RESUMEN
Benznidazole (BNZ) serves as the primary drug for treating Chagas Disease and is listed in the WHO Model List of Essential Medicines for Children. Herein, a new child-friendly oral BNZ delivery platform is developed in the form of supramolecular eutectogels (EGs). EGs address BNZ's poor oral bioavailability and provide a flexible twice-daily dose in stick-pack format. This green and sustainable formulation strategy relies on the gelation of drug-loaded Natural Deep Eutectic Solvents (NaDES) with xanthan gum (XG) and water. Specifically, choline chloride-based NaDES form stable and biocompatible 5 mg/mL BNZ-loaded EGs. Rheological and Low-field NMR investigations indicate that EGs are viscoelastic materials comprised of two co-existing regions in the XG network generated by different crosslink distributions between the biopolymer, NaDES and water. Remarkably, the shear modulus and relaxation spectrum of EGs remain unaffected by temperature variations. Upon dilution with simulated gastrointestinal fluids, EGs results in BNZ supersaturation, serving as the primary driving force for its absorption. Interestingly, after oral administration of EGs to rats, drug bioavailability increases by 2.6-fold, with a similar increase detected in their cerebrospinal fluid. The noteworthy correlation between in vivo results and in vitro release profiles confirms the efficacy of EGs in enhancing both peripheral and central BNZ oral bioavailability.
Asunto(s)
Disponibilidad Biológica , Nitroimidazoles , Polisacáridos Bacterianos , Animales , Administración Oral , Nitroimidazoles/administración & dosificación , Nitroimidazoles/farmacocinética , Nitroimidazoles/química , Polisacáridos Bacterianos/química , Masculino , Sistemas de Liberación de Medicamentos/métodos , Ratas , Tripanocidas/administración & dosificación , Tripanocidas/farmacocinética , Tripanocidas/química , Geles , Solventes/química , Ratas Sprague-Dawley , Reología , Liberación de Fármacos , Colina/química , Colina/administración & dosificación , Colina/farmacocinéticaRESUMEN
A major challenge for tuberculosis (TB) drug development is to prioritize promising combination regimens from a large and growing number of possibilities. This includes demonstrating individual drug contributions to the activity of higher-order combinations. A BALB/c mouse TB infection model was used to evaluate the contributions of each drug and pairwise combination in the clinically relevant Nix-TB regimen [bedaquiline-pretomanid-linezolid (BPaL)] during the first 3 weeks of treatment at human equivalent doses. The rRNA synthesis (RS) ratio, an exploratory pharmacodynamic (PD) marker of ongoing Mycobacterium tuberculosis rRNA synthesis, together with solid culture CFU counts and liquid culture time to positivity (TTP) were used as PD markers of treatment response in lung tissue; and their time-course profiles were mathematically modeled using rate equations with pharmacologically interpretable parameters. Antimicrobial interactions were quantified using Bliss independence and Isserlis formulas. Subadditive (or antagonistic) and additive effects on bacillary load, assessed by CFU and TTP, were found for bedaquiline-pretomanid and linezolid-containing pairs, respectively. In contrast, subadditive and additive effects on rRNA synthesis were found for pretomanid-linezolid and bedaquiline-containing pairs, respectively. Additionally, accurate predictions of the response to BPaL for all three PD markers were made using only the single-drug and pairwise effects together with an assumption of negligible three-way drug interactions. The results represent an experimental and PD modeling approach aimed at reducing combinatorial complexity and improving the cost-effectiveness of in vivo systems for preclinical TB regimen development.
