RESUMEN
The pharmacokinetics (PK) of drugs are known to be significantly altered in patients receiving extracorporeal membrane oxygenation (ECMO). However, clinical studies of the PK of drugs administered during ECMO are scarce, and the proper dosing adjustment has yet to be established. We developed a population PK model for teicoplanin, investigated covariates influencing teicoplanin exposure, and suggested an optimal dosing regimen for ECMO patients. Samples for PK analysis were collected from 10 adult patients, and a population PK analysis and simulations were performed to identify an optimal teicoplanin dose needed to provide a >50% probability of target attainment at 72 h using a trough concentration target of >10 µg/ml for mild to moderate infections and a trough concentration target of >15 µg/ml for severe infections. Teicoplanin was well described by a two-compartment PK model with first-order elimination. The presence of ECMO was associated with a lower central volume of distribution, and continuous renal replacement therapy (CRRT) was associated with a higher peripheral volume of distribution. For mild to moderate infections, an optimal dose was a loading dose (LD) of 600 mg and a maintenance dose (MD) of 400 mg for ECMO patients not receiving CRRT and an LD of 800 mg and an MD of 600 mg for those receiving CRRT. For severe infections, an optimal dose was an LD of 1,000 mg and an MD of 800 mg for ECMO patients not receiving CRRT and an LD of 1,200 mg and an MD of 1,000 mg for those receiving CRRT. In conclusion, doses higher than the standard doses are needed to achieve fast and appropriate teicoplanin exposure during ECMO. (This study has been registered at ClinicalTrials.gov under identifier NCT02581280.).
Asunto(s)
Antibacterianos/farmacocinética , Oxigenación por Membrana Extracorpórea , Choque Cardiogénico/terapia , Teicoplanina/farmacocinética , Adulto , Anciano , Enfermedad Crítica , Femenino , Enfermedades de las Válvulas Cardíacas/terapia , Humanos , Masculino , Persona de Mediana Edad , Método de Montecarlo , Micosis/prevención & control , Infarto del Miocardio/terapia , Miocarditis/terapia , Estudios Prospectivos , Terapia de Reemplazo Renal , Adulto JovenRESUMEN
BACKGROUND: An optimal therapy for the treatment of pneumonia caused by drug-resistant Acinetobacter baumannii remains unclear. This study aims to compare various antimicrobial strategies and to determine the most effective therapy for pneumonia using a network meta-analysis. METHODS: Systematic search and quality assessment were performed to select eligible studies reporting one of the following outcomes: all-cause mortality, clinical cure, and microbiological eradication. The primary outcome was all-cause mortality. A network meta-analysis was conducted with a Bayesian approach. Antimicrobial treatments were ranked based on surface under the cumulative ranking curve (SUCRA) value along with estimated median outcome rate and corresponding 95% credible intervals (CrIs). Two treatments were considered significantly different if a posterior probability of superiority (P) was greater than 97.5%. RESULTS: Twenty-three studies evaluating 15 antimicrobial treatments were included. Intravenous colistin monotherapy (IV COL) was selected as a common comparator, serving as a bridge for developing the network. Five treatments ranked higher than IV COL (SUCRA, 57.1%; median all-cause mortality 0.45, 95% CrI 0.41-0.48) for reducing all-cause mortality: sulbactam monotherapy (SUL, 100.0%; 0.18, 0.04-0.42), high-dose SUL (HD SUL, 85.7%; 0.31, 0.07-0.71), fosfomycin plus IV COL (FOS + IV COL, 78.6%; 0.34, 0.19-0.54), inhaled COL plus IV COL (IH COL + IV COL, 71.4%; 0.39, 0.32-0.46), and high-dose tigecycline (HD TIG, 71.4%; 0.39, 0.16-0.67). Those five treatments also ranked higher than IV COL (SUCRA, 45.5%) for improving clinical cure (72.7%, 72.7%, 63.6%, 81.8%, and 90.9%, respectively). Among the five treatments, SUL (P = 98.1%) and IH COL + IV COL (P = 99.9%) were significantly superior to IV COL for patient survival and clinical cure, respectively. In terms of microbiological eradication, FOS + IV COL (P = 99.8%) and SUL (P = 98.9%) were significantly superior to IV COL. CONCLUSIONS: This Bayesian network meta-analysis demonstrated the comparative effectiveness of fifteen antimicrobial treatments for drug-resistant A. baumannii pneumonia in critically ill patients. For survival benefit, SUL appears to be the best treatment followed by HD SUL, FOS + IV COL, IH COL + IV COL, HD TIG, and IV COL therapy, in numerical order.
