RESUMEN
Tuberculosis (TB) remains a leading cause of death, but antibiotic treatments for tuberculous meningitis, the deadliest form of TB, are based on those developed for pulmonary TB and not optimized for brain penetration. Here, we perform first-in-human dynamic 18F-pretomanid positron emission tomography (PET) in eight human subjects to visualize 18F-pretomanid biodistribution as concentration-time exposures in multiple compartments (NCT05609552), demonstrating preferential brain versus lung tissue partitioning. Preferential, antibiotic-specific partitioning into brain or lung tissues of several antibiotics, active against multidrug resistant (MDR) Mycobacterium tuberculosis strains, are confirmed in experimentally-infected mice and rabbits, using dynamic PET with chemically identical antibiotic radioanalogs, and postmortem mass spectrometry measurements. PET-facilitated pharmacokinetic modeling predicts human dosing necessary to attain therapeutic brain exposures. These data are used to design optimized, pretomanid-based regimens which are evaluated at human equipotent dosing in a mouse model of TB meningitis, demonstrating excellent bactericidal activity without an increase in intracerebral inflammation or brain injury. Importantly, several antibiotic regimens demonstrate discordant activities in brain and lung tissues in the same animal, correlating with tissue antibiotic exposures. These data provide a mechanistic basis for the compartmentalized activities of antibiotic regimens, with important implications for developing treatments for meningitis and other infections in compartments with unique antibiotic penetration.
Asunto(s)
Antituberculosos , Encéfalo , Pulmón , Mycobacterium tuberculosis , Adulto , Animales , Femenino , Humanos , Masculino , Ratones , Conejos , Antituberculosos/farmacocinética , Antituberculosos/uso terapéutico , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Pulmón/diagnóstico por imagen , Pulmón/metabolismo , Mycobacterium tuberculosis/efectos de los fármacos , Tomografía de Emisión de Positrones/métodos , Distribución Tisular , Tuberculosis Meníngea/diagnóstico por imagen , Tuberculosis Meníngea/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/diagnóstico por imagen , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
Polyarticular juvenile idiopathic arthritis (pJIA) is a pediatric chronic inflammatory arthritis, much like rheumatoid arthritis (RA) in adults. Drug development for pJIA can potentially be expedited by using extrapolation of efficacy from adult RA; however, the lack of understanding of the response and exposure relationship between pJIA and RA to therapeutic interventions has been a major roadblock. To address this, the objective of our analysis was to conduct a systematic response and exposure comparison between pJIA and RA trials for biologic products. Data from registration RA and pJIA clinical trials (parallel or withdrawal design) for infliximab, tocilizumab, golimumab, and adalimumab were utilized. First, exposure was compared between the pJIA trials and RA pivotal trials. Subsequently, the pJIA vs. RA response similarity was assessed by comparing similar individual subcomponents of the American College of Rheumatology (ACR) scores between the two populations. The exposure comparison demonstrated that at the pJIA trial dose, exposure in pediatric patients was similar to or higher than adults for all biologics evaluated except infliximab, where lower exposure was observed in pJIA patients ≤ 35 kg. Response comparison for individual subcomponents indicated that in a majority of the cases, pJIA response was similar or higher as compared with response from RA trials. Overall, this analysis suggests response similarity between pJIA and RA across the biologic products when exposures are matched between the two populations. These analyses provide support for the use of pharmacokinetic exposure-matching for extrapolation of efficacy from adult RA to pediatric pJIA for the products with established mechanism(s) of action.
Asunto(s)
Antirreumáticos/administración & dosificación , Artritis Juvenil/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Productos Biológicos/administración & dosificación , Adulto , Factores de Edad , Antirreumáticos/farmacocinética , Productos Biológicos/farmacocinética , Niño , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Humanos , Resultado del TratamientoRESUMEN
STUDY OBJECTIVE: To evaluate factors affecting variability in response to remimazolam in general anesthesia. DESIGN: Plasma concentration-time data from 11 Phase 1-3 clinical trials were pooled for the population pharmacokinetic (popPK) analysis and concentration-bispectral index (BIS) data were pooled from 8 trials for popPK-PD analysis. A 3-compartment model with allometric exponents on clearance and volume described remimazolam concentrations over time. An effect compartment model with an inhibitory sigmoid Emax model was fit to the concentration-BIS data. Simulations were performed to assess sedation in general anesthesia and post-surgical sedation in healthy and sensitive populations. SETTING: General anesthesia and post-surgical sedation. PATIENTS: 689 subjects included in popPK and 604 subjects included in popPK-PD. Most subjects (>85%) were ASA Class 1 or 2, with the remaining subjects being ASA Class 3. INTERVENTIONS: Serial plasma concentrations and BIS scores. MEASUREMENTS: Standard intra-operative monitoring. MAIN RESULTS: PopPK model included an effect of extracorporeal circulation, ASA class, and sex on PK and a time-dependent clearance (~30% lower at 24 h) that was not related to cumulative dose. Co-administered remifentanil had a synergistic decrease in BIS with remimazolam. Remimazolam IC50 increased with cumulative dose. Onset was faster in overweight subjects and slower in Asian subjects. If using a weight-based regimen, simulations showed that remimazolam 6 mg/kg/h until loss of consciousness followed by 1 mg/kg/h during general anesthesia and 0.25 mg/kg/h for post-surgical sedation for up to 24 h is optimal, regardless of ASA class or sensitivity of subjects. CONCLUSIONS: If using a weight-based regimen, results illustrated an appropriate regimen of remimazolam for general anesthesia and post-surgical sedation in general and sensitive populations, although lower doses can be considered in elderly patients with a significant disease burden or in ASA Class 3 patients. The time-dependent change in clearance is not clinically relevant for up to 24 h.