Asunto(s)
Antituberculosos , Diarilquinolinas , Modelos Animales de Enfermedad , Linezolid , Ratones Endogámicos BALB C , Mycobacterium tuberculosis , Animales , Antituberculosos/farmacología , Antituberculosos/farmacocinética , Antituberculosos/uso terapéutico , Linezolid/farmacología , Linezolid/farmacocinética , Diarilquinolinas/farmacología , Diarilquinolinas/farmacocinética , Ratones , Mycobacterium tuberculosis/efectos de los fármacos , Femenino , Nitroimidazoles/farmacología , Nitroimidazoles/farmacocinética , Nitroimidazoles/uso terapéutico , Quimioterapia Combinada , Pulmón/microbiología , Pulmón/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Pruebas de Sensibilidad Microbiana , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiologíaRESUMEN
BACKGROUND: Pharmacokinetic studies of bedaquiline and delamanid in patients with pre-extensively drug-resistant tuberculosis (pre-XDR TB) will help in the optimization of these drugs for both culture conversion and adverse events. METHODS: A prospective cohort of 165 adult patients (56% male with mean [SD] age 29 [9.7] years) with pre-XDR TB was treated with bedaquiline, delamanid, clofazimine, and linezolid for 24 weeks at 5 sites in India. Bedaquiline was administered at 400 mg daily for 2 weeks followed by 200 mg thrice weekly for 22 weeks, whereas delamanid was administered at 100 mg twice daily. In 23 consenting participants at 8 and 16 weeks of treatment, blood was collected at 0, 2, 4, 5, 6, 8, 12, and 24 hours postdosing for an intense pharmacokinetic study. Pharmacokinetic parameters were correlated with sputum culture conversion and adverse events. RESULTS: The mean (SD) age and weight of patients were 30 (10) years and 54 kg, respectively. The median minimum concentration (C min ) and time-concentration curve (AUC) for bedaquiline, respectively, were 0.6 mcg/mL and 27 mcg/mL·h at week 8 and 0.8 mcg/mL and 36 mcg/mL·h at week 16, suggesting drug accumulation over time. The median C min and AUC of delamanid, respectively, were 0.17 mcg/mL and 5.1 mcg/mL·h at week 8 and 0.20 mcg/mL and 7.5 mcg/mL·h at week 16. Delay in sputum conversion was observed in patients with drug concentrations lower than the targeted concentration. At weeks 8 and 16, 13 adverse events were observed. Adverse events were resolved through symptomatic treatment. Body mass index was found to be significantly associated with drug-exposure parameters. CONCLUSIONS: Bedaquiline and delamanid when co-administered exhibit plasma drug levels within the targeted concentrations, showing an exposure-response relationship.
Asunto(s)
Antituberculosos , Diarilquinolinas , Nitroimidazoles , Oxazoles , Esputo , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Diarilquinolinas/farmacocinética , Diarilquinolinas/uso terapéutico , Masculino , Adulto , Nitroimidazoles/farmacocinética , Nitroimidazoles/uso terapéutico , Nitroimidazoles/efectos adversos , Antituberculosos/farmacocinética , Antituberculosos/efectos adversos , Antituberculosos/uso terapéutico , Femenino , Oxazoles/farmacocinética , Oxazoles/uso terapéutico , Oxazoles/efectos adversos , Esputo/microbiología , Estudios Prospectivos , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Adulto Joven , Persona de Mediana Edad , Clofazimina/farmacocinética , Clofazimina/uso terapéutico , Estudios de Cohortes , AdolescenteRESUMEN
BACKGROUND: Implementation of newer anti-tuberculosis (TB) drugs may prolong the QT interval, increasing the risk of arrythmias and sudden cardiac death. The potential for cardiac adverse events has prompted recommendations for frequent cardiac monitoring during treatment. However, unknowns remain, including the association between drug concentrations and QT interval. METHODS: An observational prospective cohort study design was used. Patients undergoing treatment for drug-resistant TB in Georgia were assessed. Serial blood samples were collected at 4-6 weeks for pharmacokinetics. Electrocardiograms were recommended to be performed monthly. A generalized estimating equation spline model was used to investigate (1) the effect difference between bedaquiline and delamanid, (2) the cumulative effect of number of anti-TB drugs, and (3) the relationship between serum drug concentrations on QTc interval. RESULTS: Among 94 patients receiving either bedaquiline (n = 64) or delamanid (n = 30)-based treatment, most were male (82%), and the mean age was 39 years. The mean maximum QTc increase during the first six months was 37.5 ms (IQR: 17.8-56.8). Bedaquiline- and delamanid-based regimens displayed similar increased mean QTc change from baseline during drug administration (P = 0.12). Increasing number of anti-TB drugs was associated with an increased QTc (P = 0.01), but participants trended back towards baseline after drug discontinuation (P = 0.25). A significant association between AUC, Cmin, Cmax, and increased QTc interval was found for bedaquiline (months 1-6) and levofloxacin (months 1-12). CONCLUSION: Bedaquiline- and delamanid-based regimens and increasing number of QT prolonging agents led to modest increases in the QTc interval with minimal clinical effect.
