Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 58
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
PLoS One ; 16(11): e0260656, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34818379

RESUMO

Therapeutic drug monitoring (TDM) is essential for voriconazole to ensure optimal drug exposure, mainly in critically ill patients for whom voriconazole demonstrated a large variability. The study aimed at describing factors associated with trough voriconazole concentrations in critically ill patients and evaluating the impact of voriconazole concentrations on adverse effects. A 2-year retrospective multicenter cohort study (NCT04502771) was conducted in six intensive care units. Adult patients who had at least one voriconazole TDM were included. Univariable and multivariable linear regression analyses were performed to identify predictors of voriconazole concentrations, and univariable logistic regression analysis, to study the relationship between voriconazole concentrations and adverse effects. During the 2-year study period, 70 patients were included. Optimal trough voriconazole concentrations were reported in 37 patients (52.8%), subtherapeutic in 20 (28.6%), and supratherapeutic in 13 (18.6%). Adverse effects were reported in six (8.6%) patients. SOFA score was identified as a factor associated with an increase in voriconazole concentration (p = 0.025), mainly in the group of patients who had SOFA score ≥ 10. Moreover, an increase in voriconazole concentration was shown to be a risk factor for occurrence of adverse effects (p = 0.011). In that respect, critically ill patients who received voriconazole treatment must benefit from a TDM, particularly if they have a SOFA score ≥ 10. Indeed, identifying patients who are overdosed will help to prevent voriconazole related adverse effects. This result is of utmost importance given the recognized COVID-19-associated pulmonary aspergillosis in ICU patients for whom voriconazole is among the recommended first-line treatment.

2.
Front Med (Lausanne) ; 8: 583086, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33869238

RESUMO

Suppressive parenteral antibiotic therapy with beta-lactams may be necessary in patients with Gram-negative bone and joint infection (BJI). Subcutaneous drug administration can facilitate this therapy in outpatient setting, but there is limited information about this practice. We have developed an original approach for drug dosing in this context, based on therapeutic drug monitoring (TDM) and pharmacokinetic/pharmacodynamic (PK/PD) principles. The objective of this study was to describe our approach and its first results in a case series. We analyzed data from patients who received suppressive antibiotic therapy by subcutaneous (SC) route with beta-lactams as salvage therapy for prosthetic joint infection (PJI) and had TDM with PK/PD-based dose adjustment. Ten patients (six women and four men with a mean age of 77 years) were included from January 2017 to May 2020. The drugs administered by SC route were ceftazidime (n = 4), ertapenem (n = 4), and ceftriaxone (n = 2). In each patient, PK/PD-guided dosage individualization was performed based on TDM and minimum inhibitory concentration (MIC) measurements. The dose interval could be prolonged from twice daily to thrice weekly in some patients, while preserving the achievement of PK/PD targets. The infection was totally controlled by the strategy in nine out the 10 patients during a median follow-up of 1,035 days (~3 years). No patient acquired carbapenem-resistant Gram-negative bacteria during the follow-up. One patient presented treatment failure with acquired drug resistance under therapy, which could be explained by late MIC determination and insufficient exposure, retrospectively. To conclude, our innovative approach, based on model-based TDM, MIC determination, and individualized PK/PD goals, facilitates, and optimizes suppressive outpatient beta-lactam therapy administered by SC route for PJI. These encouraging results advocate for larger clinical evaluation.