Asunto(s)
Acinetobacter baumannii/efectos de los fármacos , Farmacorresistencia Bacteriana/efectos de los fármacos , Acinetobacter baumannii/patogenicidad , Antiinfecciosos/farmacología , Antiinfecciosos/uso terapéutico , Teorema de Bayes , Colistina/farmacología , Colistina/uso terapéutico , Enfermedad Crítica/terapia , Humanos , Pruebas de Sensibilidad Microbiana/métodosRESUMEN
PURPOSE: Long-term data are limited on the safety and efficacy of dupilumab in patients with uncontrolled, moderate-to-severe asthma from Korea. The current subgroup analysis was designed to evaluate the long-term safety and efficacy of dupilumab in patients enrolled from Korean centers in the parent studies (phase 2b and QUEST) and who participated in the TRAVERSE open-label extension (OLE) study. METHODS: TRAVERSE was a global, multicenter, OLE study that assessed the safety and efficacy of dupilumab 300 mg every 2 weeks for up to 96 weeks in patients (n = 2,282) with uncontrolled, moderate-to-severe asthma who completed prior dupilumab asthma clinical trials. The primary outcome was the incidence of any treatment-emergent adverse events (TEAEs); the secondary outcomes included annualized severe exacerbation rate, pre-bronchodilator forced expiratory volume in 1 second (pre-BD FEV1), and 5-item Asthma Control Questionnaire (ACQ-5) score. RESULTS: Safety outcomes were consistent with the parent studies and the overall TRAVERSE population; out of 74 patients, 70 experienced ≥ 1 TEAE, and 6 (8.1%) discontinued because of adverse events. During the treatment period, the unadjusted annualized severe exacerbation rate was low (0.470). Improvement in pre-BD FEV1 was seen as early as Week 2 with a mean change from the parent study baseline (PSBL), standard deviation (SD) of 0.42 L (0.47), which was sustained until Week 96. Mean change from PSBL (SD) in ACQ-5 score was -1.32 (0.76) at Week 48. CONCLUSIONS: This subgroup analysis of TRAVERSE showed the long-term safety and efficacy of dupilumab in patients with uncontrolled, moderate-to-severe asthma enrolled from Korean centers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02134028.
RESUMEN
The present study was intended to prepare and optimize agomelatine-loaded nanostructured lipid carriers (AGM-NLCs) for augmented in vivo antidepressant potential. AGM-NLCs were optimized on several parameters including cumulative hydrophilic-lipophilic balance of surfactants, proportions of solid and liquid lipids, total amounts of drug and surfactants. AGM-NLCs were assessed for their physicochemical properties, in vitro AGM release and in vivo antidepressant effects in mice model. The optimized AGM-NLCs demonstrated spherical morphology with average particle size of 99.8 ± 2.6 nm, PDI of 0.142 ± 0.017, zeta potential of - 23.2 ± 1.2 mV and entrapment efficiency of 97.1 ± 2.1%. Thermal and crystallinity studies depict amorphous nature of AGM after its incorporation into NLCs. AGM-NLCs exhibit a sustained drug release profile after initial 2 h. Mice treated with AGM-NLCs exhibited reduced immobility time in behavioral analysis. Furthermore, cresyl violet staining demonstrated an improved neuronal morphology and survival in AGM-NLCs group. The concentrations and the expression of inflammatory markers (TNF-α and COX-2) in mice brain were significantly reduced by AGM-NLCs. Taken together, therapeutic effectiveness of AGM was markedly augmented in AGM-NLCs and thereby they could be promising nanocarriers for the effective delivery of antidepressants to brain.