Asunto(s)
Síndrome de QT Prolongado , Nitroimidazoles , Tuberculosis Resistente a Múltiples Medicamentos , Humanos , Masculino , Adulto , Femenino , Antituberculosos/efectos adversos , Antituberculosos/farmacocinética , Estudios Prospectivos , Diarilquinolinas/efectos adversos , Nitroimidazoles/efectos adversos , Nitroimidazoles/farmacocinética , Oxazoles/efectos adversos , Oxazoles/farmacocinética , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Síndrome de QT Prolongado/inducido químicamenteRESUMEN
BACKGROUND AND OBJECTIVE: Delamanid is a nitroimidazole, a novel class of drug for treating tuberculosis, and is primarily metabolized by albumin into the metabolite DM-6705. The aims of this analysis were to develop a population pharmacokinetic (PK) model to characterize the concentration-time course of delamanid and DM-6705 in adults with drug-resistant tuberculosis and to explore a potential drug-drug interaction with bedaquiline when coadministered. METHODS: Delamanid and DM-6705 concentrations after oral administration, from 52 participants (of whom 26 took bedaquiline concurrently and 20 were HIV-1 positive) enrolled in the DELIBERATE trial were analyzed using nonlinear mixed-effects modeling. RESULTS: Delamanid PK were described by a one-compartment disposition model with transit compartment absorption (mean absorption time of 1.45 h [95% confidence interval 0.501-2.20]) and linear elimination, while the PK of DM-6705 metabolite were described by a one-compartment disposition model with delamanid clearance as input and linear elimination. Predicted terminal half-life values for delamanid and DM-6705 were 15.1 h and 7.8 days, respectively. The impact of plasma albumin concentrations on delamanid metabolism was not significant. Bedaquiline coadministration did not affect delamanid PK. Other than allometric scaling with body weight, no patients' demographics were significant (including HIV). CONCLUSIONS: This is the first joint PK model of delamanid and its DM-6705 metabolite. As such, it can be utilized in future exposure-response or exposure-safety analyses. Importantly, albumin concentrations, bedaquiline coadministration, and HIV co-infection (dolutegravir coadministration) did not have an effect on delamanid and DM-6705 PK.
Asunto(s)
Infecciones por VIH , Nitroimidazoles , Tuberculosis Resistente a Múltiples Medicamentos , Adulto , Albúminas , Antituberculosos , Diarilquinolinas , Infecciones por VIH/tratamiento farmacológico , Humanos , Nitroimidazoles/farmacocinética , Nitroimidazoles/uso terapéutico , Oxazoles , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológicoRESUMEN
Despite considerable progress has been achieved in hypoxia-associated anti-tumor therapy, the efficacy of utilizing hypoxia-activated prodrugs alone is not satisfied owing to the inadequate hypoxia within the tumor regions. In this work, a mitochondrial targeted nanoplatform integrating photodynamic therapy, photothermal therapy and hypoxia-activated chemotherapy has been developed to synergistically treat cancer and maximize the therapeutic window. Polydopamine coated hollow copper sulfide nanoparticles were used as the photothermal nanoagents and thermosensitive drug carriers for loading the hypoxia-activated prodrug, TH302, in our study. Chlorin e6 (Ce6) and triphenyl phosphonium (TPP) were conjugated onto the surface of the nanoplatform. Under the action of TPP, the obtained nanoplatform preferentially accumulated in mitochondria to restore the drug activity and avoid drug resistance. Using 660 nm laser to excite Ce6 can generate ROS and simultaneously exacerbate the cellular hypoxia. While under the irradiation of 808 nm laser, the nanoplatform produced local heat which can increase the release of TH302 in tumor cells, ablate cancer cells as well as intensify the tumor hypoxia levels. The aggravated tumor hypoxia then significantly boosted the anti-tumor efficiency of TH302. Both in vitro and in vivo studies demonstrated the greatly improved anti-cancer activity compared to conventional hypoxia-associated chemotherapy. This work highlights the potential of using a combination of hypoxia-activated prodrugs plus phototherapy for synergistic cancer treatment.
Asunto(s)
Hipoxia de la Célula/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Mitocondrias/metabolismo , Nanopartículas/química , Fotoquimioterapia/métodos , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Femenino , Ratones , Ratones Endogámicos C57BL , Nitroimidazoles/química , Nitroimidazoles/farmacocinética , Nitroimidazoles/farmacología , Mostazas de Fosforamida/química , Mostazas de Fosforamida/farmacocinética , Mostazas de Fosforamida/farmacología , Profármacos/química , Profármacos/farmacología , Distribución TisularRESUMEN
Clinical development of combination chemotherapies for tuberculosis (TB) is complicated by partial or restricted phase II dose-finding. Barriers include a propensity for drug resistance with monotherapy, practical limits on numbers of treatment arms for component dose combinations, and limited application of current dose selection methods to multidrug regimens. A multi-objective optimization approach to dose selection was developed as a conceptual and computational framework for currently evolving approaches to clinical testing of novel TB regimens. Pharmacokinetic-pharmacodynamic (PK-PD) modeling was combined with an evolutionary algorithm to identify dosage regimens that yield optimal trade-offs between multiple conflicting therapeutic objectives. The phase IIa studies for pretomanid, a newly approved nitroimidazole for specific cases of highly drug-resistant pulmonary TB, were used to demonstrate the approach with Pareto optimized dosing that best minimized sputum bacillary load and the probability of drug-related adverse events. Results include a population-typical characterization of the recommended 200 mg once daily dosage, the optimality of time-dependent dosing, examples of individualized therapy, and the determination of optimal loading doses. The approach generalizes conventional PK-PD target attainment to a design problem that scales to drug combinations, and provides a benefit-risk context for clinical testing of complex drug regimens.
