RESUMEN
AIM: The pharmacologic effects of sodium oxybate (SO) have a number of similarities with those of alcohol. This study evaluated the pharmacodynamic interaction of SMO.IR (a solid immediate release formulation of SO) and alcohol (0.7 (males) or 0.57 (females) g kg(-1) alcohol using 40% vodka). METHODS: In a randomized, double-blind, double-dummy, crossover trial, 24 healthy volunteers received randomly a) 2.25 g SMO.IR and placebo alcohol preparation, b) 2.25 g f SMO.IR and alcohol, c) 2.25 g SMO.IR matching placebo and alcohol and d) 2.25 g of SMO.IR matching placebo and placebo alcohol preparation. Objective and subjective cognitive parameters, adverse events and vital signs were assessed before, 15 and 165 min after treatment administration. RESULTS: Alcohol produced the expected cognitive impairment and the expected subjective sedation rapidly after intake (from 15 min). The objective effects of SMO.IR were much less pronounced than those of alcohol. The reverse was observed for subjective complaints, which were related to lesser stimulation and greater sedation. Nevertheless, 165 min after administration this sedation feeling was less with SMO.IR than with alcohol. There was a significant interaction between SMO.IR and alcohol at 15 min (i.e. increase in alertness and stimulation and decrease in sedation). In addition, an isolated mild decrease in digit vigilance accuracy occurred at 165 min post-dose after the combination. The co-administration of SMO.IR and alcohol was safe and well-tolerated. CONCLUSION: SMO.IR and alcohol have distinct adverse effect profiles. The objective effects of SMO.IR are much less marked than those of alcohol. No deleterious interaction was observed.
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Atención/efectos de los fármacos , Trastornos del Conocimiento/inducido químicamente , Etanol/efectos adversos , Movimientos Oculares/efectos de los fármacos , Equilibrio Postural/efectos de los fármacos , Oxibato de Sodio/efectos adversos , Adolescente , Adulto , Estudios Cruzados , Método Doble Ciego , Interacciones Farmacológicas , Liberación de Fármacos , Etanol/administración & dosificación , Etanol/farmacocinética , Femenino , Voluntarios Sanos , Humanos , Masculino , Estimulación Luminosa , Oxibato de Sodio/administración & dosificación , Oxibato de Sodio/farmacocinética , Adulto JovenRESUMEN
PURPOSE: Sirolimus and tacrolimus are immunosuppressive compounds that have been used concomitantly in renal transplant patients. Both drugs are dosed orally and have common intestinal and hepatic metabolism and intestinal transport mechanisms. As such, there is a potential for pharmacokinetic drug interaction. METHODS: A single-dose, open-label, four-period, four-treatment, randomized crossover study was conducted in 27 healthy fasting volunteers. Each subject received a 15-mg oral dose of sirolimus alone, a 10-mg oral dose of tacrolimus alone, sirolimus and tacrolimus administered simultaneously, and tacrolimus administered 4 h before sirolimus. Whole blood and plasma samples for sirolimus and tacrolimus testing were analyzed by liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameters were assessed using noncompartmental methods and were compared using analysis of variance (ANOVA). RESULTS: The geometric mean ratio and 90 % confidence interval (CI) area under the concentration-time curve from time 0 to infinity (AUCinf) for sirolimus administered simultaneously with tacrolimus versus sirolimus alone were 97 and 89-106, respectively, and, when administered in a staggered approach versus sirolimus alone, 107 and 98-117, respectively. The geometric mean ratio (%) and 90 % CI AUCinf for tacrolimus administered simultaneously with sirolimus versus tacrolimus alone were 92 and 82-102, respectively, and, when administered in a staggered approach versus tacrolimus alone, 94 and 84-105, respectively. CONCLUSIONS: The results of this study demonstrate a lack of any clinically important drug interaction between sirolimus and tacrolimus in healthy subjects after single-dose administration. However, due to the complexity of anti-rejection immunosuppressive therapy dosing, we suggest that sirolimus and tacrolimus concentration monitoring be performed when changes in dosing are made for either drug regimen.
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Inmunosupresores/farmacocinética , Sirolimus/farmacocinética , Tacrolimus/farmacocinética , Administración Oral , Adolescente , Adulto , Análisis de Varianza , Brasil , Estudios Cruzados , Esquema de Medicación , Interacciones Farmacológicas , Ayuno , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/sangre , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Sirolimus/sangre , Tacrolimus/administración & dosificación , Tacrolimus/efectos adversos , Tacrolimus/sangre , Adulto JovenRESUMEN
BACKGROUND: Current therapy options for patients with chronic hepatitis C virus (HCV) infection genotype 1 are effective in <50%. Danoprevir (ITMN-191/RG7227) is a potent, selective, and orally active inhibitor of the HCV NS3/4A serine protease. METHODS: The safety and antiviral efficacy of danoprevir was examined over 14 days in combination with pegylated interferon α-2a (180 µg once weekly) and ribavirin (1000-1200 mg/day) in a double-blind, placebo-controlled, phase 1b, multiple ascending dose study consisting of 6 dose cohorts (400 mg, 600 mg, and 900 mg twice daily and 100 mg, 200 mg, and 300 mg 3 times daily). RESULTS: Danoprevir in combination with pegylated interferon α-2a and ribavirin was safe and generally well tolerated. The median change in HCV RNA level from baseline to the end of treatment with danoprevir at 400 mg, 600 mg, and 900 mg twice daily was -4.7 log(10) IU/mL, -5.4 log(10) IU/mL, and -5.3 log(10) IU/mL, respectively, and at 100 mg, 200 mg, and 300 mg 3 times daily was -5.5 log(10) IU/mL, -5.7 log(10) IU/mL, and -5.6 log(10) IU/mL, respectively. Placebo administered in combination with standard of care resulted in median decrease in HCV RNA level of -2.6 log(10) IU/mL (with twice daily regimen) and -2.0 log(10) IU/mL (with 3 times daily regimen). CONCLUSIONS: Our study showed substantial antiviral efficacy of danoprevir in combination with pegylated interferon α-2a and ribavirin. Exploration of the safety and antiviral efficacy of danoprevir in longer clinical studies is warranted.