3.
Sci Rep ; 11(1): 6187, 2021 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-33731863

RESUMO

Accumulation in target cells is an essential pharmacokinetic step of targeted therapies. Tyrosine Kinase Inhibitors (TKI) against the BCR-ABL fusion protein in Chronic Phase-Chronic Myeloid Leukaemia (CP-CML) cells constitute a unique model in terms of efficacy, specificity, and in vivo demonstration of response heterogeneity by target cells. The overall therapeutic response to nilotinib is heterogeneous with no satisfactory explanation. To better understand the patients' response heterogeneity, we quantified nilotinib uptake by primary CP-CML cells in standardized conditions using flow cytometry, which allowed also distinguishing mature (polymorphonuclear cells) from immature (CD34+) cells. Nilotinib was undetectable in 13.3% of PMN and 40% of CD34+ cells. Moreover, in CD34+ cells, intracellular nilotinib did not completely abolish BCR-ABL activity (monitored by CrkL phosphorylation inhibition), although nilotinib accumulated well in most CD34+ cell samples. Intracellular nilotinib concentration was inversely correlated with disease burden parameters, Sokal score, and early haematologic response at day 6 ± 1 only in PMN, suggesting an intrinsic ability to limit nilotinib entry in the forms with higher tumor cell burdenat diagnosis. These findings suggest that nilotinib accumulation in CP-CML cells is influenced by individual characteristics and intra-clonal heterogeneity, and might be used for pharmacokinetic studies and to assess the therapeutic response.


Assuntos
Antígenos CD34/imunologia , Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia Mieloide de Fase Crônica , Pirimidinas/farmacologia , Humanos , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Leucemia Mieloide de Fase Crônica/imunologia , Leucemia Mieloide de Fase Crônica/patologia , Células Tumorais Cultivadas
4.
J Antimicrob Chemother ; 76(5): 1250-1257, 2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33550409

RESUMO

BACKGROUND: Daptomycin is increasingly used in the treatment of bone and joint infection (BJI), but its pharmacokinetics (PK) and dosage requirements have not been thoroughly investigated in this indication. Daptomycin may be co-administered with rifampicin, which raises questions about a potential drug interaction. OBJECTIVES: To investigate the population PK and dosage requirements of daptomycin in patients with BJI, and examine the influence of rifampicin co-administration. METHODS: A population approach was used to analyse PK data from patients who received daptomycin in our regional reference for BJI. We examined the influence of available covariates, including rifampicin co-administration on daptomycin PK. Simulations performed with the final model investigated the influence of dosages and covariates on PTA for both efficacy and safety. RESULTS: A total of 1303 daptomycin concentrations from 183 patients were analysed. A two-compartment model best described the data. Significant intra-individual variability was observed. Daptomycin clearance was influenced by renal function and sex, with females having a 26% lower typical clearance than males. Central volume of distribution (V1) was influenced by body weight, age, sex and rifampicin co-administration. Typical V1 was 11% lower in patients who were co-administered rifampicin. In PK/PD simulations, sex influenced the probability of AUC24/MIC target attainment, while rifampicin had a marginal effect. CONCLUSIONS: A daptomycin dosage of 8 mg/kg/24 h in women and 10 mg/kg/24 h in men should optimize efficacy but may lead to excessive trough concentrations in many patients, especially in women. Therapeutic drug monitoring appears necessary for precision dosing of daptomycin.


Assuntos
Daptomicina , Antibacterianos , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Rifampina , Caracteres Sexuais
5.
Antiviral Res ; 181: 104866, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32659293

RESUMO

In the context of the COVID-19 pandemic, several drugs have been repurposed as potential candidates for the treatment of COVID-19 infection. While preliminary choices were essentially based on in vitro potency, clinical translation into effective therapies may be challenging due to unfavorable in vivo pharmacokinetic properties at the doses chosen for this new indication of COVID-19 infection. However, available pharmacokinetic and pharmacokinetic-pharmacodynamic studies suffer from severe limitations leading to unreliable conclusions, especially in term of dosing optimization. In this paper we propose to highlight these limitations and to identify some of the major requirements that need to be addressed in designing PK and PK-PD studies in this era of COVID. A special attention should be paid to pre-analytical and analytical requirements and to the proper collection of covariates affecting dose-exposure relationships (co-medications, use of specific organ support techniques and other clinical and para-clinical data). We also promote the development of population PK and PK-PD models specifically dedicated to COVID-19 patients since those previously developed for other diseases (SEL, malaria, HIV) and clinical situations (steady-state, non-ICU patients) are not representative of severe patients. Therefore, implementation of well-designed PK and PD studies targeted to COVID-19 patients is urgently needed. For that purpose we call for multi-institutional collaborative work and involvement of clinical pharmacologists in multidisciplinary research consortia.