Asunto(s)
Portadores de Fármacos , Nanoestructuras , Acetamidas , Animales , Antidepresivos/farmacología , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Lípidos/química , Ratones , Nanoestructuras/química , Naftalenos , Tamaño de la Partícula , Tensoactivos/químicaRESUMEN
Poor aqueous solubility of eplerenone (EPL) is a major obstacle to achieve sufficient bioavailability after oral administration. In this study, we aimed to develop and evaluate eplerenone nanocrystals (EPL-NCs) for solubility and dissolution enhancement. D-optimal combined mixture process using Design-Expert software was employed to generate different combinations for optimization. EPL-NCs were prepared by a bottom-up, controlled crystallization technique during freeze-drying. The optimized EPL-NCs were evaluated for their size, morphology, thermal behavior, crystalline structure, saturation solubility, dissolution profile, in vivo pharmacokinetics, and acute toxicity. The optimized EPL-NCs showed mean particle size of 46.8 nm. Scanning electron microscopy revealed the formation of elongated parallelepiped shaped NCs. DSC and PXRD analysis confirmed the crystalline structure and the absence of any polymorphic transition in EPL-NCs. Furthermore, EPL-NCs demonstrated a 17-fold prompt increase in the saturation solubility of EPL (8.96 vs. 155.85 µg/mL). The dissolution rate was also significantly higher as indicated by â¼95% dissolution from EPL-NCs in 10 min compared to only 29% from EPL powder. EPL-NCs improved the oral bioavailability as indicated by higher AUC, Cmax, and lower Tmax than EPL powder. Acute oral toxicity study showed that EPL-NCs do not pose any toxicity concern to the blood and vital organs. Consequently, NCs prepared by controlled crystallization technique present a promising strategy to improve solubility profile, dissolution velocity and bioavailability of poorly water-soluble drugs.
Asunto(s)
Antihipertensivos/farmacocinética , Eplerenona/farmacocinética , Nanopartículas/química , Administración Oral , Animales , Antihipertensivos/administración & dosificación , Área Bajo la Curva , Peso Corporal , Rastreo Diferencial de Calorimetría , Química Farmacéutica , Liberación de Fármacos , Estabilidad de Medicamentos , Eplerenona/administración & dosificación , Liofilización , Masculino , Tasa de Depuración Metabólica , Ratones , Microscopía Electrónica de Rastreo , Tamaño de la Partícula , Ratas , Ratas Sprague-Dawley , Solubilidad , Difracción de Rayos XRESUMEN
Safety and efficacy outcomes of imatinib treatment were evaluated using extensive clinical data collected from a total of 1003 patients with newly diagnosed chronic myeloid leukemia in chronic phase between 2001 and 2018. By 12 months of imatinib treatment at a fixed dose of 400 mg/day, 45.4% of patients experienced at least one type of dose-limiting toxicities (DLTs). The DLTs that frequently occurred first were thrombocytopenia (40.0%), neutropenia/leukopenia (14.3%) and dermatological reactions (12.1%). Patients with lighter body weight (≤ 64 kg) and older age (> 43 years) experienced a markedly higher occurrence of first DLTs by 12 months than heavier and younger patients (57.9% vs. 30.1%, p < 0.001). On the other hand, 38.9% of patients achieved major molecular response (MMR) at 12 months at the fixed dose. Female patients achieved a greater rate of MMR than male patients (45.6% vs. 35.5%, p = 0.028). In conclusion, patients with light weight and old age are more vulnerable to DLTs, whereas female patients gain more efficacy benefit at the fixed dose. The authors suggest that the initial dose of imatinib should be reduced to 300 mg/day or lower for patients vulnerable to DLTs to diminish the risk of DLTs without compromising the achievement of MMR.
Asunto(s)
Mesilato de Imatinib/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Medicina de Precisión , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Peso Corporal , Femenino , Humanos , Mesilato de Imatinib/efectos adversos , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Seguridad , Trombocitopenia/inducido químicamente , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Radotinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia in chronic phase (CP-CML). Here, using the data from a Phase 3 study conducted in patients with newly diagnosed CP-CML, the dose-efficacy as well as dose-safety relationship analyses were performed to determine a safe and effective initial dosage regimen of radotinib. A significant positive association was detected between the starting dose of radotinib adjusted for body weight (Dose/BW) and the probability of dose-limiting toxicity (≥grade 3 hematologic and nonhematologic toxicity) (P = 0.003). In contrast, a significant inverse association was discovered between Dose/BW and the probability of major molecular response (BCR-ABL1/ABL1 ≤ 0.1%) when controlled for sex (P = 0.033). Moreover, frequent dose interruptions and reductions secondary to radotinib toxicities occurred in the Phase 3 study, resulting in nearly half (44%) of patients receiving a reduced dose at a 12-month follow-up. In conclusion, the results of this study demonstrate the need for initial radotinib dose attenuation to improve the long-term efficacy and safety of radotinib. Hence, the authors suggest a new upfront radotinib dose of 400 mg once daily be tested in patients with newly diagnosed CP-CML.
