RESUMO
Methotrexate is the gold standard treatment in rheumatoid arthritis. Once absorbed, it is internalized in cells, where glutamate residues are added to produce polyglutamated forms, which are responsible for the effect of methotrexate. The aim of the current study is to determine the relationship between methotrexate triglutamate concentrations and the clinical evolution in rheumatoid arthritis patients, as well as to characterize the variability in both features to propose strategies for low-dose methotrexate optimization. The quantification of methotrexate triglutamate concentration in red blood cells was performed through ultra-performance liquid chromatography coupled with mass spectrometry. Polymorphisms of genes involved in the formation of polyglutamates were determined by real-time polymerase chain reaction. A multivariate regression was performed to determine the covariates involved in the variability of methotrexate triglutamate concentrations and a population pharmacokinetics model was developed through nonlinear mixed-effects modeling. Disease activity score changed according to methotrexate triglutamate concentrations; patients with good response to treatment had higher concentrations than moderate or nonresponding patients. The methotrexate triglutamate concentrations were related to time under treatment, dose, red blood cells, and body mass index. A 1-compartment open model was selected to estimate the pharmacokinetic parameters; the typical total clearance (L/day) was determined as 1.45 * (body mass index/28 kg/m2 ) * (red blood cells/4.6 × 106 cells/µL) and the volume of distribution was 52.4 L, with an absorption rate of 0.0346/day and a fraction metabolized of 1.03%. Through the application of the model, the initial dose of methotrexate is proposed on the basis of stochastic simulations and considering methotrexate triglutamate concentrations found in responders patients.
Assuntos
Antirreumáticos/farmacocinética , Artrite Reumatoide/tratamento farmacológico , Metotrexato/análogos & derivados , Ácido Poliglutâmico/análogos & derivados , Fatores Etários , Antirreumáticos/sangue , Antirreumáticos/uso terapêutico , Índice de Massa Corporal , Peso Corporal , Relação Dose-Resposta a Droga , Eritrócitos , Genótipo , Humanos , Estudos Longitudinais , Taxa de Depuração Metabólica , Metotrexato/sangue , Metotrexato/farmacocinética , Metotrexato/uso terapêutico , México , Modelos Biológicos , Ácido Poliglutâmico/sangue , Ácido Poliglutâmico/farmacocinética , Ácido Poliglutâmico/uso terapêutico , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
OBJECTIVE: The American Academy of Ophthalmology recommends a maximum hydroxychloroquine (HCQ) dose of ≤5.0 mg/kg/day to reduce the risk of HCQ-induced retinopathy. To determine if this dose adjustment would have an impact on the clinical course of SLE, we compared outcome measures in a cohort of patients with SLE before and after adjusting HCQ dose. METHODS: Sixty Puerto Ricans with SLE (per 1997 American College of Rheumatology criteria) treated with HCQ who were changed to HCQ ≤5.0 mg/kg/day were studied. Visits were ascertained every 6 months for 2 years before and 2 years after HCQ dose adjustment (baseline visit). Disease activity (per Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)), SLE exacerbations, emergency room visits, hospitalisations, disease damage (per Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index), corticosteroids exposure, prednisone dose and immunosuppressive drugs exposure were determined before and after HCQ dose change. RESULTS: At baseline visit, the mean age was 43.8±15.1 years. All patients were women. The mean disease duration was 13.8±9.1 years. After HCQ dose adjustment, patients required a lower prednisone dose when compared with visits before HCQ dose reduction. No significant differences were observed for mean SLEDAI scores, lupus exacerbations, emergency room visits, hospitalisations, disease damage and exposure to immunosuppressive drugs before and after HCQ dose adjustment. CONCLUSIONS: This study suggests that adjustment of daily HCQ dose to ≤5.0 mg/kg/day of actual body weight does not have a significant impact on the short-term and mid-term outcomes in this group of patients with SLE.
