RESUMO
The current study evaluates the clinical effect of sirolimus exposure on the occurrence of cytomegalovirus (CMV) DNAemia necessitating preemptive antiviral therapy. A total of 167 consecutive recipients of reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) who received sirolimus- and tacrolimus-based graft-versus-host disease (GVHD) prophylaxis and whose CMV serostatus was positive for donors and/or recipients were included in this multicenter retrospective study. A parametric model with consecutive sirolimus blood levels describing the time to CMV DNAemia-RAT was developed using NONMEM version 7.4. Overall, 122 of 167 patients (73%) were allografted from an unrelated donor, and the donor CMV-serostatus was negative in 51 cases (31%). Fifty-six recipients (34%) developed CMV DNAemia necessitating preemptive therapy, with a cumulative incidence of 36% at a median follow-up of 25 months. Time to CMV DNAemia necessitating preemptive therapy was best described using a Gompertz function. CMV DNAemia necessitating preemptive therapy-predicting factors were antithymocyte globulin-based conditioning regimen (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.1 to 4.1; P < .01) and sirolimus concentration (HR, .94; 95% CI, .87 to .99; P < .01). The risk of CMV DNAemia-RAT decreased by 6% for each 1 ng/mL increase in sirolimus trough concentration. In conclusion, we provide evidence on the association between sirolimus blood concentration and incidence of CMV DNAemia necessitating preemptive therapy in allo-HSCT recipients. Moreover, this study presents the first predictive model describing the time to CMV DNAemia necessitating preemptive antiviral therapy as a function of sirolimus drug concentration.
Assuntos
Antivirais/uso terapêutico , Infecções por Citomegalovirus/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Pré-Medicação/métodos , Sirolimo/efeitos adversos , Adulto , Infecções por Citomegalovirus/etiologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunossupressores/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sirolimo/sangue , Transplante HomólogoRESUMO
BACKGROUND: To evaluate the adequacy of different dosing regimens of voriconazole for the prophylaxis of invasive candidiasis and aspergillosis in adult allogeneic stem cell transplant recipients by means of population pharmacokinetic (PK) modelling and simulation. METHODS: Allogeneic stem cell transplant recipients receiving voriconazole were included in this observational study. A population PK model was developed. Three oral voriconazole-dosing regimens were simulated: 200, 300, and 400 mg twice daily. The pharmacodynamic target was defined as fAUC0-24/0.7. A probability of target attainment ≥90% was considered optimal. The cumulative fraction of response was defined as the fraction of patients achieving the pharmacodynamic target when a population of simulated patients is matched with a simulated population of different Candida spp. and Aspergillus spp. The percentage of patients with trough plasma concentrations at steady state (Ctrough) within the reference range (1-5.5 mg/L) was also calculated. RESULTS: A 2-compartment PK model was developed using data from 40 patients, which contributed 237 voriconazole plasma samples, including trough and maximum concentrations. Voriconazole 200, 300, and 400 mg twice daily achieved probability of target attainment ≥90% for minimal inhibitory concentration values ≤0.25, ≤0.38, and ≤0.50 mg/L, respectively. The cumulative fraction of response for A. niger, A. versicolor, and A. flavus increased >10% when increasing voriconazole dose from 200 to 400 mg twice daily (from 72.5% to 89.5% for A. niger; from 77.7% to 88.7% for A. versicolor; and from 82.4% to 94.9% for A flavus). The percentage of patients with Ctrough within the reference range increased 15% when voriconazole dose was increased from 200 to 300 mg twice daily. CONCLUSIONS: The PK simulations in this study suggest that transplant recipients on voriconazole prophylaxis against invasive candidiasis or aspergillosis are likely to achieve the target concentrations associated with the desired treatment outcomes if the maintenance dose is 200 mg twice daily. However, Aspergillus spp. with high minimal inhibitory concentrations could require higher maintenance doses.
