RESUMO
Amphotericin B (AMB) is a polyene macrolide antifungal agent used for treating invasive fungal infections. Liposomal AMB is a lipid dosage form, available as AmBisome, which reduces the toxicity of the drug. A simple HPLC-UV method was developed for the determination of AMB in plasma to study its pharmacokinetic profile in a critical patient receiving AmBisome and treated with extracorporeal replacement therapies. Sample preparation was performed using plasma deproteinization and drug release from liposome by the addition of acetonitrile (ACN)/zinc sulfate and ultrasonication. Chromatographic separation was performed using a C18 column and a mobile phase consisting of phosphate buffer (pH 3.0)/ACN (65/35, v/v). The UV detector was set at 407 nm. The total run time analysis was 23 min. The method was validated according to the standard guidelines and applied to study the pharmacokinetics of AMB in a critical patient. The total run time analysis obtained was shorter than that of the previously reported methods, being useful for therapeutic drug monitoring or pharmacokinetic profile research.
Assuntos
Anfotericina B , Antifúngicos , Humanos , Anfotericina B/uso terapêutico , Anfotericina B/farmacocinética , Cromatografia Líquida de Alta Pressão , Antifúngicos/uso terapêutico , Antifúngicos/farmacocinética , LipossomosRESUMO
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
Stability studies are necessary in healthcare settings as they facilitate fast, cost-effective and efficient work related to batch manufacturing and availability of supplies. We studied the stability of 1-10 mg/mL mycophenolate mofetil (MMF) in polypropylene 5% dextrose infusion bags prepared from Cellcept® and with a generic brand name (Micofenolato de Mofetilo Accord) at different storage temperatures. To ensure chemical compatibility during preparation, we also tested MMF sorption to the Equashield® closed-system drug transfer device used in this step. For this, a validated stability-indicating high-performance liquid chromatography method was developed for the quantification and identification of MMF in the infusion bags. The analytical selectivity of the assay was determined by subjecting an MMF sample to extreme values of pH, oxidative stress and heat conditions to force degradation. Protected from light, 1-10 mg/mL MMF in infusion polypropylene bags prepared from reconstituted Cellcept® 500 mg or Accord 500 mg in 5% dextrose was stable for at least 35 days when stored at 2-8°C or between -15 and -25°C, and for 14 days when stored at 25°C. MMF loss owing to chemical sorption to the Equashield® closed-system drug transfer device set was negligible.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Glucose/química , Ácido Micofenólico , Polipropilenos/química , Cromatografia Líquida de Alta Pressão , Estabilidade de Medicamentos , Ácido Micofenólico/análise , Ácido Micofenólico/químicaRESUMO
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
There is a paucity of data evaluating acute kidney injury (AKI) incidence and its relationship with the tacrolimus-sirolimus (Tac-Sir) concentrations in the setting of reduced-intensity conditioning (RIC) after allogeneic stem cell transplantation (allo-HSCT). This multicenter retrospective study evaluated risk factors of AKI defined by 2 classification systems, Kidney Disease Improving Global Outcome (KDIGO) score and "Grade 0-3 staging," in 186 consecutive RIC allo-HSCT recipients with Tac-Sir as graft-versus-host disease prophylaxis. Conditioning regimens consisted of fludarabine and busulfan (n = 53); melphalan (n = 83); or a combination of thiotepa, fludarabine, and busulfan (n = 50). A parametric model, with detailed Tac-Sir consecutive blood levels, describing time to AKI was developed using the NONMEM software version 7.4. Overall, 81 of 186 (44%) RIC allo-HSCT recipients developed AKI with a cumulative incidence of 42% at a median follow-up of 25 months. Time to AKI was best described using a piecewise function. AKI-predicting factors were melphalan-based conditioning regimen (HR, 1.96; P < .01), unrelated donor (HR, 1.79; P = .04), and tacrolimus concentration: The risk of AKI increased 2.3% per each 1-ng/mL increase in tacrolimus whole blood concentration (P < .01). In multivariate analysis, AKI grades 2 and 3 according to KDIGO staging were independent risk factors for 2-year nonrelapse mortality (HR, 2.8; P = .05; and HR, 6.6; P < .0001, respectively). According to the KDIGO score, overall survival decreased with the increase in severity of AKI: 78% for patients without AKI versus 68%, 50%, and 30% for grades 1, 2, and 3, respectively (P < .0001). In conclusion, AKI is frequent after Tac-Sir-based RIC allo-HSCT and has a negative impact on outcome. This study presents the first predictive model describing time to AKI as a function of tacrolimus drug concentration.