Assuntos
Antivirais/farmacologia , Antivirais/farmacocinética , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Antivirais/administração & dosagem , Antivirais/sangue , COVID-19 , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Coleta de Dados , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Modelos Biológicos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia , SARS-CoV-2
7.
Ther Drug Monit ; 41(4): 444-451, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30817698

RESUMO

BACKGROUND: There are growing concerns about dolutegravir (DTG)-related neuropsychiatric adverse events and about differences in the characteristics of people living with HIV infection (PLWH) potentially associated with higher risks of said side effects. Several studies have shown that DTG was stopped more frequently among women, older PLWH, and PLWH who initiated abacavir (ABC) at the same time. This study aimed to clarify the factors affecting the pharmacokinetics (PKs) of DTG in a real-life cohort of PLWH using a population PK approach. METHODS: The model-building strategy was based on a previously published model developed from premarketing trials (1-compartment model with first-order absorption and a lag time). Sparse therapeutic drug monitoring data were obtained from a real-life cohort of 279 PLWH, and population PK analysis was performed using Monolix software. A stepwise covariate model-building strategy was used to evaluate any relevant effects of age, body weight, gender, total bilirubin, smoking status, formulations of DTG, morning versus evening dosing, backbone therapy, and other comedications including CYP/UGT inducers/inhibitors. RESULTS: For a typical 70-kg PLWH, the apparent clearance (CL/F) and apparent volume of distribution (V/F) were 0.748 L/h and 14.6 L, respectively. Of the demographic factors evaluated, body weight was a significant covariate for CL/F and for V/F. Smokers had a 17% higher CL/F relative to nonsmokers. Both strong enzyme inhibitors (eg, atazanavir) and inducers (eg, rifampicin) had marked effects on DTG exposure, with potential clinical implications. Ritonavir-boosted darunavir was found to moderately increase clearance of DTG by 23%. No significant effect of ABC-based backbone therapy was observed on the PK parameters of DTG. CONCLUSIONS: Our results did not support the hypothesis that ABC, by competing with the DTG metabolic pathway, may significantly increase DTG exposure leading to potential drug toxicity.


Assuntos
Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/farmacocinética , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Adulto , Idoso , Estudos de Coortes , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxazinas , Piperazinas , Piridonas , Adulto Jovem
8.
J Antimicrob Chemother ; 74(4): 1012-1020, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30629193

RESUMO

BACKGROUND: Daptomycin has been recognized as a therapeutic option for the treatment of bone and joint infection (BJI). Gene polymorphism of ABCB1, the gene encoding P-glycoprotein (P-gp), may influence daptomycin pharmacokinetics (PK). OBJECTIVES: We aimed to examine population PK of daptomycin and its determinants, including genetic factors, in patients with BJI. PATIENTS AND METHODS: We analysed data from patients who received daptomycin for BJI between 2012 and 2016 in our regional reference centre and who had measured daptomycin concentrations and P-gp genotyping. A population approach was used to analyse PK data. In covariate analysis, we examined the influence of three single nucleotide variations (SNVs) of ABCB1 (3435C > T, 2677G > T/A and 1236C > T) and that of the corresponding haplotype on daptomycin PK parameters. Simulations performed with the final model examined the influence of covariates on the probability to achieve pharmacodynamic (PD) targets. RESULTS: Data from 81 patients were analysed. Daptomycin body CL (CLDAP) correlated with CLCR and was 23% greater in males than in females. Daptomycin central V (V1) was allometrically scaled to body weight and was 25% lower in patients with homozygous CGC ABCB1 haplotype than in patients with any other genotype. Simulations performed with the model showed that sex and P-gp haplotype may influence the PTA for high MIC values and that a dosage of 10 mg/kg/24 h would optimize efficacy. CONCLUSIONS: Daptomycin dosages higher than currently recommended should be evaluated in patients with BJI. Gender and P-gp gene polymorphism should be further examined as determinants of dosage requirements.