Assuntos
Antifúngicos/farmacocinética , Aspergilose/microbiologia , Candidíase/microbiologia , Transplante de Células-Tronco/efeitos adversos , Voriconazol/farmacocinética , Administração Oral , Adulto , Idoso , Aloenxertos , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Aspergilose/prevenção & controle , Aspergillus/efeitos dos fármacos , Candida/efeitos dos fármacos , Candidíase/prevenção & controle , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Voriconazol/administração & dosagem , Voriconazol/uso terapêuticoRESUMO
BACKGROUND: To better understand the impact of seasonal influenza in pregnant women we analyzed data collected during four seasons at a hospital for acute respiratory infection that specializes in treating pregnant women. METHODS: This was a single-center active surveillance study of women 15-44 years of age hospitalized for acute respiratory diseases between 2012/2013 and 2015/2016 in Moscow, Russian Federation. Women had to have been hospitalized within 7 days of the onset of symptoms. Swabs were taken within 48 h of admission, and influenza was detected by reverse transcription-polymerase chain reaction. RESULTS: During the four seasons, of the 1992 hospitalized women 1748 were pregnant. Laboratory-confirmed influenza was detected more frequently in pregnant women (825/1748; 47.2%) than non-pregnant women (58/244; 23.8%) (OR for influenza = 2.87 [95% CI, 2.10-3.92]; p < 0.001). This pattern was homogenous across seasons (p = 0.112 by test of homogeneity of equal odds). Influenza A(H1N1)pdm09 was the dominant strain in 2012/2013, A(H3N2) in 2013/2014, B/Yamagata lineage and A(H3N2) in 2014/2015, and A(H1N1)pdm09 in 2015/2016. Influenza-positive pregnant admissions went to the hospital sooner than influenza-negative pregnant admissions (p < 0.001). The risk of influenza increased by 2% with each year of age and was higher in women with underlying conditions (OR = 1.52 [95% CI, 1.16 to 1.99]). Pregnant women positive for influenza were homogeneously distributed by trimester (p = 0.37 for homogeneity; p = 0.49 for trend). Frequencies of stillbirth, delivery, preterm delivery, and caesarean delivery did not significantly differ between influenza-positive and influenza-negative hospitalized pregnant women or between subtypes/lineages. CONCLUSIONS: Pregnant women are at increased risk for hospitalization due to influenza irrespective of season, circulating viruses, or trimester.
Assuntos
Hospitalização/estatística & dados numéricos , Influenza Humana/epidemiologia , Vigilância da População , Complicações Infecciosas na Gravidez/epidemiologia , Infecções Respiratórias/epidemiologia , Doença Aguda , Adolescente , Adulto , Feminino , Hospitais/estatística & dados numéricos , Humanos , Moscou/epidemiologia , Gravidez , Complicações Infecciosas na Gravidez/virologia , Infecções Respiratórias/virologia , Estações do Ano , Adulto JovemRESUMO
Sirolimus appears to protect against cytomegalovirus (CMV) in organ transplant recipients. The effect of this drug in allogeneic hematopoietic stem cell transplantation recipients remains unexplored. By means of multivariate continuous-time Markov model analyses, we identified 3 independent covariates that significantly impacted the risk of CMV DNAemia: recipient/donor CMV serostatus, tacrolimus exposure, and sirolimus exposure. CMV-seropositive recipients with CMV-seronegative donors had a significantly higher probability of having detectable CMV DNAemia. Increasing the tacrolimus trough concentration from 0 to 16 ng/mL increased the probability of patients having detectable CMV DNAemia by 40% (from 40% to 80%), whereas this probability decreased by 25% (from 40% to 15%) when trough concentrations of sirolimus increased from 0 to 16 ng/mL. Sensitivity analysis showed that sirolimus exposure between 0 and 6 ng/mL has no or negligible effect on CMV DNAemia, but levels >8 ng/mL significantly decreased the number of detectable CMV DNAemia cases (the risk ratios decreased from 0.68 to 0.21 when whole blood sirolimus concentrations changed from 8 to 18 ng/mL, P < .01). In conclusion, we used a pharmacometric statistical tool to provide the first clinical evidence that fewer CMV DNAemia events become detectable as sirolimus exposure increases.