Asunto(s)
Nitroimidazoles/farmacocinética , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto , Antituberculosos , Ensayo de Unidades Formadoras de Colonias/métodos , Simulación por Computador , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Quimioterapia Combinada , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Masculino , Nitroimidazoles/administración & dosificación , Seguridad , Esputo/microbiología , Resultado del TratamientoRESUMEN
Tuberculosis (TB) continues to be a serious threat to public health throughout the world. Newer treatments are needed that could offer simplified regimens with activity against both drug-sensitive and drug-resistant bacilli, while optimizing safety. Pretomanid (PA-824), a nitroimidazooxazine compound, is a new drug for the treatment of pulmonary TB that was recently approved in the United States and Europe in the context of a regimen combined with bedaquiline and linezolid. This phase 1 double-blind, randomized, placebo-controlled crossover study specifically examined the effect of single-dose administration of pretomanid 400 or 1000 mg and pretomanid 400 mg plus moxifloxacin 400 mg on the QTc interval in 74 healthy subjects. Subjects were fasting at the time of drug administration. Pretomanid concentrations following single 400- or 1000-mg doses were not associated with any QT interval prolongation of clinical concern. Moxifloxacin did not alter the pharmacokinetics of pretomanid, and the effect of pretomanid 400 mg plus moxifloxacin 400 mg on the individually corrected QT interval was consistent with the effect of moxifloxacin alone. Both drugs were generally well tolerated. Although supratherapeutic exposure of pretomanid relative to the now-recommended dosing with food was not achieved, these findings contribute to the favorable assessment of cardiac safety for pretomanid.
Asunto(s)
Antituberculosos/administración & dosificación , Síndrome de QT Prolongado/inducido químicamente , Moxifloxacino/administración & dosificación , Nitroimidazoles/administración & dosificación , Adolescente , Adulto , Antituberculosos/efectos adversos , Antituberculosos/farmacocinética , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Interacciones Farmacológicas , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Moxifloxacino/efectos adversos , Nitroimidazoles/efectos adversos , Nitroimidazoles/farmacocinética , Adulto JovenRESUMEN
Chagas disease (CD), caused by the flagellate protozoan Trypanosoma cruzi, is one of the major public health problems in developing countries. Benznidazole (BNZ) is the only drug available for CD treatment in most countries, however, it presents high toxicity and low bioavailability. To address these problems this study used Zeolitic Imidazolate Framework-8 (ZIF-8), which has garnered considerable attention due to its potential applications, enabling the controlled delivery of drugs. The present work developed and characterized a BNZ@ZIF-8 system, and the modulation of BNZ release from the ZIF-8 framework was evaluated through the in vitro dialysis release method under sink conditions at different pH values. Moreover, the in vitro evaluation of cell viability and cytotoxicity by MTT assay were also performed. The dissolution studies corroborated that a pH sensitive Drug Delivery System capable of vectorizing the release of BNZ was developed, may leading to the improvement in the bioavailability of BNZ. The MTT assay showed that no statistically significant toxic effects occurred in the developed system, nor significant effects on cell viability.