Assuntos
Injúria Renal Aguda/etiologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/métodos , Sirolimo/uso terapêutico , Tacrolimo/uso terapêutico , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Sirolimo/farmacologia , Tacrolimo/farmacologia , Adulto JovemRESUMO
AIMS: To evaluate the effectiveness of nivolumab as second-line treatment compared to standard therapy with docetaxel in adult patients with non-small cell lung cancer (NSCLC) in clinical practice. METHODS: This is an observational, retrospective cohort study of adult patients diagnosed with NSCLC, stage III-IV, treated with docetaxel or nivolumab as second-line treatment. The end points evaluated were overall survival (OS) and progression-free survival (PFS). PFS and OS were described using the Kaplan-Meier method. The Cox proportional hazards model was applied to identify independent prognostic and predictive factors related to disease progression or death. RESULTS: Thirty-three patients were included in this study (i.e., 14 in the nivolumab group and 19 in the docetaxel group). Nonsquamous NSCLC was the most frequent histological subtype. Cohorts were homogeneous. The follow-up time was 116 ± 87.3 days. The median PFS was 84 days (95% CI 39-300) for patients treated with nivolumab and 61 days (95% CI 48-76) for patients treated with docetaxel. The risk of progression was 60% lower for patients treated with nivolumab (HR 0.40; 95% CI 0.16-0.97; p = 0.043) compared to patients receiving docetaxel. Among the patients treated with docetaxel, the median OS was 129 days (95% CI 106-300). More than 50% of the patients treated with nivolumab were alive at the end of the follow-up period; nevertheless, the risk difference was not statistically significant (HR 0.55; 95% CI 0.20-1.51; p = 0.244). CONCLUSION: NSCLC patients treated with nivolumab as second-line therapy had a longer PFS compared to patients treated with docetaxel in a health care environment.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Taxoides/uso terapêutico , Idoso , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Intervalo Livre de Doença , Docetaxel , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Nivolumabe , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Anti-TNF dose modifications in rheumatoid arthritis have implications on healthcare resource utilization. The objective was to systematically review the dose modifications, both escalations and reductions, of currently available anti-TNF drugs (adalimumab, certolizumab, etanercept, golimumab and infliximab) in the real-world setting. We performed a systematic literature search of MEDLINE, ISI Web of Science, EMBASE, Indice Médico Español databases and American College of Rheumatology and European League Against Rheumatism annual congresses databases. PRISMA and MOOSE guidelines were followed. Only observational studies were included. Clinical trials were excluded since they do not reflect routine clinical practice. Dose escalations and reductions of the anti-TNF drug and their magnitude were collected. Thirty-four studies fulfill the inclusion criteria. Etanercept was associated with the lower percentage of patients under dose escalation (4.5 %; range 0-22 %), both in naïve (4.9 %) and non-naïve patients (1.3 %). Adalimumab and infliximab were associated with significantly higher percentages. Dose modification magnitude in those patients compared to basal dose was significantly different between treatments; 7.1 % (95 % CI 6.3-7.9 %) in etanercept, 30.4 % (95 % CI 28.3-32.5 %) in adalimumab and 21 % (95 % CI 20.3-21.7 %) in infliximab. Adalimumab and infliximab were associated with a higher risk of dose escalation relative to etanercept. There were no significant differences in the dose reduction percentages for the whole group of patients between treatments. In rheumatoid arthritis, etanercept is associated with a significantly lower percentage of dose-escalated patients and a lower magnitude of dose modification. Significant differences in the dose reduction between anti-TNF drugs evaluated were not observed.
Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/administração & dosagem , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Produtos Biológicos/efeitos adversos , Distribuição de Qui-Quadrado , Cálculos da Dosagem de Medicamento , Humanos , Razão de Chances , Fatores de Risco , Resultado do Tratamento , Fator de Necrose Tumoral alfa/imunologiaRESUMO
BACKGROUND: Infliximab, an anti-tumour necrosis factor approved for treatment of Crohn´s disease and ulcerative colitis, is administered at predefined interdose intervals. On insufficient response or loss of response, treatment can be intensified. The lack or loss of response is likely related to complex pharmacokinetics of infliximab. AIMS: To explore optimal dosing strategies of infliximab in treatment-naïve patients with ulcerative colitis through predictive Monte Carlo simulations based on a validated population PK model. METHODS: A population of 2,000 treatment-naïve patients was generated by Montecarlo simulation. Six dosing strategies for maintenance therapy were simulated on this population. Strategies 1 and 2 consisted on 5 mg/kg and 6 mg/kg doses, respectively, and 8 weeks inter-dose interval. Strategies 3 and 4 used Individualized doses, adjusted to albumin level, sex and body weight, and a fix interdose interval of 8 weeks to achieve a target trough concentration of 5 mg/L or 6 mg/L, respectively. Strategies 5 and 6 used a fix dose of 5 mg/kg and individualized inter-dose intervals, adjusted to the same covariates, to achieve a target concentration, of 5 mg/L or 6 mg/L, respectively. RESULTS: Strategies 2-6 reached trough levels statistically higher than strategy 1 (p < 0.05). Strategy 5 proved to be the best dosing strategy. It was associated with a higher proportion of responder patients than strategy 1 (62 % vs. 40 %) without reaching higher peak concentrations. CONCLUSIONS: Optimization of maintenance treatment of colitis with infliximab by a pharmacokinetic approach could benefit infliximab-naive patients with ulcerative colitis.
Assuntos
Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/metabolismo , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/farmacocinética , Infliximab/administração & dosagem , Infliximab/farmacocinética , Simulação por Computador , Relação Dose-Resposta a Droga , Feminino , Fármacos Gastrointestinais/uso terapêutico , Humanos , Infliximab/uso terapêutico , Masculino , Modelos Estatísticos , Método de Monte Carlo , Resultado do TratamentoAssuntos
Estado Terminal/classificação , Equinocandinas/química , Lipopeptídeos/química , Obesidade Mórbida/sangue , Antifúngicos/efeitos adversos , Antifúngicos/química , Antifúngicos/uso terapêutico , Candidíase , Caspofungina , Estado Terminal/epidemiologia , Equinocandinas/efeitos adversos , Equinocandinas/uso terapêutico , Humanos , Unidades de Terapia Intensiva/organização & administração , Lipopeptídeos/efeitos adversos , Lipopeptídeos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/complicações , Choque SépticoRESUMO
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
AIM: A simple, rapid, economical and sensitive HPLC-UV method was developed for the simultaneous quantification of ceftolozane and tazobactam in plasma samples. METHODOLOGY: After deproteinization followed by a liquid-liquid back-extraction, the compounds were separated on a C18 column (150 mm × 4.6 mm, 5 µm) with UV-visible detection at 220 nm. The mobile phase consisted of acetonitrile and potassium dihydrogenphosphate buffer at pH 3.0 (8:92, v/v), delivered isocratically at a flow rate of 1.0 ml/min and at a column oven temperature of 30°C. Cefepime was used as an internal standard. RESULTS: Linearity was achieved in the concentration range of 0.50-100.00 µg/ml for ceftolozane and 0.25-50.00 µg/ml for tazobactam. The intra- and interday precision showed good reproducibility with coefficients of variation of less than 9.26% for ceftolozane and 9.62% for tazobactam. CONCLUSION: The sample preparation procedure avoids expensive or time-consuming steps used by other previously published methods. The methodology was validated according to standard guidelines and was used for quantification of ceftolozane and tazobactam in plasma samples from critically ill patients.