Assuntos
Infecções por Citomegalovirus/epidemiologia , Citomegalovirus/efeitos dos fármacos , Citomegalovirus/genética , DNA Viral/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Sirolimo/uso terapêutico , Viremia/tratamento farmacológico , Adulto , Idoso , Citomegalovirus/isolamento & purificação , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/microbiologia , Feminino , Seguimentos , Humanos , Imunossupressores/uso terapêutico , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Espanha/epidemiologia , Transplantados , Transplante Homólogo , Viremia/epidemiologia , Viremia/microbiologiaRESUMO
IntroductionSeasonal influenza vaccination is widely recommended for people with risk factors, especially for people who are elderly. However, influenza vaccine effectiveness (IVE) varies year after year because of the variable antigenic composition of the circulating viruses and the vaccine composition. Methods: We summarise the results of IVE and the impact of previous vaccination among subjects 60 years of age and over in a multicentre prospective study in the Valencia Hospital Surveillance Network for the Study of Influenza and Respiratory Viruses Disease (VAHNSI) in Spain. We applied the test-negative design taking laboratory-confirmed influenza as outcome and vaccination status as exposure. Information about potential confounders was obtained from clinical registries or directly from patients. Results: Adjusted IVE was 19% (95% confidence interval (CI): -15 to 43). For patients vaccinated in the current season but not in the two previous seasons, effectiveness was 49% (95% CI: -20 to 78) and for patients vaccinated in the current and any of two previous seasons, effectiveness was 29% (95% CI: -3 to 52). For those patients not vaccinated in the current season but vaccinated in any of the two previous seasons, effectiveness was 53% (95% CI: 8 to 76). Conclusions: Our data show a low vaccine effectiveness for the 2016/17 influenza season.
Assuntos
Hospitalização/estatística & dados numéricos , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Vacinas contra Influenza/administração & dosagem , Influenza Humana/diagnóstico , Influenza Humana/prevenção & controle , Vacinação/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Vacinas contra Influenza/imunologia , Vacinas contra Influenza/farmacologia , Influenza Humana/epidemiologia , Laboratórios , Masculino , Pessoa de Meia-Idade , Vigilância da População , Estudos Prospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estações do Ano , Espanha/epidemiologiaRESUMO
The etiology of undernourishment in cancer patients is multifactorial: tumor-related mechanisms (such as obstruction, metabolic abnormalities, and functionality changes) in addition to the influence of anticancer therapies, which can induce or worsen undernutrition. The evident role of undernutrition in cancer treatment outcomes suggests the need of considering nutritional status when evaluating anticancer drugs. In order to merge the available data and offer researchers and clinicians a global view of this phenomenon, the present manuscript reviews on a drug-by-drug basis the undernutrition-related pharmacokinetic and pharmacodynamic aspects of anticancer treatments. This review notes interesting trends in the relationship between undernourishment and pharmacokinetics across studies, and indicates that dosing modifications of these drugs may be necessary to optimize chemotherapeutic treatments. Furthermore, this review has compiled evidence regarding undernourishment's capacity of enhancing treatment-related myelosuppression, cardiotoxicity, ototoxicity, neurotoxicity, and malignancies.