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Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Lactamas/uso terapéutico , Polietilenglicoles/uso terapéutico , Ribavirina/uso terapéutico , Sulfonamidas/uso terapéutico , Antivirales/administración & dosificación , Ciclopropanos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Genotipo , Hepacivirus/genética , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Isoindoles , Lactamas/administración & dosificación , Lactamas/efectos adversos , Lactamas Macrocíclicas , Polietilenglicoles/administración & dosificación , Prolina/análogos & derivados , Proteínas Recombinantes , Ribavirina/administración & dosificación , Sulfonamidas/administración & dosificación , Sulfonamidas/efectos adversos , Proteínas no Estructurales ViralesRESUMEN
BACKGROUND: Mutations in the genes encoding the large-conductance calcium-activated potassium channel, especially KCNMA1 encoding its α-subunit, have been linked to several neurological features, including intellectual disability or autism. Associated with neurodevelopmental phenotypes, sensory function disturbances are considered to be important clinical features contributing to a variety of behavioral impairments. Large-conductance calcium-activated potassium channels are important in regulating neurotransmission in sensory circuits, including visual pathways. Deficits in visual function can contribute substantially to poor quality of life, while therapeutic approaches aimed at addressing such visual deficits represent opportunities to improve neurocognitive and neurobehavioral outcomes. CASE PRESENTATION: We describe the case of a 25-year-old Caucasian male with autism spectrum disorder and severe intellectual disability presenting large-conductance calcium-activated potassium channel haploinsufficiency due to a de novo balanced translocation (46, XY, t [9; 10] [q23;q22]) disrupting the KCNMA1 gene. The visual processing pathway of the subject was evaluated using both electroretinography and visual contrast sensitivity, indicating that both retinal bipolar cell function and contrast discrimination performance were reduced by approximately 60% compared with normative control values. These findings imply a direct link between KCNMA1 gene disruption and visual dysfunction in humans. In addition, the subject reported photophobia but did not exhibit strabismus, nystagmus, or other visual findings on physical examination. CONCLUSIONS: This case study of a subject with large-conductance calcium-activated potassium channel haploinsufficiency and photophobia revealed a visual pathway deficit at least at the retinal level, with diminished retinal light capture likely due to bipolar cell dysfunction and an associated loss of contrast sensitivity. The data suggest that large-conductance calcium-activated potassium channels play an important role in the normal functioning of the visual pathway in humans, and that their disruption may play a role in visual and other sensory system symptomatology in large-conductance calcium-activated potassium channelopathies or conditions where disruption of large-conductance calcium-activated potassium channel function is a relevant feature of the pathophysiology, such as fragile X syndrome. This work suggests that the combined use of physiological (electroretinography) and functional (contrast sensitivity) approaches may have utility as a biomarker strategy for identifying and characterizing visual processing deficits in individuals with large-conductance calcium-activated potassium channelopathy. Trial registration ID-RCB number 2019-A01015-52, registered 17/05/2019.
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Trastorno del Espectro Autista , Discapacidad Intelectual , Calcio , Haploinsuficiencia , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/genética , Subunidades alfa de los Canales de Potasio de Gran Conductancia Activados por Calcio/genética , Canales de Potasio de Gran Conductancia Activados por el Calcio/genética , Masculino , Fotofobia , Potasio , Calidad de Vida , Órganos de los SentidosRESUMEN
BACKGROUND & AIMS: Danoprevir is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. The present study assessed the safety, pharmacokinetics, and antiviral activity of danoprevir in a randomized, placebo-controlled, 14-day multiple ascending dose study in patients with chronic HCV genotype 1 infection. METHODS: Four cohorts of treatment-naïve (TN) patients (100 mg q12 h, 100 mg q8 h, 200 mg q12 h, 200 mg q8 h) and one cohort of non-responders (NR) to prior pegylated interferon alfa-ribavirin treatment (300 mg q12 h) were investigated. RESULTS: Danoprevir was safe and well tolerated; adverse events were generally mild, transient and were not associated with treatment group or dose level. Danoprevir displayed a slightly more than proportional increase in exposure with increasing daily dose and was rapidly eliminated from the plasma compartment. Maximal decreases in HCV RNA were: -3.9 log(10)IU/ml and -3.2 log(10)IU/ml in TN receiving 200 mg q8 h and 200 mg q12 h, respectively. End of treatment viral decline in these two cohorts was within 0.1 log(10)IU/ml of the viral load nadir. HCV RNA reduction in NR was more modest than that observed in upper dose TN cohorts. The overall incidence of viral rebound was low (10/37) and was associated with the R155K substitution in NS3 regardless of the HCV subtype. CONCLUSIONS: Danoprevir was safe and well tolerated when administered for 14 days in patients with chronic HCV genotype 1 infection. Treatment resulted in sustained, multi-log(10) IU/ml reductions in HCV RNA in upper dose cohorts. These results support further clinical evaluation of danoprevir in patients with chronic HCV.