Assuntos
Antibacterianos/sangue , Cefalosporinas/sangue , Cromatografia Líquida de Alta Pressão/métodos , Ácido Penicilânico/análogos & derivados , Plasma/química , Humanos , Ácido Penicilânico/sangue , TazobactamRESUMO
PURPOSE: The stability of 0.3-mg/mL tacrolimus ophthalmic solution at different storage temperatures was studied. METHODS: A sterile ophthalmic solution of 0.3 mg/mL tacrolimus was prepared in triplicate under aseptic conditions by diluting tacrolimus in eye drops. Three aliquots of this solution were transferred into polypropylene bottles and stored at 25, 2-8, or -15 to -25 °C. Samples were collected immediately after preparation and at selected time points and assayed in triplicate using high-performance liquid chromatography (HPLC). Samples were also visually examined for macroscopic changes. The 0.3-mg/mL tacrolimus solution was also exposed to acidic treatment and heat to force its degradation and to evaluate the selectivity of the analytic method. The tacrolimus ophthalmic solution was considered stable if at least 90% of the mean initial concentration remained when analyzed by HPLC. RESULTS: When stored at 2-8 °C and between -15 and -25 °C, at least 90% of the initial tacrolimus concentration remained throughout the 85-day study period. There were no significant differences in tacrolimus concentrations between the starting and ending points (p > 0.05). However, when tacrolimus solution was stored at 25 °C, the percentage of the initial tacrolimus concentration remaining had decreased to less than 90% on day 28. CONCLUSION: Tacrolimus diluted to 0.3 mg/mL in eye drop solution was stable for 20 days when stored at 25 °C and for at least 85 days when stored at 2-8 °C or between -15 and -25 °C in polypropylene bottles and protected from light.
Assuntos
Imunossupressores/química , Soluções Oftálmicas/química , Tacrolimo/química , Administração Oftálmica , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Armazenamento de Medicamentos/métodos , Armazenamento de Medicamentos/normas , Humanos , Imunossupressores/administração & dosagem , Soluções Oftálmicas/análise , Soluções Farmacêuticas/análise , Soluções Farmacêuticas/química , Tacrolimo/análise , TemperaturaRESUMO
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
BACKGROUND: CYP2D6 is a key enzyme in tamoxifen metabolism, transforming it into its main active metabolite, endoxifen. Poor CYP2D6 metabolizers (PM) have lower endoxifen plasma concentrations and possibly benefit less from treatment with tamoxifen. We evaluated tamoxifen dose adjustment in CYP2D6 PM patients in order to obtain plasma concentrations of endoxifen comparable to patients with extensive CYP2D6 metabolism (EM). PATIENTS AND METHODS: Comprehensive CYP2D6 genotyping and plasma tamoxifen metabolite concentrations were performed among 249 breast cancer patients in adjuvant treatment with tamoxifen. Tamoxifen dose was increased in PM patients to 40 mg and to 60 mg daily for a 4-month period each, repeating tamoxifen metabolite measurements on completion of each dose increase. We compared the endoxifen levels between EM and PM patients, and among the PM patients at each dose level of tamoxifen (20, 40 and 60 mg). RESULTS: Eleven PM patients (4.7%) were identified. The mean baseline endoxifen concentration in EM patients (11.30 ng/ml) was higher compared to the PM patients (2.33 ng/ml; p < 0.001). In relation to the 20 mg dose, increasing the tamoxifen dose to 40 and 60 mg in PM patients significantly raised the endoxifen concentration to 8.38 ng/ml (OR 3.59; p = 0.013) and to 9.30 ng/ml (OR 3.99; p = 0.007), respectively. These concentrations were comparable to those observed in EM patients receiving 20 mg of tamoxifen (p = 0.13 and p = 0.64, respectively). CONCLUSION: In CYP2D6 PM patients, increasing the standard tamoxifen dose two-fold or three-fold raises endoxifen concentrations to levels similar to those of patients with EM phenotype.