Assuntos
Antineoplásicos/farmacocinética , Desnutrição/fisiopatologia , Antraciclinas/farmacocinética , Etoposídeo/farmacocinética , Fluoruracila/farmacocinética , Humanos , Metotrexato/farmacocinética , Alcaloides de Vinca/farmacocinéticaRESUMO
The main objective of this study was to develop a pharmacokinetic model in order to describe the intestinal absorption of erlotinib in rat and to quantify the interaction of levofloxacin on this process in well- and under-nourished rats. Absorption studies were performed in male Wistar rats. Concentration-time profiles in proximal and distal intestine were analysed through non-linear mixed effect modelling using the NONMEM software version 7.3. Simulations were performed in order to explore the influence of covariates on the apparent absorption rate constant. A passive absorption and an active secretion process best-described erlotinib absorption from lumen to enterocyte. The developed model indicates that levofloxacin exerts an inhibition on erlotinib efflux transporters of the gut epithelium. Undernourishment proved to significantly decrease the maximum capacity of the secretion process. Simulations evidenced that erlotinib absorption only takes place at high enough drug concentrations to overcome the effect of efflux transporters. On the other hand, when levofloxacin is present in the intestinal lumen of undernourished rats, erlotinib drug absorption takes place even at low erlotinib concentrations. In the clinical setting, this interaction may result in increased exposure to erlotinib, especially in undernourished cancer patients. Copyright © 2017 John Wiley & Sons, Ltd.
Assuntos
Antibacterianos/farmacologia , Antineoplásicos/farmacocinética , Cloridrato de Erlotinib/farmacocinética , Levofloxacino/farmacologia , Desnutrição/metabolismo , Modelos Biológicos , Inibidores de Proteínas Quinases/farmacocinética , Animais , Interações Medicamentosas , Absorção Intestinal , Mucosa Intestinal/metabolismo , Masculino , Ratos Wistar , Albumina Sérica/análiseRESUMO
To evaluate the effectiveness and toxicity profile of ipilimumab treatment and to examine the cost-effectiveness relation in a real-world sample of patients with metastasic melanoma. This was a multicenter, observational, retrospective cohorts study. To assess the effectiveness and safety of ipilimumab treatment progression-free survival (PFS), overall survival (OS) and adverse events were registered. An economic evaluation was performed and cost-effectiveness ratios (CERs) were calculated. Eleven patients were included, mean age 59 (SD=11) years. The median PFS was 3.83 months (95% confidence interval 0.98-9.80) and the median OS was 5.15 months (95% confidence interval 1.70-8.48). None of the patients included in the study achieved an objective response. A stable disease was achieved in four (36%) patients. The most commonly reported analytical adverse event was anemia, with all patients developing anemia in any grade. The most severe adverse event was neutropenia (n=6; 55%), with three patients developing grade 4 neutropenia (3/11; 27%). The total cost of ipilimumab treatment was &OV0556;483 397, with a median of 43 033 (interquartile range=9555) euros per patient. The median-based CER was 136 675 (28 539-474 865) euros per progression-free year gained and the median-based CER was 100 112 (23 107-374 893) euros per life-year gained. PFS observed in real-world patients was higher than that reported in clinical trials and OS was lower. The incidence of adverse events was higher. The additional cost per progression-free year gained was â¼&OV0556;136 675. The data from this study fill an important need for information on the relative value of this treatment in terms of cost-effectiveness.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Melanoma/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/economia , Antineoplásicos/efeitos adversos , Antineoplásicos/economia , Antineoplásicos/uso terapêutico , Análise Custo-Benefício , Feminino , Humanos , Ipilimumab , Masculino , Melanoma/economia , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos RetrospectivosRESUMO
The aim of this study was to evaluate the effectiveness and toxicity profile of the vinflunine chemotherapy regimen and to examine the cost-effectiveness relation in a real-world sample of patients with transitional cell carcinoma of the bladder. This is a multicenter, observational, retrospective cohort study. To assess the effectiveness and safety of vinflunine treatment, progression-free survival, overall survival, and adverse events were registered. An economic evaluation was performed and cost-effectiveness ratios were calculated. A total of 37 patients were included in the study, with a mean age of 67 (SD=9) years. The median progression-free survival was 2.61 months (95% confidence interval 1.79-4.23) and the median overall survival was 5.72 months (95% confidence interval 3.34-10.35). An objective response was achieved in eight (22%) patients. Statistically significant differences were found between patients treated with vinflunine as a second-line therapy and those treated with vinflunine as a third-line therapy (P=0.036). The most commonly reported analytical adverse event was anemia (n=34; 92%), and the most severe was neutropenia (n=19; 51%), with nine patients developing grade 4 neutropenia (9/19; 47%). The total cost of vinflunine treatment was &OV0556;553 873, with a median of &OV0556;8524 (interquartile range, &OV0556;9220) per patient. The median-based cost-effectiveness ratio was &OV0556;44 789 (&OV0556;31 706-58 022) per progression-free year gained and &OV0556;22 750 (&OV0556;14 526-34 085) per life-year gained. The data from this study fill an important need for information on the relative value of this treatment in terms of cost-effectiveness and might help achieve an optimal quality healthcare system.
Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Vimblastina/análogos & derivados , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/economia , Carcinoma de Células de Transição/economia , Análise Custo-Benefício , Feminino , Hospitais com mais de 500 Leitos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Espanha , Análise de Sobrevida , Neoplasias da Bexiga Urinária/economia , Vimblastina/efeitos adversos , Vimblastina/economia , Vimblastina/uso terapêuticoRESUMO
INTRODUCTION: The aim of the study was to analyze the incidence, management and cost associated to hematological and dermatological adverse effects (AE) in chronic hepatitis C patients on triple therapy (TT) with telaprevir (TVR) or boceprevir (BOC). METHODS: An analysis was made on the data recorded on patients who started treatment with TVR or BOC associated with peginterferon alfa and ribavirin in a 12-week follow-up period. RESULTS: Fifty-three patients were included (TVR n=36; BOC n=17). Thrombocytopenia (83% TVR vs. 88% BOC) followed by neutropenia (89% TVR vs. 82% BOC) were the most common AE. Dermatological AE were observed in 32% of patients. Eleven patients required treatment discontinuation (all of them received TVR), and toxicity was the main reason for discontinuation (64%). The percentage of patients who required supportive treatment for management of AE was 66%. The most used supportive treatment was erythropoietin. Eight patients required emergency health care, and 2 were hospitalized due to AE. Total cost of additional supportive resources was 32,522 (625 [SD=876]/patient) (TVR 759 [SD=1,022]/patient vs. BOC 349 [SD=327]/patient; P>.05). Patients with gradeiii-iv toxicity required greater supportive care with higher costs, compared to patients with gradei-ii toxicity (849 [SD=1,143]/patient vs. 387 [SD=397]/patient; P=.053). CONCLUSION: The addition of new protease inhibitors to conventional treatment leads to a higher incidence of hematological AE in our study, compared to data described in clinical trials. The elevated incidence of AE involves the use of supportive care, increasing total costs of therapy.
Assuntos
Antivirais/administração & dosagem , Antivirais/economia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/economia , Oligopeptídeos/administração & dosagem , Oligopeptídeos/economia , Prolina/análogos & derivados , Análise Custo-Benefício , Quimioterapia Combinada , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/economia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Feminino , Humanos , Incidência , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/economia , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/economia , Prolina/administração & dosagem , Prolina/economia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/economia , Estudos Retrospectivos , Ribavirina/administração & dosagem , Ribavirina/economia , Fatores de TempoRESUMO
Regulatory T cells (Tregs) are essential for maintaining immune homeostasis by serving as negative regulators of adaptive immune system effector cell responses. Reduced production or function of Tregs has been implicated in several human autoimmune diseases. The cytokine interleukin 2 plays a central role in promoting Treg differentiation, survival, and function in vivo and may therefore have therapeutic benefits for autoimmune diseases. mRNA-6231 is an investigational, lipid nanoparticle-encapsulated, mRNA-based therapy that encodes a modified human interleukin 2 mutein fused to human serum albumin (HSA-IL2m). Herein, we report the development of a semi-mechanistic kinetic-pharmacodynamic model to quantify the relationship between subcutaneous dose(s) of mRNA-6231, HSA-IL2m protein expression, and Treg expansion in nonhuman primates. The nonclinical kinetic-pharmacodynamic model was extrapolated to humans using allometric scaling principles and the physiological basis of pharmacological mechanisms to predict the clinical response to therapy a priori. Model-based simulations were used to inform the dose selection and design of the first-in-human clinical study (NCT04916431). The modeling approach used to predict human responses was validated when data became available from the phase I clinical study. This validation indicates that the approach is valuable in informing clinical decision-making.