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Antivirales/administración & dosificación , Proteínas Portadoras/antagonistas & inhibidores , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/virología , Lactamas/administración & dosificación , Inhibidores de Serina Proteinasa/administración & dosificación , Sulfonamidas/administración & dosificación , Proteínas no Estructurales Virales/antagonistas & inhibidores , Adulto , Anciano , Alanina Transaminasa/sangre , Antivirales/efectos adversos , Antivirales/sangre , Ciclopropanos , Método Doble Ciego , Farmacorresistencia Viral/genética , Femenino , Hepacivirus/efectos de los fármacos , Hepacivirus/enzimología , Hepacivirus/genética , Humanos , Interferón alfa-2 , Interferón-alfa/administración & dosificación , Péptidos y Proteínas de Señalización Intracelular , Isoindoles , Lactamas/efectos adversos , Lactamas/sangre , Lactamas Macrocíclicas , Masculino , Persona de Mediana Edad , Polietilenglicoles/administración & dosificación , Prolina/análogos & derivados , ARN Viral/sangre , Proteínas Recombinantes , Ribavirina/administración & dosificación , Inhibidores de Serina Proteinasa/efectos adversos , Inhibidores de Serina Proteinasa/sangre , Sulfonamidas/efectos adversos , Sulfonamidas/sangre , Carga Viral/efectos de los fármacos , Proteínas no Estructurales Virales/genéticaRESUMEN
BACKGROUND: Disturbances in sensory function are an important clinical feature of neurodevelopmental disorders such as fragile X syndrome (FXS). Evidence also directly connects sensory abnormalities with the clinical expression of behavioral impairments in individuals with FXS; thus, positioning sensory function as a potential clinical target for the development of new therapeutics. Using electroretinography (ERG) and contrast sensitivity (CS), we previously reported the presence of sensory deficits in the visual system of the Fmr1-/y genetic mouse model of FXS. The goals of the current study were two-folds: (1) to assess the feasibility of measuring ERG and CS as a biomarker of sensory deficits in individuals with FXS, and (2) to investigate whether the deficits revealed by ERG and CS in Fmr1-/y mice translate to humans with FXS. METHODS: Both ERG and CS were measured in a cohort of male individuals with FXS (n = 20, 18-45 years) and age-matched healthy controls (n = 20, 18-45 years). Under light-adapted conditions, and using both single flash and flicker (repeated train of flashes) stimulation protocols, retinal function was recorded from individual subjects using a portable, handheld, full-field flash ERG device (RETeval®, LKC Technologies Inc., Gaithersburg, MD, USA). CS was assessed in each subject using the LEA SYMBOLS® low-contrast test (Good-Lite, Elgin, IL, USA). RESULTS: Data recording was successfully completed for ERG and assessment of CS in most individuals from both cohorts demonstrating the feasibility of these methods for use in the FXS population. Similar to previously reported findings from the Fmr1-/y genetic mouse model, individuals with FXS were found to exhibit reduced b-wave and flicker amplitude in ERG and an impaired ability to discriminate contrasts compared to healthy controls. CONCLUSIONS: This study demonstrates the feasibility of using ERG and CS for assessing visual deficits in FXS and establishes the translational validity of the Fmr1-/y mice phenotype to individuals with FXS. By including electrophysiological and functional readouts, the results of this study suggest the utility of both ERG and CS (ERG-CS) as complementary translational biomarkers for characterizing sensory abnormalities found in FXS, with potential applications to the clinical development of novel therapeutics that target sensory function abnormalities to treat core symptomatology in FXS. TRIAL REGISTRATION: ID-RCB number 2019-A01015-52 registered on the 17 May 2019.
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Síndrome del Cromosoma X Frágil , Animales , Biomarcadores , Sensibilidad de Contraste , Electrorretinografía , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/genética , Síndrome del Cromosoma X Frágil/complicaciones , Síndrome del Cromosoma X Frágil/diagnóstico , Síndrome del Cromosoma X Frágil/genética , Masculino , RatonesRESUMEN
AIM: To propose a relevant grading scale for clinical adverse events or laboratory results, electrocardiogram (ECG) and vital sign findings supporting both dose escalation and stopping decisions in first-entry-into-man (FIM) studies conducted in young healthy subjects. METHODS: A three-level scale was used for the proposed grading system. The grading is directly derived from the observed severity of discontinuous variables, as are most of clinical adverse events. A 'combined method' based on normal ranges and spontaneous variation is suggested for grading the findings which are continuous variables mainly numerical in nature. One grade, at the subject level, and one algorithm, at the cohort level, support the proposed decision rules. This work was managed by a Club Phase I working group. RESULTS: Examples of grade 1, 2 and 3 limits are given for the most frequent clinical adverse events and laboratory tests, ECG and vital sign findings. When available, the proposed NIH and FDA limits are also provided. The safety recommendation is to use the grade 2 at least as an alert for caution and the grade 3 as a maximum for stopping, applying the algorithm at the cohort level. CONCLUSIONS: This paper proposes a safety grading system based on relevant criteria which might be used by investigators and sponsors to support and rationalize dose escalation decisions in healthy young subject FIM studies. These proposals are designed not to be a guideline but some 'points to consider' helping the dose escalation process. This paper supports the recent reinforcement of the safety requirements for FIM studies by European authorities.