Asunto(s)
Portadores de Fármacos , Nitroimidazoles/administración & dosificación , Tripanocidas/administración & dosificación , Diálisis , Humanos , Concentración de Iones de Hidrógeno , Imidazoles , Nitroimidazoles/efectos adversos , Nitroimidazoles/farmacocinética , Espectrometría por Rayos X , Espectroscopía Infrarroja por Transformada de Fourier , Tripanocidas/efectos adversos , Tripanocidas/farmacocinética , ZeolitasRESUMEN
BACKGROUND: Chagas disease (CD) continues to be a neglected infectious disease with one of the largest burdens globally. Despite the modest cure rates in adult chronic patients and its safety profile, benznidazole (BNZ) is still the drug of choice. Its current recommended dose is based on nonrandomized studies, and efficacy and safety of the optimal dose of BNZ have been scarcely analyzed in clinical trials. METHODS/DESIGN: MULTIBENZ is a phase II, randomized, noninferiority, double-blind, multicenter international clinical trial. A total of 240 patients with Trypanosoma CD in the chronic phase will be recruited in four different countries (Argentina, Brazil, Colombia, and Spain). Patients will be randomized to receive BNZ 150 mg/day for 60 days, 400 mg/day for 15 days, or 300 mg/day for 60 days (comparator arm). The primary outcome is the efficacy of three different BNZ therapeutic schemes in terms of dose and duration. Efficacy will be assessed according to the proportion of patients with sustained parasitic load suppression in peripheral blood measured by polymerase chain reaction. The secondary outcomes are related to pharmacokinetics and drug tolerability. The follow-up will be 12 months from randomization to end of study participation. Recruitment was started in April 2018. CONCLUSION: This is a clinical trial conducted for the assessment of different dose schemes of BNZ compared with the standard treatment regimen for the treatment of CD in the chronic phase. MULTIBENZ may help to clarify which is the most adequate BNZ regimen in terms of efficacy and safety, predicated on sustained parasitic load suppression in peripheral blood. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03191162. Registered on 19 June 2017.
Asunto(s)
Enfermedad de Chagas/tratamiento farmacológico , Enfermedades Desatendidas/parasitología , Nitroimidazoles/uso terapéutico , Tripanocidas/uso terapéutico , Trypanosoma cruzi/aislamiento & purificación , Adulto , Cuidados Posteriores , Argentina/epidemiología , Brasil/epidemiología , Estudios de Casos y Controles , Enfermedad de Chagas/parasitología , Enfermedad Crónica , Colombia/epidemiología , Método Doble Ciego , Femenino , Humanos , Masculino , Nitroimidazoles/farmacocinética , Carga de Parásitos/estadística & datos numéricos , Seguridad , España/epidemiología , Resultado del Tratamiento , Tripanocidas/farmacocinética , Trypanosoma cruzi/genéticaRESUMEN
This study was aimed to design a simple and novel prototype device for the production of polymeric microparticles. To prove the effectiveness of this device, benznidazole microparticles using chitosan as carrier and NaOH, KOH, or SLS as counter ions were used. For comparison, benznidazole microparticles were prepared by the conventional dripping technique (syringe and gauge) using the same excipients. Microparticles were characterized in terms of encapsulation efficiency, particle shape, size and surface topography, crystallinity characteristics, thermal behavior, and dissolution rate. Then, the pharmacokinetic parameters were evaluated after the oral administration of the microparticles to healthy Wistar rats. The prepared formulations, by means of this device, showed good drug encapsulation efficiency (> 70%). Release studies revealed an increased dissolution of benznidazole from chitosan microparticles prepared using the novel device. It achieved more than 90% in 60 min, while those of the conventional microparticles and raw drug achieved 65% and 68%, respectively, during the same period. Almost spherical benznidazole microparticles with a smooth surface and size around 10-30 µm were observed using scanning electron microscopy. Thermal analysis and X-ray diffraction studies suggested a partial reduction of drug crystallinity. Moreover, the relative oral bioavailability of the novel benznidazole microparticles showed that the area under the curve for the microencapsulated drug was 10.3 times higher than the raw drug. Thus, these findings indicate that the designed glass prototype device is a useful alternative to formulate benznidazole polymeric microparticles with improved biopharmaceutical properties and could be useful for other therapeutic microparticulate systems.
Asunto(s)
Composición de Medicamentos/instrumentación , Nitroimidazoles/química , Animales , Quitosano/química , Liberación de Fármacos , Nitroimidazoles/farmacocinética , Ratas , Ratas WistarRESUMEN
The effects of multiple-dose administration of tenofovir disoproxil fumarate (TDF) on the pharmacokinetics of morinidazole (MOR) were compared in healthy subjects. MOR exposure was similar, with an area under the curve from 0 h to infinity (AUC0-∞) treatment ratio for MOR+TDF/MOR of 1.01 (90% confidence interval, 0.97 to 1.06). No relevant differences were observed regarding plasma exposure of metabolites. Renal clearances of MOR and its metabolites were not affected by TDF. No unexpected safety or tolerability issues were observed.