Assuntos
Interleucina-2 , RNA Mensageiro , Humanos , Interleucina-2/farmacocinética , Interleucina-2/genética , Interleucina-2/farmacologia , Interleucina-2/administração & dosagem , Animais , RNA Mensageiro/genética , Linfócitos T Reguladores/efeitos dos fármacos , Nanopartículas , Modelos Biológicos , Masculino , LipossomosRESUMO
OBJECTIVE: To determine a safe dose of clonidine (CLON) to be used in infants with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH). STUDY DESIGN: A pilot prospective study was performed to determine the effect of CLON on autonomic parameters, the pharmacokinetics (PK) of CLON, and the amount of morphine (MOR) given "as needed" for shivering and agitation in a cohort of infants (n = 12) with HIE undergoing TH compared to a historical control group (n = 28). RESULTS: The CLON group received less "as needed" MOR than the MOR-only group for agitation/shivering (p < 0.001), and the CLON vs. MOR-only group spent 92% vs. 79% of cooling time at the target core body temperature (CBT; p = 0.03, CLON vs. MOR). CONCLUSIONS: Intravenous CLON (1 mcg/kg Q8h) is well tolerated in infants treated with TH for HIE. CLON stabilizes CBT in the ideal range during cooling, which may be optimal for neuroprotection.
Assuntos
Hipotermia Induzida , Hipóxia-Isquemia Encefálica , Doenças do Recém-Nascido , Clonidina/uso terapêutico , Humanos , Hipóxia-Isquemia Encefálica/terapia , Lactente , Recém-Nascido , Doenças do Recém-Nascido/terapia , Morfina , Projetos Piloto , Estudos ProspectivosRESUMO
INTRODUCTION: The study objective was to evaluate the efficacy of different dosages of caspofungin in the treatment of invasive candidiasis and aspergillosis, in relation to the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment, using modelling and Monte Carlo simulations in critically ill adult patients on continuous haemodiafiltration. METHODS: Critically ill adult patients on continuous venovenous haemodiafiltration treated with caspofungin were analysed. A population PK model was developed. Four caspofungin dosing regimens were simulated: the licensed regimen, 70 mg/day, 100 mg/day or 200 mg/day. A PK/PD target was defined as the ratio between the area under the caspofungin concentration-time curve over 24 hours and the minimal inhibitory concentration (AUC/MIC) for candidiasis or the minimal effective concentrations (AUC/MEC) for Aspergillus spp. Target attainment based on preclinical target for Candida and Aspergillus was assessed for different MIC or MEC, respectively. RESULTS: Concentration-time data were described by a two-compartment model. Body-weight and protein concentration were the only covariates identified by the model. Goodness-of-fit plots and bootstrap analysis proved the model had a satisfactory performance. As expected, a higher maintenance dose resulted in a higher exposure. Target attainment was >90% for candidiasis (MIC≤0.06 mg/L) and aspergillosis (MEC≤0.5 mg/L), irrespective of the dosing regimen, but not for C. parapsilosis. Standard regimen was insufficient to reach the target for C. albicans and C. parapsilosis with MIC≥0.1 mg/L. CONCLUSION: The licensed regimen of caspofungin is insufficient to achieve the PK/PD targets in critically ill patients on haemodiafiltration. The determination of MICs will enable dose scheme selection.