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Ensayos Clínicos Fase I como Asunto/efectos adversos , Drogas en Investigación/administración & dosificación , Drogas en Investigación/efectos adversos , Relación Dosis-Respuesta a Droga , HumanosRESUMEN
AIMS: To determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of oral immediate release (IR) lecozotan in healthy young and elderly subjects. METHODS: Three randomized, double-blind, placebo-controlled, sequential, ascending dose Phase I studies of lecozotan were conducted. In a single-dose study, ascending doses of 2, 5 and 10 mg were administered to cohorts of eight young subjects. In the two ascending 14-day multiple-dose studies, 41 young subjects received 0.1, 0.25, 0.5, 1 and 5 mg q12h of lecozotan or placebo and 24 elderly received 0.5 mg and 5 mg q12h of lecozotan or placebo. Assessments included safety evaluations, a complete PK profile and PD. RESULTS: Lecozotan was safe and well tolerated at steady state up to 5 mg q12. The maximum tolerated dose after multiple doses was >10 mg (5 mg q12). In the single-dose study, the maximum tolerated dose was 10 mg. Dose-limiting mild-to-moderate adverse events included paraesthesia, dizziness and visual disturbances peaking at t(max) and disappearing concomitantly with plasma concentrations. No clinically relevant changes in vital signs, ECG intervals or routine laboratory tests occurred. Lecozotan did not significantly change cognitive function, EEG or hormone levels. PK was characterized by rapid absorption, dose proportionality, extensive distribution and rapid elimination. The mean CL/F was approximately 35% lower in the elderly. CONCLUSIONS: Lecozotan IR was safe and well tolerated after administration of multiple oral doses up to 5 mg q12h in young and elderly subjects. These results support the development of lecozotan in patients with Alzheimer's disease.
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Enfermedad de Alzheimer/tratamiento farmacológico , Dioxanos/efectos adversos , Nootrópicos/efectos adversos , Piperazinas/efectos adversos , Antagonistas del Receptor de Serotonina 5-HT1 , Antagonistas de la Serotonina/efectos adversos , Administración Oral , Adolescente , Adulto , Anciano , Dioxanos/administración & dosificación , Dioxanos/farmacocinética , Dioxanos/farmacología , Método Doble Ciego , Femenino , Humanos , Masculino , Nootrópicos/farmacocinética , Nootrópicos/farmacología , Piperazinas/administración & dosificación , Piperazinas/farmacocinética , Piperazinas/farmacología , Antagonistas de la Serotonina/farmacocinética , Antagonistas de la Serotonina/farmacología , Resultado del Tratamiento , Adulto JovenRESUMEN
Nine subjects with severe hepatic impairment (Child-Pugh grade C) and 9 healthy matched control subjects were given a single 15-mg dose of sirolimus by oral solution. Increases (P < or = .002) in mean whole-blood sirolimus t(1/2) (168%), AUC(0-infinity) (210%), and MRT(oral) (261%), together with a decrease (P = .001) in CL/F (-67%), were observed in subjects with severe hepatic impairment compared with healthy matched controls. Sirolimus pharmacokinetic data in Child-Pugh grade A (n = 13, mild) and B (n = 5, moderate) subjects from a previous identically designed study were available for an inter-study comparison. Overall, mean t(1/2), weight-normalized AUC, and MRT(oral) increased steadily, whereas mean CL/F decreased steadily, with increasing degrees of hepatic impairment. CL/F showed large intersubject variabilities within subject types and extensive overlap among the subject types. The results of this study suggest that an initial sirolimus dose reduction of approximately 60% is appropriate in patients with acute severe hepatic impairment; this should be followed by further dose adjustment, based on therapeutic drug monitoring, until the trough concentrations have stabilized at sirolimus levels existing prior to the onset of acute liver failure.
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Hepatopatías/tratamiento farmacológico , Sirolimus/farmacocinética , Administración Oral , Anciano , Alanina Transaminasa/sangre , Fosfatasa Alcalina/sangre , Área Bajo la Curva , Aspartato Aminotransferasas/sangre , Aspartato Aminotransferasas/metabolismo , Bilirrubina/metabolismo , Estudios de Casos y Controles , Colecistitis/inducido químicamente , Creatinina/sangre , Femenino , Semivida , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inmunosupresores/farmacocinética , Hepatopatías/metabolismo , Hepatopatías/patología , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Sirolimus/efectos adversos , Sirolimus/sangreRESUMEN
Bazedoxifene, a selective estrogen receptor modulator with proestrogenic effects on bone and lipid metabolism and antiestrogenic effects on the breast and endometrium, is a treatment option for osteoporosis in postmenopausal women. It is extensively metabolized by the liver; therefore, a decrease in liver function was expected to decrease bazedoxifene clearance. This single-dose, open-label, inpatient/outpatient, nonrandomized study assessed the pharmacokinetics of bazedoxifene 20 mg in 18 postmenopausal women with hepatic impairment and 18 matched healthy postmenopausal women. Bazedoxifene elimination was slower, and exposure was higher, in hepatically impaired subjects compared with healthy subjects. In subjects with severe (Child-Pugh C) liver impairment, bazedoxifene mean half-life was 50% longer than that of healthy subjects. Area under the concentration-time curve geometric mean ratios (90%CI) for Child-Pugh A, B, and C liver impairment vs healthy subjects were 243% (156-379), 209% (135-326), and 368% (236-572), respectively. Although there were no severe adverse events in this study, bazedoxifene use in patients with hepatic impairment is not recommended.