Asunto(s)
Benzamidas/administración & dosificación , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Pirazinas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Benzamidas/efectos adversos , Relación Dosis-Respuesta a Droga , Cálculo de Dosificación de Drogas , Femenino , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Masculino , Persona de Mediana Edad , Peso Molecular , Pirazinas/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
The present study aimed to assess the clinical impact of BCR-ABL1 transcript levels determined at an earlier time point than the 3-month early molecular response (EMR) in chronic-phase chronic myeloid leukemia (CML-CP) patients. BCR-ABL1 transcript levels of CML-CP patients (n = 258; median age, 43 [range, 18-81] years) treated with various tyrosine kinase inhibitors (TKIs) were determined at 4 weeks (28 ± 3 days) and at every 3 months of treatment initiation. At 4 weeks, receiver operating characteristic curves revealed that cutoff values of BCR-ABL1 transcripts for achieving major molecular responses (MMRs) by 12 and 60 months were 40.89% and 39.16%, respectively (95% CI, 0.658-0.772 and 95% CI, 0.643-0.758; P < 0.0001). With 40% of BCR-ABL1 transcripts at 4 weeks (very early MR; VEMR), patients with VEMR achieved higher 3-month EMR and 4-week VEMR significantly associated with higher cumulative incidences of 5-year MMR (89.1% vs 72.3%; P < 0.001) and 5-year deep molecular response (DMR) (56.5% vs 29.4%; P = 0.001). Furthermore, event-free survival (EFS)-a (93.0% vs 84.8%; P = 0.068) and EFS-b (71.1% vs 57.9%; P = 0.061) by 5 years were also marginally significant. VEMR and 3-month EMR were achieved in 89 patients, with significantly superior outcomes. In multivariate analyses, lower leukocyte count (P = 0.008) and frontline second-generation TKI therapy size (P < 0.001) were significantly associated with VEMR achievement, but not baseline BCR-ABL1 level and CML duration. In conclusion, the 4-week BCR-ABL1 transcript levels including VEMR could be important to predict long-term outcomes and may provide additional information about innate intrinsic sensitivity to CML among individuals.
Asunto(s)
Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Pronóstico , Inhibidores de Proteínas Quinasas/farmacología , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Extracorporeal membrane oxygenation (ECMO) is associated with pharmacokinetic (PK) changes of drugs. It presents considerable challenges to providing optimal dosing regimens for patients receiving ECMO. We aimed to describe the population PK of remifentanil in critically ill adult patients receiving venoartrial extracorporeal membrane oxygenation (VA-ECMO) and to identify determinants associated with altered remifentanil concentrations. The population PK model of remifentanil was developed using nonlinear mixed effects modelling (NONMEM). Fifteen adult patients who received a continuous infusion of remifentanil during VA-ECMO participated in the study. The PK of remifentanil was best described by a one-compartment model with additive and proportional residual errors. Remifentanil concentrations were affected by sex and ECMO pump speed. The final PK model included the effect of sex and ECMO pump speed on clearance is developed as followed: clearance (L/h) = 366 × 0.502sex × (ECMO pump speed/2350)2.04 and volume (L) = 41. Remifentanil volume and clearance were increased in adult patients on VA-ECMO compared with previously reported patients not on ECMO. We suggest that clinicians should consider an increased remifentanil dosing to achieve the desired level of sedation and provide a dosing regimen according to sex and ECMO pump speed.
Asunto(s)
Enfermedad Crítica , Oxigenación por Membrana Extracorpórea/métodos , Remifentanilo/farmacocinética , Remifentanilo/uso terapéutico , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
A fixed dose regimen for tyrosine kinase inhibitors (TKIs) is postulated to be responsible for variable safety outcomes in the treatment of chronic myelogenous leukemia (CML). The objective of this study was to explore an optimal dosing regimen for a TKI, radotinib, to improve its safety profile. Clinical data were obtained from a Phase 2 study of fixed-dose radotinib in 77 Asian patients with CML. The magnitude of radotinib dose adjusted for patient's body weight (Dose/BW) and the probability of dose-limiting toxicity (DLT) demonstrated a positive association (Logit[P] = 0.86*[Dose/BW]-4.45, p = 0.001). There was a significant difference in the Kaplan-Meier curves for time to first DLT between the patient subgroups of Dose/BW <6 and ≥6 mg/kg (259 versus 83 days). Consequently, a two-tier weight-based dosing regimen may improve the safety of radotinib: 300 mg or 400 mg twice daily for patients weighing ≤65 or >65 kg, respectively.