Assuntos
Antibacterianos/farmacocinética , Daptomicina/farmacocinética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Alelos , Área Sob a Curva , Artrite Infecciosa/tratamento farmacológico , Artrite Infecciosa/epidemiologia , Artrite Infecciosa/genética , Doenças Ósseas Infecciosas/tratamento farmacológico , Doenças Ósseas Infecciosas/epidemiologia , Doenças Ósseas Infecciosas/genética , Monitoramento de Medicamentos , Feminino , Genótipo , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética/métodos , Vigilância da População
9.
Curr Drug Saf ; 13(1): 69-71, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29345598

RESUMO

OBJECTIVE: Dolutegravir (DTG), a highly effective second-generation HIV integrase inhibitor with high genetic barrier to resistance, has shown excellent tolerability and safety profiles in clinical trials. However, some patients may experience neurological or psychiatric adverse effects leading to DTG discontinuation. CASE REPORT: This report describes a case of 29-year-old woman who developed neurological adverse events after starting the DTG-based antiretroviral therapy. Serum DTG concentrations were supratherapeutic which has required a dosing interval adjustment. The findings of this case report suggest that Therapeutic Drug Monitoring might be useful in individuals expressing unusual DTG pharmacokinetics.


Assuntos
Monitoramento de Medicamentos/métodos , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Doenças do Sistema Nervoso/induzido quimicamente , Doenças do Sistema Nervoso/terapia , Adulto , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Doenças do Sistema Nervoso/diagnóstico , Oxazinas , Piperazinas , Piridonas
10.
J Antimicrob Chemother ; 73(4): 987-994, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29244077

RESUMO

Background: Ertapenem is a therapeutic option in patients with Gram-negative bone and joint infection (BJI). The subcutaneous (sc) route of administration is convenient in the outpatient setting and has shown favourable pharmacokinetics (PK), but available data on ertapenem are limited. Objectives: To perform population PK analysis and pharmacokinetic/pharmacodynamic (PK/PD) simulation of ertapenem administered by the intravenous (iv) or sc route to patients with BJI. Patients and methods: This was a retrospective analysis of PK data collected in patients with BJI who received iv or sc ertapenem. Measured ertapenem concentrations were analysed with a non-parametric population approach. Then, simulations were performed based on the final model to investigate the influence of ertapenem route of administration, dosage and renal function on the probability of achieving a pharmacodynamic (PD) target, defined as the percentage of time for which free plasma concentrations of ertapenem remained above the MIC (fT>MIC) of 40%. Results: Forty-six PK profiles (13 with iv and 33 with sc ertapenem) with a total of 133 concentrations from 31 subjects were available for the analysis. A two-compartment model with linear sc absorption and linear elimination best fitted the data. Creatinine clearance was found to significantly influence ertapenem plasma clearance. Simulations showed that twice daily dosing, sc administration and renal impairment were associated with an increase in fT>MIC and target attainment. Conclusions: Our results indicate that 1 g of ertapenem administered twice daily, by the iv or sc route, may optimize ertapenem exposure and achievement of PK/PD targets in patients with BJI.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Ertapenem/administração & dosagem , Ertapenem/farmacocinética , Osteoartrite/tratamento farmacológico , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/sangue , Simulação por Computador , Creatinina/sangue , Ertapenem/sangue , Feminino , Humanos , Injeções Subcutâneas , Masculino , Taxa de Depuração Metabólica , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Modelos Estatísticos , Plasma/química , Estudos Retrospectivos , Adulto Jovem
11.
Pract Lab Med ; 7: 19-26, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28856214