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Indoles/efectos adversos , Indoles/farmacocinética , Hepatopatías/sangre , Posmenopausia/sangre , Adulto , Anciano , Área Bajo la Curva , Estudios de Casos y Controles , Femenino , Semivida , Humanos , Indoles/administración & dosificación , Hepatopatías/complicaciones , Persona de Mediana EdadRESUMEN
The purpose of this article was to evaluate the potential for a pharmacokinetic interaction between bazedoxifene and ibuprofen. In a randomized crossover study, 12 healthy postmenopausal women (aged 45-65 years) received either a single oral dose of ibuprofen (600-mg tablet), bazedoxifene (20-mg capsule), or both ibuprofen and bazedoxifene during the 3 treatment periods. Serial blood samples were collected for pharmacokinetic analyses. There was no relationship between the UGT1A1 genotype and bazedoxifene clearance. The 90% log-transformed confidence intervals (CIs) for bazedoxifene Cmax , 96% to 144%, and AUC, 85% to 134%, were slightly above the bioequivalence limits of 80% to 125%. The 90% log-transformed CIs for ibuprofen pharmacokinetic parameters were within these limits (Cmax , 92%-122%; AUC, 94%-106%). The increase in bazedoxifene plasma concentrations when combined with ibuprofen versus bazedoxifene alone is unlikely to be clinically significant. The lack of interaction between bazedoxifene and ibuprofen suggests that they may be coadministered without dose adjustment.
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Glucuronosiltransferasa/genética , Ibuprofeno/farmacocinética , Indoles/farmacocinética , Posmenopausia/sangre , Administración Oral , Área Bajo la Curva , Disponibilidad Biológica , Estudios Cruzados , Esquema de Medicación , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Ibuprofeno/administración & dosificación , Indoles/administración & dosificación , Persona de Mediana EdadRESUMEN
An open-label, 3-period study was conducted in 30 healthy postmenopausal women (mean age, 58.4 years) who received a single oral dose of atorvastatin 20 mg on day 1 (period 1), multiple daily dosing of bazedoxifene 40 mg on days 4-11 (period 2), and coadministration of atorvastatin 20 mg + bazedoxifene 40 mg on day 12 (period 3). Serial blood samples were collected (24 hours after bazedoxifene and 72 hours after atorvastatin) and assayed for bazedoxifene, atorvastatin, and its ortho-hydroxy and para-hydroxy metabolites. Pharmacokinetic parameters were calculated using noncompartmental methods. Bazedoxifene exposure was not altered with coadministration of atorvastatin 20 mg (Cmax and AUCss were within bioequivalence limits). Similarly, atorvastatin and ortho-hydroxyatorvastatin exposure was equivalent with or without coadministration with bazedoxifene. Para-hydroxyatorvastatin concentrations were below the limit of quantitation under both conditions. Cmax for atorvastatin and ortho-hydroxyatorvastatin was 14% and 18% lower, respectively, and Tmax was 20% and 34% longer, respectively, with the combination compared with atorvastatin alone. There were no serious adverse events, and no subjects discontinued the study because of safety. No clinically significant pharmacokinetic interaction was observed between bazedoxifene and atorvastatin or its active metabolites, indicating they may be safely coadministered without dosage adjustment.
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Atorvastatina/farmacocinética , Indoles/farmacocinética , Anticolesterolemiantes/sangre , Anticolesterolemiantes/farmacocinética , Atorvastatina/sangre , Estudios Cruzados , Interacciones Farmacológicas , Femenino , Voluntarios Sanos , Humanos , Indoles/sangre , Persona de Mediana Edad , Posmenopausia/sangre , Moduladores Selectivos de los Receptores de Estrógeno/sangre , Moduladores Selectivos de los Receptores de Estrógeno/farmacocinéticaRESUMEN
This Phase I, open-label, two-group, fixed-sequence study evaluated the pharmacokinetics and safety of AL-335, odalasvir, and simeprevir in healthy subjects. Group 1 (n = 16) received AL-335 800 mg once daily (QD) (days 1-3, 11-13, and 21-23), simeprevir 150 mg QD (days 4-23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15-23). Group 2 (n = 16) received the same AL-335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5-23) and simeprevir 150 mg QD (days 14-23). Blood samples were collected to determine plasma concentrations of AL-335 (prodrug) and its metabolites, ALS-022399 (monophosphate precursor) and ALS-022227 (parent nucleoside), odalasvir, and simeprevir. Thirty-two subjects were enrolled. Odalasvir and simeprevir given alone, or in combination, increased AL-335 area under plasma concentration-time curve over 24 hours (AUC 0-24 h) 3-, 4-, and 7- to 8-fold, respectively; ALS-022399 AUC 0-24 h increased 2-, 2-, and 3-fold, respectively. Simeprevir had no effect on ALS-022227 AUC 0-24 h, whereas odalasvir with/without simeprevir increased ALS-022227 AUC 0-24 h 1.5-fold. AL-335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC 0-24 h increased 1.5- to 2-fold for both drugs when coadministered irrespective of AL-335 coadministration. Study medications were well tolerated with no serious adverse events. One subject prematurely discontinued study drugs (unrelated event). This study defined the preliminary pharmacokinetic and safety profiles of the combination of AL-335, odalasvir, and simeprevir in healthy subjects. These data support the further evaluation of this combination for the treatment of chronic hepatitis C virus infection.