Asunto(s)
Antivirales/farmacología , Antivirales/farmacocinética , Interacciones Farmacológicas , Nitroimidazoles/farmacocinética , Tenofovir/farmacología , China , Voluntarios Sanos , HumanosRESUMEN
We investigated the usefulness of diffusion-weighted imaging (DWI) for detecting changes in the structure of hypoxic cells by evaluating the correlation between 18F-fluoroazomycin arabinoside (FAZA) positron emission tomography activity and DWI parameters in head and neck carcinoma. The diffusion coefficient corresponding to the slow compartment of a two-compartment model had a significant positive correlation with FAZA activity (ρ = 0.58, P = 0.016), whereas the diffusional kurtosis from diffusion kurtosis imaging had a significant negative correlation (ρ = -0.62, P = 0.008), which suggests that those DWI parameters might be useful as indicators for changes in cell structure.
Asunto(s)
Hipoxia de la Célula/fisiología , Imagen de Difusión por Resonancia Magnética/métodos , Neoplasias de Cabeza y Cuello , Nitroimidazoles/farmacocinética , Tomografía de Emisión de Positrones/métodos , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/fisiopatología , Humanos , Nitroimidazoles/uso terapéutico , Radiofármacos/farmacocinética , Radiofármacos/uso terapéuticoRESUMEN
PURPOSE: Hypoxia is linked to aggressiveness, resistance to therapy, and poor prognosis of pancreatic tumors. Liposomal irinotecan (nal-IRI, ONIVYDE®) has shown potential in reducing hypoxia in the HT29 colorectal cancer model, and here, we investigate its therapeutic activity and ability to modulate hypoxia in patient-derived orthotopic tumor models of pancreatic cancer. PROCEDURES: Mice were randomized into nal-IRI treated and untreated controls. Magnetic resonance imaging was used for monitoring treatment efficacy, positron emission tomography (PET) imaging with F-18-labelled fluoroazomycinarabinoside ([18F]FAZA) for tumor hypoxia quantification, and F-18-labelled fluorothymidine ([18F]FLT) for tumor cell proliferation. RESULTS: The highly hypoxic OCIP51 tumors showed significant response following nal-IRI treatment compared with the less hypoxic OCIP19 tumors. [18F]FAZA-PET detected significant hypoxia reduction in treated OCIP51 tumors, 8 days before significant changes in tumor volume. OCIP19 tumors also responded to therapy, although tumor volume control was not accompanied by any reduction in [18F]FAZA uptake. In both models, no differences were observable in [18F]FLT uptake in treated tumors compared with control mice. CONCLUSIONS: Hypoxia modulation may play a role in nal-IRI's mechanism of action. Nal-IRI demonstrated greater anti-tumor activity in the more aggressive and hypoxic tumor model. Furthermore, hypoxia imaging provided early prediction of treatment response.
Asunto(s)
Hipoxia de la Célula/fisiología , Irinotecán/administración & dosificación , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/tratamiento farmacológico , Tomografía de Emisión de Positrones/métodos , Animales , Femenino , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacocinética , Liposomas/administración & dosificación , Liposomas/química , Estudios Longitudinales , Ratones , Ratones Endogámicos NOD , Ratones SCID , Nitroimidazoles/química , Nitroimidazoles/farmacocinética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Radiofármacos/química , Radiofármacos/farmacocinética , Inhibidores de Topoisomerasa I/farmacología , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A patient enrolled in a clinical trial (NCT02802969) with suspicion of chordoma underwent an [F]FAZA PET/CT, a radiolabeled nitroimidazole analog of hypoxia PET imaging. The patient's images showed a different tumor profile compared to those observed in other hypoxic or nonhypoxic chordoma patients. The motivation for using [F]FAZA pharmacokinetic imaging was to compare this profile with histologically confirmed cases of chordoma. Through visual imaging and quantification of blood and tumor time-activity curves, we excluded the hypothesis that it was a chordoma, diagnosing a paraganglioma.