RESUMO

BACKGROUND: For TDM of mycophenolate acid (MPA), the Roche Total Mycophenolic Acid® assay based on the inhibition of recombinant inosine monophosphate dehydrogenase (IMPDH) has been shown to be a simple and reliable alternative to chromatographic methods. We have adapted this assay on the ABX Pentra 400 analyzer (HORIBA). OBJECTIVE: To investigate the analytical performances of the Roche Total Mycophenolic Acid® assay on the ABX Pentra 400 and to compare it to an LC-MS method using samples from children with nephrotic syndrome treated with mycophenolate mofetil (MMF). MATERIAL AND METHODS: Configuration of the open-channel on the ABX Pentra 400 was based on the Roche MPA assay package insert. Precision was determined as described in the CLSI protocol EP5-A2. Comparison with the LC-MS method was performed using 356 plasma samples from 42 children with nephrotic syndrome (8 h pharmacokinetic profiles). RESULTS: The enzymatic assay demonstrated high precision. The %CV for Within Run Imprecision ranged from 5.5% at 1.2 mg/L to 1.5% at 14.1 mg/L and Total Imprecision ranged from 9.3% to 2.5%. The method comparison with plasma samples from children yielded overall a good correlation and a good agreement between both methods. The Passing Bablok regression analysis showed the following results: [Roche MPA assay]=1.058 [MPA LC-MS] -0.06; rho=0.996. CONCLUSION: The Roche Total Mycophenolic Acid® assay is adaptable to the ABX Pentra 400 analyzer, and demonstrates accurate and precise measurement of MPA in plasma obtained from children with nephrotic syndrome.

13.
Future Oncol ; 13(8): 679-693, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28076966

RESUMO

AIM: This novel multiparameter Phase I study aimed to optimize doses/dosing schedules of everolimus and sorafenib drug combination, based on modeling/simulation (NCT01932177). PATIENTS & METHODS: About 26 patients with solid tumors were treated in four different dosing schedules. Everolimus once daily + sorafenib twice daily were given continuously in arms A and B, and intermittently in arms C (alternating every other week) and D (everolimus continuous and sorafenib 3 days on/4 days off). RESULTS: Continuous schedules exhibited higher toxicity risks than intermittent schedules (64.1 vs 35.9%; p < 0.0001), and trends for lower disease control rates (80 vs 100%). No significant pharmacokinetic interaction was identified. CONCLUSION: Feasibility of EVESOR trial is demonstrated. Intermittent schedules might provide better tolerance and efficacy than continuous schedules.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Everolimo/administração & dosagem , Everolimo/farmacocinética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Niacinamida/farmacocinética , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Sorafenibe , Tomografia Computadorizada por Raios X , Resultado do Tratamento
14.
Nephrol Dial Transplant ; 32(12): 2065-2071, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27760839

RESUMO

Background: Chronic hepatitis C virus (HCV) infection is the most common chronic liver disease in patients with end-stage renal disease (ESRD). Over the last few years, second-generation direct-acting antivirals have been revolutionary in the treatment of hepatitis C, and sofosbuvir (SOF) is the backbone of most modern treatment strategies. Since SOF is eliminated through the kidney, the aim of this multicentre retrospective study was to assess its antiviral efficacy and safety in HCV-infected patients with severe renal failure [including haemodialysis (HD) patients]. Methods: Fifty patients (36 males, mean age ± standard deviation 60.5 ± 7.5 years) with chronic HCV infection (G1: 28/56%, cirrhosis: 27/54%) and severe renal failure [i.e. MDRD estimated glomerular filtration rate (eGFR) <35 mL/min], including 35 on HD, were enrolled. Antiviral treatment consisted of SOF/ribavirin (RBV) (n = 7), SOF/RBV/pegylated interferon (n = 2), SOF/daclatasvir ± RBV (n = 30) or SOF/simeprevir ± RBV (n = 11) for 12 or 24 weeks. A reduced dose of SOF (400 mg three times a week or 400 mg every other day) was given to all HD patients. Initial dose of RBV (n = 12) ranged from 400 to 4200 mg/week. Results: On an intent-to-treat-based analysis, sustained virological response rate was 86% at 12 weeks. During therapy, haemoglobin levels were not significantly modified, but recombinant erythropoietin (rEPO) dose significantly increased in patients treated with RBV. Two patients (4%) required blood transfusion. No patient had treatment discontinuation due to side effects. Dose of RBV was reduced in two patients (16.7%) during antiviral therapy. Dose of SOF was reduced in two non-HD patients because of side effects. In non-HD patients, median eGFR was not significantly modified during treatment. Conclusions: Our results strongly suggest that SOF-based antiviral therapy, with a reduced dose of SOF, is safe and effective for the treatment of HCV patients with ESRD, including HD patients.