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Alanina/análogos & derivados , Antivirales/farmacocinética , Bencimidazoles/farmacocinética , Carbamatos/farmacocinética , Quimioterapia Combinada/efectos adversos , Indoles/farmacocinética , Profármacos/farmacocinética , Simeprevir/farmacocinética , Uridina/análogos & derivados , Administración Oral , Adulto , Alanina/efectos adversos , Alanina/farmacocinética , Antivirales/efectos adversos , Área Bajo la Curva , Bencimidazoles/efectos adversos , Carbamatos/efectos adversos , Esquema de Medicación , Femenino , Voluntarios Sanos , Humanos , Indoles/efectos adversos , Masculino , Persona de Mediana Edad , Fosforamidas , Profármacos/efectos adversos , Simeprevir/efectos adversos , Uridina/efectos adversos , Uridina/farmacocinética , Proteínas no Estructurales Virales/antagonistas & inhibidores , Adulto JovenRESUMEN
BACKGROUND: The nucleotide analog AL-335 is a pangenotypic hepatitis C virus (HCV) nonstructural protein (NS)5B inhibitor being evaluated as treatment for chronic HCV infection. METHODS: This three-part randomized, double-blind study evaluated the safety and pharmacokinetics of single and multiple ascending oral doses of AL-335. Healthy volunteers (HVs) received single doses of AL-335 (100-1,200 mg) or placebo in a fasted or fed (400 mg) state. Non-cirrhotic subjects (HCV genotype [GT]1-4) and GT1-infected subjects with Child Pugh A cirrhosis received multiple doses of AL-335 (400, 800, 1,200 mg) or placebo once daily (QD) for 7 days. RESULTS: Forty-eight HVs and 64 subjects with HCV GT1-4 were randomized and received treatment. AL-335 was well tolerated in HVs and HCV-infected subjects with/without cirrhosis. AL-335 was rapidly absorbed and converted to the metabolites ALS-022399 and ALS-022227. ALS-022227 exposure increased less than dose-proportionally and was unaffected by food, while AL-335 and ALS-022399 exposure increased with food by 85% and 50%, respectively, in HVs. Rapid and dose-dependent reductions in HCV-RNA were observed in GT1-infected subjects. In non-cirrhotic, GT1-4-infected subjects receiving AL-335 800 mg QD, potent antiviral activity was observed, regardless of genotype (mean maximum reductions in HCV-RNA of 4.0-4.8 log10 IU/mL). The same dose in GT1-infected cirrhotic subjects resulted in a 3.5 log10 IU/mL mean maximum reduction in HCV-RNA. CONCLUSIONS: AL-335 was well tolerated when administered as single and multiple doses, with an acceptable pharmacokinetic profile. The drug also demonstrated potent antiviral activity in HCV GT1-4-infected subjects, including GT1-infected subjects with cirrhosis.
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Alanina/análogos & derivados , Antivirales/uso terapéutico , Hepatitis C/tratamiento farmacológico , Uridina/análogos & derivados , Adulto , Alanina/efectos adversos , Alanina/farmacocinética , Alanina/uso terapéutico , Antivirales/efectos adversos , Antivirales/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Genotipo , Semivida , Hepacivirus/genética , Hepatitis C/complicaciones , Humanos , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Fosforamidas , Efecto Placebo , ARN Viral/sangre , Uridina/efectos adversos , Uridina/farmacocinética , Uridina/uso terapéuticoRESUMEN
BACKGROUND AND OBJECTIVES: This phase I, open-label, sequential design study assessed the effect of multiple oral doses of the potent cytochrome P450 (CYP) 3A4 inhibitor clarithromycin on the pharmacokinetics of a single oral dose of vonoprazan. METHODS: During the 10-day treatment period, 16 healthy male subjects received vonoprazan 40 mg on days 1 and 8, and clarithromycin 1000 mg on days 3-9, with the pharmacokinetics of both examined. Primary endpoints included the maximum observed plasma concentration (C max) and area under the plasma concentration-time curve (AUC) of vonoprazan and its major metabolites (M-I, M-II, M-III, and M-IV-Sul). Safety was also assessed. RESULTS: Following administration, vonoprazan was rapidly absorbed (time to reach C max, 2 h), consistent with its known pharmacokinetic profile. This was unchanged in the presence of clarithromycin. Plasma concentrations declined thereafter, with a mean apparent terminal elimination half-life of 7.2 h on day 1 and 9.4 h on day 8. Small-to-moderate increases (1.6- and 1.4-fold) in mean AUC and C max of vonoprazan, respectively, were observed following clarithromycin. In contrast, AUC and C max for vonoprazan metabolites decreased, except for M-IV-Sul, which increased approximately 2.1- and 1.5-fold, respectively. Overall, vonoprazan was well tolerated, with mild or moderate treatment-emergent adverse events occurring in six (37.5%) subjects receiving either vonoprazan and/or clarithromycin. CONCLUSIONS: Modest increases in plasma concentrations of the potent CYP3A4 inhibitor clarithromycin and vonoprazan were observed during coadministration, however these differences were not considered clinically significant. Vonoprazan had a favorable safety and tolerability profile, and no serious adverse events were reported. CLINICALTRIALS.GOV: NCT02774902.