Asunto(s)
Anestesia General , Hipnóticos y Sedantes , Anciano , Anestesia General/efectos adversos , Benzodiazepinas , Relación Dosis-Respuesta a Droga , Voluntarios Sanos , HumanosRESUMEN
Tuberculosis (TB) is the leading cause of death from a single infectious agent, requiring at least 6 months of multidrug treatment to achieve cure1. However, the lack of reliable data on antimicrobial pharmacokinetics (PK) at infection sites hinders efforts to optimize antimicrobial dosing and shorten TB treatments2. In this study, we applied a new tool to perform unbiased, noninvasive and multicompartment measurements of antimicrobial concentration-time profiles in humans3. Newly identified patients with rifampin-susceptible pulmonary TB were enrolled in a first-in-human study4 using dynamic [11C]rifampin (administered as a microdose) positron emission tomography (PET) and computed tomography (CT). [11C]rifampin PET-CT was safe and demonstrated spatially compartmentalized rifampin exposures in pathologically distinct TB lesions within the same patients, with low cavity wall rifampin exposures. Repeat PET-CT measurements demonstrated independent temporal evolution of rifampin exposure trajectories in different lesions within the same patients. Similar findings were recapitulated by PET-CT in experimentally infected rabbits with cavitary TB and confirmed using postmortem mass spectrometry. Integrated modeling of the PET-captured concentration-time profiles in hollow-fiber bacterial kill curve experiments provided estimates on the rifampin dosing required to achieve cure in 4 months. These data, capturing the spatial and temporal heterogeneity of intralesional drug PK, have major implications for antimicrobial drug development.
Asunto(s)
Antituberculosos/farmacocinética , Pulmón/diagnóstico por imagen , Pulmón/metabolismo , Rifampin/farmacocinética , Tuberculosis/diagnóstico , Tuberculosis/tratamiento farmacológico , Adulto , Animales , Antituberculosos/administración & dosificación , Antituberculosos/sangre , Disponibilidad Biológica , Quimioterapia Combinada , Femenino , Humanos , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Mycobacterium tuberculosis/fisiología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Conejos , Rifampin/administración & dosificación , Rifampin/sangre , Distribución Tisular , Tuberculosis/metabolismo , Tuberculosis/patología , Tuberculosis Pulmonar/diagnóstico , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/metabolismo , Tuberculosis Pulmonar/patologíaRESUMEN
Tuberculous meningitis (TBM) is a devastating form of tuberculosis (TB), and key TB antimicrobials, including rifampin, have restricted brain penetration. A lack of reliable data on intralesional drug biodistribution in infected tissues has limited pharmacokinetic (PK) modeling efforts to optimize TBM treatments. Current methods to measure intralesional drug distribution rely on tissue resection, which is difficult in humans and generally limited to a single time point even in animals. In this study, we developed a multidrug treatment model in rabbits with experimentally induced TBM and performed serial noninvasive dynamic 11C-rifampin positron emission tomography (PET) over 6 weeks. Area under the curve brain/plasma ratios were calculated using PET and correlated with postmortem mass spectrometry. We demonstrate that rifampin penetration into infected brain lesions is limited, spatially heterogeneous, and decreases rapidly as early as 2 weeks into treatment. Moreover, rifampin concentrations in the cerebrospinal fluid did not correlate well with those in the brain lesions. First-in-human 11C-rifampin PET performed in a patient with TBM confirmed these findings. PK modeling predicted that rifampin doses (≥30 mg/kg) were required to achieve adequate intralesional concentrations in young children with TBM. These data demonstrate the proof of concept of PET as a clinically translatable tool to noninvasively measure intralesional antimicrobial distribution in infected tissues.