Assuntos
Antirreumáticos/efeitos adversos , Hidroxicloroquina/efeitos adversos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Retinopatia da Prematuridade/induzido quimicamente , Corticosteroides/efeitos adversos , Corticosteroides/uso terapêutico , Adulto , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Comorbidade , Progressão da Doença , Feminino , Humanos , Hidroxicloroquina/farmacocinética , Hidroxicloroquina/uso terapêutico , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/complicações , Pessoa de Meia-Idade , Oftalmologia/organização & administração , Avaliação de Resultados em Cuidados de Saúde , Guias de Prática Clínica como Assunto/normas , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Porto Rico/epidemiologia , Retinopatia da Prematuridade/prevenção & controle , Estudos Retrospectivos , Estados UnidosRESUMO
R788 (fostamatinib) is an oral prodrug that is rapidly converted into a relatively selective spleen tyrosine kinase (SYK) inhibitor R406, evaluated for the treatment of rheumatoid arthritis (RA). This analysis aimed at developing a pharmacodynamic model for efficacy using pooled ACR20 data from two phase II studies in patients with rheumatoid arthritis (TASKi1 and TASKi2), describing the effect of fostamatinib as a function of fostamatinib exposure (dose, R406 plasma concentration) and other explanatory variables. The exposure-response relationship of fostamatinib was implemented into a continuous time Markov model describing the time course of transition probabilities between the three possible states of ACR20 non-responder, responder, and dropout at each visit. The probability of transition to the ACR20 response state was linearly (at the rate constant level) related to average R406 plasma concentrations and the onset of this drug effect was fast. Further, increases of fostamatinib dose resulted in increased dropout and subsequent loss of efficacy. This analysis provided an increased understanding of the exposure-response relationship, and provided support for fostamatinib 100 mg BID an appropriate dose regimen for further clinical evaluation.
Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Cálculos da Dosagem de Medicamento , Oxazinas/administração & dosagem , Pró-Fármacos/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridinas/administração & dosagem , Quinase Syk/antagonistas & inibidores , Administração Oral , Aminopiridinas , Antirreumáticos/sangue , Antirreumáticos/farmacocinética , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/enzimologia , Biotransformação , Ensaios Clínicos Fase II como Assunto , Europa (Continente) , Humanos , América Latina , Modelos Lineares , Cadeias de Markov , México , Morfolinas , Oxazinas/sangue , Oxazinas/farmacocinética , Pró-Fármacos/farmacocinética , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/sangue , Piridinas/farmacocinética , Pirimidinas , Ensaios Clínicos Controlados Aleatórios como Assunto , Quinase Syk/metabolismo , Resultado do Tratamento , Estados UnidosRESUMO
Patents for many key biological agents will soon expire. Third-party companies are, therefore, in the process of developing their own versions, termed biosimilar agents, of these innovator products. However, manufacture of biosimilar agents is complicated by the requirement for their production in biological systems, small variations in which can influence the structure, activity and metabolism of the biosimilar product. The development of biosimilar therapies for the treatment of patients with rheumatic diseases could potentially result in substantial cost savings for patients and health care providers, and consequently, increased availability of effective therapies. However, legislation that regulates the manufacture, registration and approval of biosimilar therapies varies considerably between different countries. In addition, major safety and efficacy concerns must be addressed before a rheumatologist can routinely substitute an innovator pharmaceutical with a biosimilar product.
Assuntos
Antirreumáticos/uso terapêutico , Medicamentos Biossimilares/uso terapêutico , Doenças Reumáticas/tratamento farmacológico , Reumatologia/métodos , Equivalência Terapêutica , Antirreumáticos/farmacocinética , Medicamentos Biossimilares/farmacocinética , Aprovação de Drogas/legislação & jurisprudência , Substituição de Medicamentos , Humanos , Doenças Reumáticas/metabolismoRESUMO
Rheumatoid arthritis (RA) is the prototype of the rheumatic diseases worldwide. Methotrexate (MTX) is the drug of first choice in the treatment of this disease due to its immunosuppressant effect. However, side events are present in 30% of the patients. The C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene are involved in the metabolism of MTX. Earlier studies reported an association between these polymorphisms and elevation of hepatic enzymes. We analyzed the frequencies of both polymorphisms and the presence of transaminasemia in 70 Mexican patients with rheumatic arthritis treated with MTX. The 19% (13/70) of patients had an increase in the serum level of transaminases. The A1298C polymorphism was associated with elevation of transaminases (P=0.024). The identification of MTHFR genotypes for C677T and A1298C polymorphisms could lead clinicians to identify patients in risk of elevation of transaminases, and give them an individualized treatment, as is a goal of pharmacogenetics.