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Claritromicina/farmacología , Inhibidores del Citocromo P-450 CYP3A/farmacología , Pirroles/farmacocinética , Sulfonamidas/farmacocinética , Adulto , Área Bajo la Curva , Semivida , Humanos , MasculinoRESUMEN
RATIONALE: Hypofunction of NMDA receptors has been implicated in neuropsychiatric disorders including schizophrenia. NMDA receptor neurotransmission can be enhanced through inhibition of glycine reuptake by the glycine transporter type 1 (GlyT1). OBJECTIVES: The primary objective of these studies was to explore the relationship between plasma exposure and glycine cerebrospinal fluid (CSF) concentrations following administration of bitopertin and RG7118 in healthy volunteers. METHODS: The bitopertin study comprised four dose levels (3, 10, 30 and 60 mg) administered once daily for 10 days. In the RG7118 study, placebo, 15 or 30 mg RG7118 was administered once daily for 28 days. CSF samples were taken on day -2 and day 10, and day -1 and day 26 for bitopertin and RG7118, respectively. RESULTS: Twenty-two and 24 subjects participated in the bitopertin and RG7118 study, respectively. In the bitopertin study, CSF glycine concentrations showed a dose-dependent increase from baseline to day 10. The geometric mean ratios (coefficient of variation) of AUC0-12 h on day 10 over baseline were 1.3 (17 %), 1.3 (49 %), 1.7 (18 %) and 2.3 (14 %) after 3, 10, 30 and 60 mg, respectively. In the RG7118 study, the geometric mean ratio of glycine concentration (CV) on day 26 at 6 h post-dose over time-matched baseline was approx. 1.9 (24 and 15 %) for 15 and 30 mg. CONCLUSIONS: The mechanism of action of bitopertin and RG7118, i.e. inhibition of glycine reuptake in the brain, was confirmed. The maximal increase observed in healthy volunteers was similar to the one observed in animals showing the good translatability of this biomarker.
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Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Glicina/líquido cefalorraquídeo , Voluntarios Sanos , Imidazoles/farmacología , Inhibidores de la Captación de Neurotransmisores/farmacología , Piperazinas/farmacología , Sulfonas/farmacología , Transmisión Sináptica/efectos de los fármacos , Adulto , Área Bajo la Curva , Encéfalo/efectos de los fármacos , Humanos , Imidazoles/farmacocinética , Masculino , Inhibidores de la Captación de Neurotransmisores/farmacocinética , Piperazinas/farmacocinética , Receptores de N-Metil-D-Aspartato/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Sulfonas/farmacocinéticaRESUMEN
The aim of this review is to establish the relationship between treatment with hypnotics and the risk of postural instability and as a consequence, falls and hip fractures, in the elderly. A review of the literature was performed through a search of the MEDLINE, Ingenta and PASCAL databases from 1975 to 2005. We considered as hypnotics only those drugs approved for treating insomnia, i.e. some benzodiazepines and the more recently launched 'Z'-compounds, i.e. zopiclone, zolpidem and zaleplon. Large-scale surveys consistently report increases in the frequency of falls and hip fractures when hypnotics are used in the elderly (2-fold risk). Benzodiazepines are the major class of hypnotics involved in this context; falls and fractures in patients taking Z-compounds are less frequently reported, and in this respect, zolpidem is considered as at risk in only one study. It is important to note, however, that drug adverse effect relationships are difficult to establish with this type of epidemiological data-mining. On the other hand, data obtained in laboratory settings, where confounding factors can be eliminated, prove that benzodiazepines are the most deleterious hypnotics at least in terms of their effects on body sway. Z-compounds are considered safer, probably because of their pharmacokinetic properties as well as their selective pharmacological activities at benzodiazepine-1 (BZ(1)) receptors. The effects of hypnotics on balance, gait and equilibrium are the consequence of differential negative impacts on vigilance and cognitive functions, and are highly dose- and time-dependent. Z-compounds have short half-lives and have less cognitive and residual effects than older medications. Some practical rules need to be followed when prescribing hypnotics in order to prevent falls and hip fractures as much as possible in elderly insomniacs, whether institutionalised or not. These are: (i) establish a clear diagnosis of the sleep disorder; (ii) take into account chronic conditions leading to balance and gait difficulties (motor and cognitive status); (iii) search for concomitant prescription of psychotropics and sedatives; (iv) use half the recommended adult dosage; and (v) declare any adverse effect to pharmacovigilance centres. Comparative pharmacovigilance studies focused on the impact of hypnotics on postural stability are very much needed.