Asunto(s)
Procesamiento de Imagen Asistido por Computador , Nitroimidazoles/farmacocinética , Tomografía Computarizada por Tomografía de Emisión de Positrones , Sacro/diagnóstico por imagen , Neoplasias de la Columna Vertebral/diagnóstico por imagen , Neoplasias de la Columna Vertebral/metabolismo , Ensayos Clínicos como Asunto , Femenino , Humanos , MasculinoRESUMEN
A population pharmacokinetic (PopPK) model for pretomanid was developed using data from 14 studies in the pretomanid development program: six phase 1 studies, six phase 2 studies, and two phase 3 studies. The final analysis data set contained 17,725 observations from 1,054 subjects, including healthy subjects and subjects with drug-sensitive, multidrug-resistant, or extensively drug-resistant pulmonary tuberculosis dosed pretomanid in monotherapy or combination therapy for up to 6 months. Pretomanid pharmacokinetic behavior was described by a one-compartment model that at a given dose was linear in its absorption and clearance processes but where the rate of absorption and extent of bioavailability changed with dose. Clearance and volume of distribution scaled allometrically with weight. Apparent clearance in females was 18% less than in males. Among HIV-positive subjects, absent the effect of CYP3A4-inducing antiretrovirals, apparent clearance was 6% higher. Some effects of total bilirubin and albumin were found, but the impacts on exposure were small. Bioavailability in the fasted condition was about half that in the fed condition. Relative bioavailability decreased with increasing dose in the fasted condition, but not for doses of ≤200 mg in the fed condition. HIV-positive subjects taking efavirenz and lopinavir/ritonavir had exposures that were reduced by 46 and 17%, respectively. There was little evidence for noteworthy effects of regimen partners on pretomanid. Standard diagnostics indicated that the model described the voluminous, diverse data well, so that the model could be used to generate exposure metrics for exposure/response analyses to be reported elsewhere.
Asunto(s)
Antituberculosos/farmacocinética , Nitroimidazoles/farmacocinética , Antituberculosos/uso terapéutico , Disponibilidad Biológica , Ensayos Clínicos como Asunto , Tuberculosis Extensivamente Resistente a Drogas/tratamiento farmacológico , Tuberculosis Extensivamente Resistente a Drogas/microbiología , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Lopinavir/farmacocinética , Lopinavir/uso terapéutico , Masculino , Nitroimidazoles/uso terapéutico , Rifampin/farmacocinética , Rifampin/uso terapéutico , Ritonavir/farmacocinética , Ritonavir/uso terapéutico , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/microbiología , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/microbiologíaRESUMEN
Central nervous system tuberculosis (TB) is devastating and affects vulnerable populations. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculous meningitis (TBM) specifically are nearly uniformly fatal, with little information being available to guide the treatment of these patients. Delamanid (DLM), a nitro-dihydro-imidazooxazole, is a new, well-tolerated anti-TB drug with a low MIC (1 to 12 ng/ml) against Mycobacterium tuberculosis It is used for the treatment of pulmonary MDR-TB, but pharmacokinetic (PK) data for DLM in the central nervous system (CNS) of patients with TBM are not available. In the present study, we measured DLM concentrations in the brain and cerebrospinal fluid (CSF) of six rabbits with and without experimentally induced TBM receiving single-dose DLM. We report the steady-state CSF concentrations from three patients receiving DLM as part of multidrug treatment who underwent therapeutic drug monitoring. Drug was quantified using liquid chromatography-tandem mass spectrometry. In rabbits and humans, mean concentrations in CSF (in rabbits, 1.26 ng/ml at 9 h and 0.47 ng/ml at 24 h; in humans, 48 ng/ml at 4 h) were significantly lower than those in plasma (in rabbits, 124 ng/ml at 9 h and 14.5 ng/ml at 24 h; in humans, 726 ng/ml at 4 h), but the estimated free CSF/plasma ratios were generally >1. In rabbits, DLM concentrations in the brain were 5-fold higher than those in plasma (means, 518 ng/ml at 9 h and 74.0 ng/ml at 24 h). All patients with XDR-TBM receiving DLM experienced clinical improvement and survival. Collectively, these results suggest that DLM achieves adequate concentrations in brain tissue. Despite relatively low total CSF drug levels, free drug may be sufficient and DLM may have a role in treating TBM. More studies are needed to develop a fuller understanding of its distribution over time with treatment and clinical effectiveness.
Asunto(s)
Antituberculosos/farmacocinética , Antituberculosos/uso terapéutico , Sistema Nervioso Central/metabolismo , Nitroimidazoles/farmacocinética , Oxazoles/farmacocinética , Tuberculosis Meníngea/tratamiento farmacológico , Animales , Femenino , Humanos , Masculino , Mycobacterium tuberculosis/efectos de los fármacos , Conejos , Resultado del Tratamiento , Tuberculosis Meníngea/metabolismo , Tuberculosis Resistente a Múltiples Medicamentos/tratamiento farmacológico , Tuberculosis Resistente a Múltiples Medicamentos/metabolismoRESUMEN
The synthesis of SCF3 as well as SeCF3 isosteres of two OCF3 -containing drugs was achieved through visible light and copper-catalyzed processes. Herein, we show that chalcogen replacement modulates physicochemical and ADME properties without introducing intrinsic liabilities. The SCF3 and SeCF3 groups are more lipophilic than their oxygen counterpart; however, microsomal stability is unchanged, indicating that these molecular changes may be beneficial for inâ vivo half-life. Enabled by modern synthetic methods, we present the chalcogen-CF3 groups as potential key players for future fluorinated pharmaceuticals.