Assuntos
Candidíase Invasiva/tratamento farmacológico , Candidíase/tratamento farmacológico , Equinocandinas/administração & dosagem , Equinocandinas/uso terapêutico , Aspergilose Pulmonar Invasiva/tratamento farmacológico , Lipopeptídeos/administração & dosagem , Lipopeptídeos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/farmacologia , Aspergillus/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Candida glabrata/efeitos dos fármacos , Candida parapsilosis/efeitos dos fármacos , Caspofungina , Estado Terminal , Feminino , Hemodiafiltração , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Radioisótopos de Carbono/química , Tomografia por Emissão de Pósitrons , Rifampina/uso terapêutico , Tuberculose Meníngea/diagnóstico por imagem , Tuberculose Meníngea/tratamento farmacológico , Animais , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Encéfalo/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Probabilidade , Coelhos , Rifampina/farmacocinética , Rifampina/farmacologia , Fatores de Tempo , Distribuição Tecidual/efeitos dos fármacosRESUMO
PURPOSE: Lenalidomide disease-specific toxicity profiles and potentially life-threatening adverse events support the consideration of diversity in starting doses. The aim of this study was to conduct a population pharmacokinetic analysis of lenalidomide in multiple myeloma patients to identify and evaluate non-studied covariates that could be used for dose individualization. METHODS: Blood samples were collected from 15 multiple myeloma patients. Nonlinear mixed-effects modeling was used to develop a population pharmacokinetic model and perform covariate analysis. The developed model was used to simulate dose schedules in order to explore the need of different dosing regimens in patients with different covariate values. RESULTS: The data were accurately described by a one-compartment model with first-order elimination. Absorption was best described using three transit compartments. Creatinine clearance and body surface area were identified as covariates affecting apparent clearance and apparent volume of distribution, respectively. Simulations revealed that lower starting doses than the standard 25 mg/daily could be used in patients with body surface area below 1.8 m2 and even higher doses might be necessary for patients with normal renal function and large body surface area. CONCLUSIONS: This study identified creatinine clearance and body surface area as covariates that have a clinically relevant impact on lenalidomide pharmacokinetics using population pharmacokinetics. In addition, the developed population pharmacokinetic model can be used to individualize lenalidomide dose in multiple myeloma patients, taking into account not only creatinine clearance but also body surface area.
Assuntos
Inibidores da Angiogênese/farmacocinética , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Superfície Corporal , Creatinina/metabolismo , Humanos , Lenalidomida , Modelos Biológicos , Talidomida/farmacocinéticaRESUMO
BACKGROUND: The 2015/2016 influenza season was characterized in Europe by the circulation of A(H1N1)pdm09 clade 6B.1 and B/Victoria-lineage influenza viruses. The components of the vaccines used in the current and past two seasons in the Valencia region were similar but not well matched to the 2015/2016 dominant influenza-circulating strains. We estimate influenza vaccine effectiveness (IVE) and interference of previous vaccination in preventing admission with A(H1N1)pdm09 or B/Victoria-lineage in this particular season. METHODS: The Valencia Hospital Network for the Study of Influenza runs an active surveillance hospital-based study to collect clinical and virological data from consecutive admissions possibly related to influenza. Combined nasopharyngeal and pharyngeal swabs are analyzed by reverse transcription polymerase chain reaction, and the hemagglutinin is sequenced in a sample of positive influenza specimens. Vaccination is ascertained consulting a population vaccine information system. We estimate IVE using a test-negative approach. RESULTS: During the 2015-2016 season, we recruited 1049 eligible admissions of patients 60â¯years or older, and 187 tested positive for influenza. The adjusted IVE in preventing admission with A(H1N1)pdm09 was 20.2%; 95% confidence interval (CI) -21.3-47.5% and -33.2%; 95% CI, -140.1-26.1% in preventing admission with B/Victoria-lineage. The majority of A(H1N1)pdm09 sequenced viruses belonged to the emerging 6B.1 subclade, defined by S162N and I216T mutations in the hemagglutinin protein. When we restricted our analysis to those not vaccinated in the previous year, unadjusted IVE was 84.9% (95% CI 9.9-100.0) overall, 77.9% (-32.7-100.0%) in preventing A(H1N1)pdm09 and 48.8% (-219.5-100.0%) in preventing B/Yamagata-lineage admission. CONCLUSIONS: Our findings indicate that IVE was low in preventing A(H1N1)pdm09 and strongly correlated with vaccination in the previous season. No effect in preventing admission with B/Victoria-lineage was observed. For the 2015/2016 season, IVE was low due to a mismatch and lack of concordance between the circulating and vaccine viruses.
