening. There were no adverse events considered to be related to sugammadex. CONCLUSION: Administration of flucloxacillin or diclofenac does not result in recurrence of NMB through displacement of sugammadex from the sugammadex-rocuronium or sugammadex-vecuronium complex.