Asunto(s)
Radioisótopos de Carbono/química , Tomografía de Emisión de Positrones , Rifampin/uso terapéutico , Tuberculosis Meníngea/diagnóstico por imagen , Tuberculosis Meníngea/tratamiento farmacológico , Animales , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Encéfalo/patología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Probabilidad , Conejos , Rifampin/farmacocinética , Rifampin/farmacología , Factores de Tiempo , Distribución Tisular/efectos de los fármacosRESUMEN
Diazepam rectal gel (Diastat(®)) is the only FDA-approved product indicated for acute repetitive seizures. Despite its proven efficacy, most older children and adults object to this route of administration. As a result, many patients do not realize the benefit of a therapy that can improve outcomes and decrease healthcare costs. Intranasal administration of benzodiazepines offers a potential alternative. The primary objective of this study was to compare the bioavailability and pharmacokinetics of two novel intranasal (IN) diazepam (DZP) formulations versus intravenous (IV) administration in healthy volunteers. Twenty-four healthy volunteers were randomized into an open-label, three-way crossover study. 10mg doses of two investigational intranasal DZP formulations (solution, suspension) and a 5mg IV dose of commercially available DZP injectable, USP were given. A two-week washout period separated treatments. Plasma samples for DZP analysis were collected pre-dose and at regular intervals up to 240 h post-dose. DZP concentration-time data were analyzed using a non-compartmental pharmacokinetics approach. Exposure following administration of DZP IN solution (absolute bioavailability - 97%) was greater than the IN suspension (absolute bioavailability - 67%). Mean Cmaxvalues for the suspension and solution formulations were 221 ng/mL and 272 ng/mL, respectively. Median time to maximum concentration (Tmax) was 1h and 1.5h for suspension and solution formulation, respectively. Both investigational intranasal formulations were well tolerated. The results of this pilot study indicate that development of an intranasal diazepam formulation with high bioavailability, reasonable variability, and good tolerability is feasible.
Asunto(s)
Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/farmacocinética , Diazepam/farmacocinética , Administración Intranasal , Administración Intravenosa , Adolescente , Adulto , Análisis de Varianza , Anticonvulsivantes/sangre , Disponibilidad Biológica , Estudios Cruzados , Diazepam/administración & dosificación , Diazepam/sangre , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Factores de Tiempo , Adulto JovenRESUMEN
Intranasal therapy has been proposed as an alternative for the management of seizure emergencies. The bioavailability, dose proportionality and tolerability of a supersaturated intranasal formulation of diazepam (DZP) solubilized in a glycofurol-water cosolvent system was investigated. Eight healthy volunteers were randomized into a single-blind, three-way crossover study to compare 5 and 10mg intranasal DZP doses of the investigational formulation with a 5mg dose of a DZP solution (DZP injectable, 5mg/mL) administered intravenously. Treatments were separated by a two-week washout period. Plasma samples for DZP analysis were collected pre-dose and at regular intervals up to 48h post-dose and assayed by HPLC. Visual analog scales (VAS) were used to assess tolerability (1-tolerable; 10-extremely intolerable) and pain (1-no pain; 4-extreme pain) at predefined time points. Following the 5 and 10mg doses, the median t(max) were 20 and 30min and the mean C(max) were 134.3+/-62 and 247.6+/-61ng/mL. Estimated bioavailability was 75% for both doses. Pain scores of 2 and 2.3 were observed following the 5 and 10mg doses; tolerability scores were 4.4 and 4.7. Pain and tolerability scores returned to baseline within 10h. Our formulation provided reasonable bioavailability, but was not well tolerated.
Asunto(s)
Anticonvulsivantes/farmacocinética , Diazepam/farmacocinética , Administración Intranasal , Adulto , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Área Bajo la Curva , Disponibilidad Biológica , Diazepam/administración & dosificación , Diazepam/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Método Simple Ciego , Factores de TiempoRESUMEN
Ion paired solutions of methotrexate in L-arginine/water/propylene glycol systems were evaluated for their potential to enhance the permeation of methotrexate across rabbit nasal mucosa in vitro. The partition coefficient of methotrexate in the methotrexate: L-arginine ion paired systems was observed to be 24 times greater than that of the methotrexate system without L-arginine. The ion pair formation between methotrexate and L-arginine was confirmed by a decrease in the conductivity of the systems in the presence of propylene glycol, a dielectric constant reducing agent. The permeation of methotrexate across the rabbit nasal mucosa from the ion paired systems was observed to be significantly greater (p < 0.05) as compared to control systems of methotrexate solution in water and a sodium salt. Furthermore, a threefold increase in the flux of methotrexate was observed when propylene glycol was added to the ion paired systems. These results suggest that methotrexate: L-arginine ion paired systems have potential in improving the permeation of methotrexate across rabbit nasal mucosa and may form the basis for further development of an intranasal therapeutic system of methotrexate.