Assuntos
Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza B/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/epidemiologia , Influenza Humana/prevenção & controle , Potência de Vacina , Idoso , Antígenos Virais/genética , Monitoramento Epidemiológico , Europa (Continente)/epidemiologia , Feminino , Testes de Inibição da Hemaglutinação , Hospitalização , Humanos , Vírus da Influenza A Subtipo H3N2/imunologia , Vacinas contra Influenza/administração & dosagem , Influenza Humana/imunologia , Masculino , Pessoa de Meia-Idade , RNA Viral/genética , Vigilância de Evento Sentinela , Análise de Sequência de DNA , VacinaçãoRESUMO
The objective of this study was to compare the efficacy of sofosbuvir-based treatments in patients with chronic hepatitis C virus (HCV) infection using a model-based meta-analysis (MBMA). A bibliographic search was performed to identify clinical trials involving sofosbuvir as a unique direct-acting antiviral (DAA) agent or together with daclatasvir, ledipasvir or simeprevir for the treatment of diagnosed HCV infection. The time course of the virological response (VR) was modelled to estimate the effect of treatment and the influence of population characteristics on the longitudinal efficacy profile. The model was validated and simulations of 10 different treatment schedules were performed. Data from 19 clinical trials were included in the analysis. According to the developed model, therapy with sofosbuvir+ledipasvir is the most effective therapy in all scenarios, but it does not differ greatly in terms of sustained VR with respect to other combinations of DAA treatments. In conclusion, this MBMA generates knowledge regarding hypothetical head-to-head trials that have not been conducted previously. Therapies with sofosbuvir+ledipasvir are probably the most effective sofosbuvir-based treatments.
Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Imidazóis/uso terapêutico , Simeprevir/uso terapêutico , Sofosbuvir/uso terapêutico , Carbamatos , Quimioterapia Combinada , Feminino , Hepacivirus/efeitos dos fármacos , Humanos , Masculino , Modelos Teóricos , Pirrolidinas , Valina/análogos & derivadosRESUMO
A wide linearity range analytical method for the determination of lenalidomide in patients with multiple myeloma for pharmacokinetic studies is required. Plasma samples were ultrasonicated for protein precipitation. A solid-phase extraction was performed. The eluted samples were evaporated to dryness under vacuum, and the solid obtained was diluted and injected into the high-performance liquid chromatography (HPLC) system. Separation of lenalidomide was performed on an Xterra RP C18 (250 mm length × 4.6 mm i.d., 5 µm) using a mobile phase consisting of phosphate buffer/acetonitrile (85:15, v/v, pH 3.2) at a flow rate of 0.5 mL · min-1 The samples were monitored at a wavelength of 311 nm. A linear relationship with good correlation coefficient (r = 0.997, n = 9) was found between the peak area and lenalidomide concentrations in the range of 100 to 950 ng · mL-1 The limits of detection and quantitation were 28 and 100 ng · mL-1, respectively. The intra- and interassay precisions were satisfactory, and the accuracy of the method was proved. In conclusion, the proposed method is suitable for the accurate quantification of lenalidomide in human plasma with a wide linear range, from 100 to 950 ng · mL-1 This is a valuable method for pharmacokinetic studies of lenalidomide in human subjects.