Assuntos
Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/tratamento farmacológico , Insuficiência Renal/complicações , Sofosbuvir/uso terapêutico , Antivirais/uso terapêutico , Feminino , Taxa de Filtração Glomerular , Hepatite C Crônica/epidemiologia , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/virologia , Estudos Retrospectivos
15.
Ther Drug Monit ; 38(6): 684-692, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27559840

RESUMO

BACKGROUND: Ribavirin exposure after the first dose (D0AUC0-4h) >1755 mcg·h·L is predictive of sustained virological response (SVR) in patients with hepatitis C treated with peginterferon and ribavirin. The aim of this study was to test the benefit of ribavirin early dose adjustment based on this target in naïve patients infected with genotype 1. METHODS: A multicenter randomized controlled trial with two parallel groups; fixed-dose (FD) group: standard of care in 2010-2011, ie, peginterferon-α2a 180 mcg·wk and weight-based ribavirin 1000-1200 mg/d during 48 weeks; adapted-dose (AD) group: increase of ribavirin dose if D0AUC0-4h <1755 mcg·h·L. RESULTS: A total of 221 patients were included, 110 in the AD group and 111 in the FD group with similar baseline characteristics. In the perprotocol analysis, SVR was higher in the AD group (55.1% versus 40.4%; P = 0.042), especially in patients with D0AUC0-4h <1755 mcg·h·L (54.3% versus 31.9%; P = 0.029). In the intention-to-treat analysis, the difference was not significant (50% versus 41%; P = 0.197). Ribavirin trough concentrations (C0s) at week 4 of treatment (intention-to-treat analysis) were higher in patients achieving SVR (2.06 versus 1.72 mg/L, P = 0.003). In the subgroup of patients with AUC0-4h <1755 mcg·h·L, 46% of patients with AD achieved a C0 >2.0 mg/L versus 22% of patients with FD (P = 0.013). Grade 1 anemia (but not other grades) was more frequent in the AD group (70% versus 48%, P = 0.001). The number of dose reductions or discontinuation of ribavirin was similar in both groups. CONCLUSIONS: Early ribavirin dose adjustment increases SVR in patients underexposed to ribavirin without increasing grade II-IV anemia. Such a strategy could be useful in patients with no access to new antiviral drugs.


Assuntos
Antivirais/administração & dosagem , Antivirais/efeitos adversos , Hepatite C/tratamento farmacológico , Interferons/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Adulto , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Pragmáticos como Assunto
16.
Dig Liver Dis ; 48(11): 1351-1356, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27498075

RESUMO

BACKGROUND: Sofosbuvir (SOF) plus daclatasvir (DCV) with or without ribavirin is one of the currently recommended treatment option for chronic hepatitis C. AIMS: Our objectives were to identify factors associated with SOF/DCV plasma concentrations [C] variations and to evaluate their impact on viral kinetics. METHODS: 130 consecutive HCV patients initiating SOF/DCV therapy with or without ribavirin were enrolled. Clinical, biological, virological and pharmacological data were collected at baseline, at week 4, 8, 12, and 24 of therapy and 12 weeks after the end of therapy. RESULTS: Mean age was 57 years, 68% of patients were males, 69% were infected by HCV genotype 1 and cirrhosis was observed in 76% of patients. Multivariate analysis showed that higher SOF [C] and DCV [C] during treatment were associated with eGFR impairment and absence of cirrhosis. We found a significant correlation between the magnitude of HCV viral load decrease from day 0 to week 4 and a higher SOF [C] at week 4 (p=0.032) and a higher DCV [C] at week 8 (p=0.013). CONCLUSIONS: Pharmacological monitoring showed significant associations between elevated SOF or DCV [C] and absence of cirrhosis, decreased eGFR and viral load decrease during the first month of treatment.