Asunto(s)
Nitroimidazoles/farmacología , Compuestos de Organoselenio/farmacología , Riluzol/análogos & derivados , Riluzol/farmacología , Sulfuros/farmacología , Animales , Perros , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Células de Riñón Canino Madin Darby , Microsomas Hepáticos/metabolismo , Estructura Molecular , Nitroimidazoles/síntesis química , Nitroimidazoles/farmacocinética , Compuestos de Organoselenio/síntesis química , Compuestos de Organoselenio/farmacocinética , Riluzol/farmacocinética , Sulfuros/síntesis química , Sulfuros/farmacocinéticaRESUMEN
The nitroimidazole DNDI-0690 is a clinical drug candidate for visceral leishmaniasis (VL) that also shows potent in vitro and in vivo activity against cutaneous leishmaniasis (CL). To support further development of this compound into a patient-friendly oral or topical formulation for the treatment of CL, we investigated the free drug exposure at the dermal site of infection and subsequent elimination of the causative Leishmania pathogen. This study evaluates the pharmacokinetics (PK) and pharmacodynamics (PD) of DNDI-0690 in mouse models of CL. Skin microdialysis and Franz diffusion cell permeation studies revealed that DNDI-0690 permeated poorly (<1%) into the skin lesion upon topical drug application (0.063% [wt/vol], 30 µl). In contrast, a single oral dose of 50 mg/kg of body weight resulted in the rapid and nearly complete distribution of protein-unbound DNDI-0690 from the plasma into the infected dermis (ratio of the area under the curve [0 to 6 h] of the free DNDI-0690 concentration in skin tissue to blood [fAUC0-6 h, skin tissue/fAUC0-6 h, blood] is greater than 80%). Based on in vivo bioluminescence imaging, two doses of 50 mg/kg DNDI-0690 were sufficient to reduce the Leishmania mexicana parasite load by 100-fold, while 6 such doses were needed to achieve similar killing of L. major; this was confirmed by quantitative PCR. The combination of rapid accumulation and potent activity in the Leishmania-infected dermis indicates the potential of DNDI-0690 as a novel oral treatment for CL.
Asunto(s)
Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Visceral/tratamiento farmacológico , Nitroimidazoles/farmacocinética , Nitroimidazoles/uso terapéutico , Animales , Desarrollo de Medicamentos , Femenino , Ratones , Ratones Endogámicos BALB C , Microdiálisis , Reacción en Cadena de la Polimerasa , Piel/efectos de los fármacos , Piel/microbiologíaRESUMEN
Concentration-QTc modeling was applied to pretomanid, a new nitroimidazooxazine antituberculosis drug. Data came from eight phase 2 and phase 3 studies. Besides pretomanid alone, various combinations with bedaquiline, linezolid, moxifloxacin, and pyrazinamide were considered; special attention was given to the bedaquiline-pretomanid-linezolid (BPaL) regimen that has demonstrated efficacy in the Nix-TB study in subjects with extensively drug-resistant or treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. Three heart rate corrections to QT were considered: Fridericia's QTcF, Bazett's QTcB, and a population-specific correction, QTcN. QTc increased with the plasma concentrations of pretomanid, bedaquiline's M2 metabolite, and moxifloxacin in a manner described by a linear model in which the three slope coefficients were constant across studies, visits within study, and times postdose within visit but where the intercept varied across those dimensions. The intercepts tended to increase on treatment to a plateau after several weeks, a pattern termed the secular trend. The slope terms were similar for the three QTc corrections, but the secular trends differed, suggesting that at least some of the secular trend was due to the elevated heart rates of tuberculosis patients decreasing to normal levels on treatment. For pretomanid 200 mg once a day (QD) alone, a typical steady-state maximum concentration of drug in plasma (Cmax) resulted in a mean change from baseline of QTcN of 9.1 ms, with an upper 90% confidence interval (CI) limit of 10.2 ms. For the BPaL regimen, due to the additional impact of the bedaquiline M2 metabolite, the corresponding values were 13.6 ms and 15.0 ms. The contribution to these values from the secular trend was 4.0 ms.