Assuntos
Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Metotrexato/efeitos adversos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Transaminases/sangue , Antirreumáticos/farmacocinética , Artrite Reumatoide/enzimologia , Artrite Reumatoide/etnologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Frequência do Gene , Genótipo , Humanos , Metotrexato/farmacocinética , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , México/epidemiologia , Razão de Chances , Farmacogenética , Fenótipo , Medicina de Precisão , Medição de Risco , Fatores de Risco , Resultado do Tratamento , Regulação para CimaRESUMO
INTRODUCTION: Preclinical work has suggested that IL-1 plays a critical role in the pathogenesis of rheumatoid arthritis (RA). The objective of the present study was to determine the effect of a long-acting IL-1 receptor inhibitor, AMG 108, in a double-blind, placebo-controlled, parallel-dosing study in patients with active RA who were receiving stable methotrexate (15 to 25 mg/week). METHODS: Patients were randomized equally to receive placebo or 50, 125, or 250 mg AMG 108 subcutaneously every 4 weeks for 6 months. The primary efficacy endpoint was a 20% improvement in the American College of Rheumatology response (ACR20) at week 24; other efficacy endpoints included the ACR50, the ACR70, and the RA disease activity score (28-joint count Disease Activity Score) responses, patient-reported outcomes, and pharmacokinetic parameters. Safety endpoints included treatment-emergent adverse events (AEs), infectious AEs, serious AEs, serious infections, injection site reactions, laboratory abnormalities, and antibodies to AMG 108. RESULTS: Of 813 patients enrolled in the study, 204 patients were randomized to the 50 mg group, 203 to the 125 mg group, 203 to the 250 mg group, and 203 to placebo. At week 24, 40.4% of the 250 mg group, 36% of the 125 mg group, 30.9% of the 50 mg group, and 29.1% of the placebo group achieved an ACR20 (P = 0.022, 250 mg vs. placebo). Of the individual ACR components, numerical dose-dependent improvements were only seen in tender joint counts, pain (visual analog scale), and the acute phase reactants, erythrocyte sedimentation rate and C-reactive protein. No dose-related increase was observed in the incidence of treatment-emergent AEs. No deaths were reported, and the incidence of AEs and infections, serious AEs and infections, and withdrawals from study for safety were similar in the AMG 108 and placebo groups. CONCLUSIONS: This large double-blind randomized trial with a long-acting IL-1 receptor blocker, AMG 108, is consistent with the experience of other IL-1 blockers, represents a definitive experiment showing that IL-1 inhibition provides only moderate symptomatic amelioration of arthritis activity in the majority of RA patients, and provides an answer to a question that has been discussed for many years in the rheumatologic community. TRIAL REGISTRATION: ClinicalTrials.gov NCT00293826.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Receptores de Interleucina-1/imunologia , Anticorpos Monoclonais/farmacocinética , Antirreumáticos/farmacocinética , Artrite Reumatoide/imunologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Medição da DorRESUMO
BACKGROUND AND PURPOSE: Chemokine receptors CXCR1 and CXCR2 may mediate influx of neutrophils in models of acute and chronic inflammation. The potential benefits of oral administration of a CXCR1/2 inhibitor, DF 2162, in adjuvant-induced polyarthritis (AIA) were investigated. EXPERIMENTAL APPROACH: A model of AIA in rats was used to compare the therapeutic effects of the treatment with DF2162, anti-TNF or anti-CINC-1 antibodies on joint inflammation and local production of cytokines and chemokines. KEY RESULTS: DF2162 prevented chemotaxis of rat and human neutrophils induced by chemokines acting on CXCR1/2. DF2162 was orally bioavailable and metabolized to two major metabolites. Only metabolite 1 retained CXCR1/2 blocking activity. Treatment with DF2162 (15 mg kg(-1), twice daily) or metabolite 1, but not metabolite 2, starting on day 10 after arthritis induction diminished histological score, the increase in paw volume, neutrophil influx and local production of TNF, IL-1beta, CCL2 and CCL5. The effects of DF2162 were similar to those of anti-TNF, and more effective than those of anti-CINC-1, antibodies. DF2162 prevented disease progression even when started 13 days after arthritis induction. CONCLUSIONS AND IMPLICATIONS: DF 2162, a novel orally-active non-competitive allosteric inhibitor of CXCR1 and CXCR2, significantly ameliorates AIA in rats, an effect quantitatively and qualitatively similar to those of anti-TNF antibody treatment. These findings highlight the contribution of CXCR2 in the pathophysiology of AIA and suggest that blockade of CXCR1/2 may be a valid therapeutic target for further studies aiming at the development of new drugs for treatment of rheumatoid arthritis.