Assuntos
Antivirais/sangue , Hepatite C Crônica/tratamento farmacológico , Imidazóis/sangue , Sofosbuvir/sangue , Carga Viral , Idoso , Antivirais/uso terapêutico , Monitoramento de Medicamentos , Quimioterapia Combinada , Feminino , França , Taxa de Filtração Glomerular , Hepacivirus , Hepatite C Crônica/complicações , Humanos , Imidazóis/uso terapêutico , Modelos Lineares , Cirrose Hepática/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Ribavirina/uso terapêutico , Sofosbuvir/uso terapêutico , Resultado do Tratamento
17.
J Antimicrob Chemother ; 71(11): 3235-3241, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27432606

RESUMO

OBJECTIVE: We assessed the virological efficacy of a 6 month maraviroc/raltegravir simplification strategy following 6 months of quadruple therapy combining tenofovir disoproxil fumarate/emtricitabine with maraviroc/raltegravir. METHODS: HIV-1-infected naive patients were enrolled in an open label, single-arm, Phase 2 trial. All patients received maraviroc 300 mg twice daily, raltegravir 400 mg twice daily and tenofovir/emtricitabine for 24 weeks. Patients with stable HIV-RNA <50 copies/mL stopped tenofovir/emtricitabine at week (W) 24 and pursued maraviroc/raltegravir until W48. The primary endpoint was the virological response defined by HIV-RNA <50 copies/mL at W48. RESULTS: Thirty-three patients were analysed. Patients were mostly male (94%), Caucasians (91%), MSM (82%); their median age was 42 years. At baseline, median CD4 cell count was 453 cells/mm3 and HIV-RNA was 4.3 log copies/mL. All patients had CCR5-tropic viruses by genotropism and phenotropism assays. All but one patient had an HIV-RNA < 50 copies/mL at W24 and entered the simplification phase. Virological success was maintained at W48 in 88% (90% CI 79%-97%) of patients. N155H mutation was detected at failure in one patient. No tropism switch was observed. Raltegravir and maraviroc plasma exposure were satisfactory in 92% and 79% of 41 samples from 21 patients. Five severe adverse events (SAEs) were observed up to W48; none was related to the study drugs. Four patients presented grade 3 AEs; none was related to the study. No grade 4 AE was observed. No patient died. CONCLUSIONS: Maraviroc/raltegravir maintenance therapy following a 6 month induction phase with maraviroc/raltegravir/tenofovir/emtricitabine was well tolerated and maintained virological efficacy in these carefully selected patients.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade/métodos , Cicloexanos/administração & dosagem , Infecções por HIV/tratamento farmacológico , Quimioterapia de Manutenção/métodos , Raltegravir Potássico/administração & dosagem , Triazóis/administração & dosagem , Adolescente , Adulto , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Cicloexanos/efeitos adversos , Emtricitabina/administração & dosagem , Feminino , HIV-1/isolamento & purificação , Humanos , Quimioterapia de Manutenção/efeitos adversos , Masculino , Maraviroc , Pessoa de Meia-Idade , Raltegravir Potássico/efeitos adversos , Tenofovir/administração & dosagem , Resultado do Tratamento , Triazóis/efeitos adversos , Carga Viral , Adulto Jovem
18.
Antimicrob Agents Chemother ; 60(5): 3148-51, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26902764

RESUMO

The interindividual and intraindividual variabilities in daptomycin pharmacokinetics were investigated in 23 patients (69 pharmacokinetic profiles) who were treated for several months for bone and joint infections. Population daptomycin clearance was significantly influenced by renal function and was significantly higher in male than in female patients. We observed significant intraindividual changes in daptomycin clearance, which were uncorrelated with changes in renal function, suggesting that therapeutic drug monitoring is important in patients receiving prolonged daptomycin therapy.


Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Artrite Infecciosa/tratamento farmacológico , Daptomicina/farmacocinética , Daptomicina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Adulto Jovem
19.
BMC Infect Dis ; 16: 83, 2016 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-26888539

RESUMO

BACKGROUND: Even if daptomycin does not have approval for the treatment of bone and joint infections (BJI), the Infectious Diseases Society of America guidelines propose this antibiotic as alternative therapy for prosthetic joint infection. The recommended dose is 6 mg/kg/d, whereas recent data support the use of higher doses in these patients. METHODS: We performed a cohort study including consecutive patients that have received daptomycin >6 mg/kg/d for complex BJI between 2011 and 2013 in a French regional reference center. Factors associated with treatment failure were determined on univariate Cox analysis and Kaplan-Meier curves. RESULTS: Forty-three patients (age, 61 ± 17 years) received a mean dose of 8 ± 0.9 mg/kg/d daptomycin, for a mean 81 ± 59 days (range, 6-303 days). Most had chronic (n = 37, 86 %) implant-associated (n = 37, 86 %) BJI caused by coagulase-negative staphylococci (n = 32, 74 %). A severe adverse event (SAE) occurred in 6 patients (14 %), including 2 cases of eosinophilic pneumonia, concomitant with daptomycin Cmin >24 mg/L. Outcome was favorable in 30 (77 %) of the 39 clinically assessable patients. Predictors for treatment failure were age, non-optimal surgery and daptomycin withdrawal for SAE. CONCLUSIONS: Prolonged high-dose daptomycin therapy was effective in patients with complex BJI. However, optimal surgery remains the cornerstone of medico-surgical strategy; and a higher incidence of eosinophilic pneumonia than expected was recorded.


Assuntos
Antibacterianos/uso terapêutico , Daptomicina/uso terapêutico , Prótese Articular/efeitos adversos , Infecções Relacionadas à Prótese/tratamento farmacológico , Terapia de Salvação/métodos , Infecções Estafilocócicas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Falha de Tratamento , Resultado do Tratamento , Adulto Jovem
20.
Curr HIV Res ; 14(4): 316-23, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26577801

RESUMO

BACKGROUND: The semen of HIV-1 infected men represents the main vector of HIV-1 spread following sexual transmission of cell-free or cell-associated virions. OBJECTIVE: The present study aimed to assess the impact of HAART on HIV-1 RNA/DNA and on inflammatory environment in the semen of long-term HAART-experienced men. METHODS: Forty-five paired samples of semen and blood were obtained from 37 consenting men, 10 untreated and 27 under HAART. Blood and seminal HIV RNA and DNA loads were quantified by the Abbott RealTime m2000rt assay and an inhouse real-time PCR protocol, respectively. Tat/rev/nef intra-cellular mRNA was tested by qualitative PCR. Interleukin (IL)- 1ß, IL-2, IL-6, IL-7, IL-8, IL-10, GM-CSF and TNFα were quantified in 20 paired samples by Bio-plex® assay. RESULTS: No semen was found HIV RNA positive in men under HAART. Twenty-six percent of semen samples from HAART-experienced men remained positive for HIV DNA. Seminal HIV DNA was significantly associated with the duration of infection and the HIV DNA load in blood. No seminal mononuclear cells were found positive for intracellular HIV RNA in HAART experienced men. All the tested chemokines exhibited significantly higher concentration in semen than in blood in both treated and untreated men. No effect of HAART on cytokines/chimiokines loads was observed. CONCLUSION: These results demonstrate the efficacy of HAART on the reduction of seminal RNA HIV-1 loads despite the persistence of local inflammation. Moreover, in our hands the seminal cell-associated virus reservoir was not reactivated in an inflammatory environment was not productive and its reactivation seems unlikely.


Assuntos
Antirretrovirais/uso terapêutico , DNA Viral/análise , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Sêmen/virologia , Adulto , Sangue/virologia , Citocinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , RNA Viral/análise , Reação em Cadeia da Polimerase em Tempo Real , Carga Viral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...