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Accidentes por Caídas , Benzodiazepinas/uso terapéutico , Fracturas de Cadera , Hipnóticos y Sedantes/uso terapéutico , Equilibrio Postural/efectos de los fármacos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Accidentes por Caídas/economía , Acetamidas/uso terapéutico , Anciano , Anciano de 80 o más Años , Compuestos de Azabiciclo , Benzodiazepinas/efectos adversos , Estudios de Casos y Controles , Fracturas de Cadera/economía , Fracturas de Cadera/etiología , Humanos , Hipnóticos y Sedantes/efectos adversos , Hipnóticos y Sedantes/farmacocinética , Farmacoepidemiología , Piperazinas/uso terapéutico , Postura , Estudios Prospectivos , Piridinas/uso terapéutico , Pirimidinas/uso terapéutico , Estudios Retrospectivos , Medición de Riesgo , ZolpidemRESUMEN
PURPOSE: Onapristone is an antiprogestin with activity in breast cancer and is under investigation for use in endometrial, ovarian and prostate cancers. Megestrol acetate and abiraterone generally show variability in absorption and, depending on the formulation, food effect. This study was conducted to determine the effect of food on 10 mg oral immediate-release (IR) onapristone and to help identify a formulation to minimize variability. METHODS: This is an open-label, randomized, crossover study to determine the pharmacokinetic profile of onapristone and its main metabolite, N-mono-desmethyl onapristone. Twelve healthy female subjects received 10 mg of oral IR onapristone after an overnight fast, or within 30 min of a high-fat, high-calorie meal with a 2-week washout between dosing periods. RESULTS: Onapristone plasma t1/2 (mean ± SD) was 4.36 ± 0.81 h for the fasted state and 3.76 ± 0.36 h for the fed state. Following food, onapristone tmax was delayed from 1 to 4 h. Food intake was also associated with a small increase in AUC0-∞ of approximately 13 % and a statistically significant decrease in Cmax of approximately 18 %. One subject experienced a 23-day delay in menses after one 10 mg onapristone dose, while another subject experienced transient grade 2 NCI-CTCAE liver enzyme elevation 3 weeks post dose. CONCLUSION: The results are consistent with previous observations, indicating that there is a small increase in onapristone exposure and a significant decrease in Cmax when taken with food. These changes are within acceptable limits set out by the FDA. Thus, our findings indicate that onapristone could be administered without regard to food.
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Antineoplásicos/farmacocinética , Interacciones Alimento-Droga , Gonanos/farmacocinética , Adulto , Antineoplásicos/sangre , Estudios Cruzados , Ayuno/sangre , Ayuno/metabolismo , Femenino , Gonanos/sangre , Humanos , Absorción Intestinal , Estructura Molecular , Adulto JovenRESUMEN
Opicapone, a novel third-generation catechol-O-methyltransferase inhibitor for use as adjunctive therapy in levodopa-treated Parkinson's disease patients, was investigated on cardiac repolarization in healthy adult volunteers. This was a single-center, randomized, double-blind, placebo-controlled, open-label active-controlled, 4-period crossover study conducted in 64 subjects. In each period, subjects received a single oral dose of 50 mg opicapone, 800 mg opicapone, placebo, or 400 mg moxifloxacin and 24-hour 12-lead Holter monitoring was performed on day -1 (baseline) and after each single dose. After a single oral administrations of 50 and 800 mg opicapone, opicapone was the major entity in the circulation, with a median tmax of 1.5-2.0 hours. Opicapone was rapidly eliminated, with an elimination half-life of 1-2 hours. There was no clinically relevant effect of 50 and 800 mg opicapone versus placebo on cardiac depolarization or repolarization. All upper bounds of the 1-sided 95% confidence interval (CI) were below 10 milliseconds, confirming that opicapone has no QT-prolonging effect. Moxifloxacin caused an increase in the QTcI, with a lower bound of the 2-sided 95% CI always higher than 5 milliseconds, around the tmax of peak concentration, demonstrating assay sensitivity. In conclusion, administration of opicapone at therapeutic (50 mg) and supratherapeutic (800 mg) doses did not induce a clinically significant prolongation of the QTc interval.
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Inhibidores de Catecol O-Metiltransferasa/efectos adversos , Sistema de Conducción Cardíaco/efectos de los fármacos , Síndrome de QT Prolongado/inducido químicamente , Oxadiazoles/efectos adversos , Potenciales de Acción , Adolescente , Adulto , Inhibidores de Catecol O-Metiltransferasa/administración & dosificación , Inhibidores de Catecol O-Metiltransferasa/farmacocinética , Estudios Cruzados , Método Doble Ciego , Electrocardiografía Ambulatoria , Femenino , Fluoroquinolonas/efectos adversos , Francia , Voluntarios Sanos , Sistema de Conducción Cardíaco/fisiopatología , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/fisiopatología , Masculino , Persona de Mediana Edad , Moxifloxacino , Oxadiazoles/administración & dosificación , Oxadiazoles/farmacocinética , Medición de Riesgo , Factores de Tiempo , Adulto JovenRESUMEN
STUDY OBJECTIVES: To compare residual effects of zaleplon 10 mg, zopiclone 7.5 mg, and placebo, and a social dose of alcohol on car driving, memory, and psychomotor performance. DESIGN: Two-part placebo controlled, crossover study. Part 1 was single blind, Part 2 double blind. SETTING: University research institute. PARTICIPANTS: Thirty healthy volunteers (15 men and 15 women, mean age 32 +/- 7 years) INTERVENTIONS: In Part 1 alcohol and alcohol-placebo drinks were administered around noon. In Part 2 single oral doses of zaleplon 10 mg, zopiclone 7.5 mg and placebo were administered at bedtime. MEASUREMENT AND RESULTS: A highway driving test, laboratory tests of word learning, critical tracking and divided attention, and subjective assessments of sleep, mood, and effects of treatments on driving. Driving started 40 minutes after a second alcohol dose in Part 1, and 10 hours after drug intake in Part 2. The results demonstrated that alcohol, at average plasma concentrations of approximately 0.030 g/dl, significantly impaired performance in all tests. Zaleplon's residual effects did not differ significantly from those of placebo in any test. In contrast, zopiclone had significant residual effects on driving, divided attention, and memory. The magnitude of impairment in the driving test observed the morning after zopiclone 7.5 mg was twice that observed with alcohol. CONCLUSION: Zaleplon 10 mg has no residual effects on driving when taken at bedtime, 10 hours before driving. In contrast, zopiclone 7.5 mg can cause marked residual impairment. Patients should be advised to avoid driving the morning after zopiclone administration.