Assuntos
Antirreumáticos/farmacologia , Artrite Experimental/tratamento farmacológico , Benzenoacetamidas/farmacologia , Mesilatos/farmacologia , Receptores de Interleucina-8B/antagonistas & inibidores , Administração Oral , Animais , Anticorpos/farmacologia , Antirreumáticos/farmacocinética , Artrite Experimental/fisiopatologia , Benzenoacetamidas/farmacocinética , Disponibilidade Biológica , Quimiocina CXCL1/metabolismo , Progressão da Doença , Feminino , Humanos , Mesilatos/farmacocinética , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Interleucina-8A/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismoRESUMO
OBJECTIVE: To compare the pharmacokinetics and report on the clinical effects of methotrexate (MTX) in patients with juvenile idiopathic arthritis (JIA), receiving long-term MTX or MTX plus chloroquine (CQ). METHODS: The pharmacokinetics of MTX, clinical characteristics (morning stiffness, joint tenderness and number of swollen joints) and biochemical markers (A-amyloid substance, C-reactive protein, erythrocyte sedimentation rate, fibrinogen and alpha-glycoprotein acid, alanine transaminase and aspartate transaminase) of the JIA patients were determined. Eight patients were treated with MTX (0.15 mg/kg) and another eight with MTX (0.15 mg/kg) plus CQ (4 mg/kg) for at least 6 months. RESULTS: All patients had polyarticular involvement and the clinical characteristics and biochemical markers were similar for the two groups. The pharmacokinetics of MTX were also similar with the Cmax and AUC values being 455.00 +/- 101.00 nm and 1469.92 +/- 299.77 nm/h for MTX group and 425.00 +/- 169.60 nm and 1560.73 +/- 615.49 nm/h for MTX plus CQ group, respectively. The respective creatinine clearance was 117.95 +/- 12.58 for MTX group and 99.17 +/- 22.65 mL/min for MTX plus CQ. CONCLUSION: The pharmacokinetics of MTX in JIA patients treated chronically with MTX are similar, with or without CQ co-treatment.
Assuntos
Antirreumáticos/farmacocinética , Cloroquina/administração & dosagem , Metotrexato/farmacocinética , Adolescente , Adulto , Área Sob a Curva , Artrite Juvenil , Criança , Quimioterapia Combinada , Feminino , Humanos , Masculino , Metotrexato/administração & dosagemRESUMO
Liquid-phase microextraction based on polypropylene hollow fibers and CE were applied for the chiral determination of hydroxychloroquine (HCQ) and its metabolites (desethylchloroquine, DCQ; desethylhydroxychloroquine, DHCQ; bisdesethylchloroquine, BDCQ) in human urine. The analytes were extracted from 3 mL of urine spiked with the internal standard (metoprolol) and alkalinized with 250 muL of 2 M NaOH. The analytes were extracted into 1-octanol impregnated in the pores of the hollow fiber, and into an acid acceptor solution inside the hollow fiber. The electrophoretic separations were carried out in 100 mmol/L Tris buffer (pH adjusted to 9.0 with phosphoric acid) containing 1% w/v S-beta-CD and 30 mg/mL HP-beta-CD with a constant voltage of +18 kV. The method was linear over the concentration range of 10-1000 ng/mL for each HCQ stereoisomer and 21-333 ng/mL for each metabolite stereoisomer. Within-day and between-day assay precision and accuracy for the analytes were studied at three concentration levels for each stereoisomer and were lower than 15%. The developed method was applied for the determination of the cumulative urinary excretion of HCQ, DCQ, and DHCQ after oral administration of rac-HCQ to a health volunteer. The results obtained are in agreement with previous literature data.