RESUMO
OBJECTIVE: Characterise the relationship between hydroxychloroquine (HCQ) blood levels and the number of missed doses, accounting for dosage, dose timing and the large variability in pharmacokinetics (PK) between patients. METHODS: We externally validated a published PK model and then conducted dosing simulations. We developed a virtual population of 1000 patients for each dosage across a range of body weights and PK variability. Using the model, 10 Monte Carlo simulations for each patient were conducted to derive predicted whole blood concentrations every hour over 24 hours (240 000 HCQ levels at steady state). To determine the impact of missed doses on levels, we randomly deleted a fixed proportion of doses. RESULTS: For patients receiving HCQ 400 mg daily, simulated random blood levels <200 ng/mL were exceedingly uncommon in fully adherent patients (<0.1%). In comparison, with 80% of doses missed, approximately 60% of concentrations were <200 ng/mL. However, this cut-off was highly insensitive and would miss many instances of severe non-adherence. Average levels quickly dropped to <200 ng/mL after 2-4 days of missed doses. Additionally, mean levels decreased by 29.9% between peak and trough measurements. CONCLUSIONS: We propose an algorithm to optimally interpret HCQ blood levels and approximate the number of missed doses, incorporating the impact of dosage, dose timing and pharmacokinetic variability. No single cut-off has adequate combinations of both sensitivity and specificity, and cut-offs are dependent on the degree of targeted non-adherence. Future studies should measure trough concentrations to better identify target HCQ levels for non-adherence and efficacy.
Assuntos
Hidroxicloroquina , Adesão à Medicação , Método de Monte Carlo , Hidroxicloroquina/farmacocinética , Hidroxicloroquina/uso terapêutico , Hidroxicloroquina/sangue , Humanos , Adesão à Medicação/estatística & dados numéricos , Antirreumáticos/farmacocinética , Antirreumáticos/sangue , Antirreumáticos/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/sangue , Simulação por Computador , Modelos BiológicosRESUMO
BACKGROUND AND OBJECTIVE: Juvenile idiopathic arthritis (JIA) is a chronic autoimmune disorder that primarily affects the joints in children. Notably, it is known to co-occur with uveitis. Adalimumab, a monoclonal anti-TNF antibody, is effective in treating both conditions. A deeper understanding of the pharmacokinetics (PK) of adalimumab in JIA is crucial to advance in more personalized treatment approaches. The objective of this study is to evaluate the population PK profile of adalimumab in JIA and to explain causes for its variability. MATERIALS AND METHODS: Adalimumab and antidrug antibody concentrations were retrospectively retrieved from the charts of patients with JIA. Initially, five literature-based population PK models of adalimumab were evaluated to assess their ability to describe the observed concentration-time profiles in the JIA cohort. These models included one specifically for the pediatric Crohn's disease population and four derived from studies in adult populations in healthy subjects and rheumatoid arthritis patients. Subsequently, a novel population PK model tailored to the JIA population was developed using NONMEM software. Monte Carlo simulations were then conducted utilizing the final PK model to visualize the concentration-time profile of adalimumab in patients with JIA and the impact of covariates. RESULTS: A cohort of 50 patients with JIA with 78 available adalimumab samples was assessed. The mean age was 11.8 ± 3.9 years, with a median body weight of 49 kg (interquartile range 29.4-59.8 kg). All literature models adequately described the concentration-time profiles in JIA. The best model, which was developed in patients with rheumatoid arthritis during the maintenance phase of treatment, served as a basis for estimating clearance in JIA, resulting in a value of 0.37 L per day per 70 kg. Patient body weight, antidrug antibodies, methotrexate use, CRP level, and comorbidity of uveitis were found to have a significant impact on adalimumab clearance, and these reduced the inter-patient variability from 58.6 to 28.0%. On steady state in the simulated patient population, the mean trough level was 7.4 ± 5.5 mg/L. The two dosing regimens of 20 and 40 mg every other week, based on patients' body weight, resulted in comparable simulated overall drug exposure. CONCLUSIONS: Five literature models effectively described adalimumab PK in this pediatric cohort, highlighting the potential for extrapolating existing models to the pediatric population. The new JIA model confirmed the effect of several known covariates and found a novel association for drug clearance with methotrexate use (lower) and uveitis (higher), which might have clinical relevance for personalized dosing in JIA.
Assuntos
Adalimumab , Antirreumáticos , Artrite Juvenil , Humanos , Artrite Juvenil/tratamento farmacológico , Adalimumab/farmacocinética , Adalimumab/uso terapêutico , Adalimumab/administração & dosagem , Criança , Estudos Retrospectivos , Masculino , Feminino , Adolescente , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Antirreumáticos/administração & dosagem , Modelos Biológicos , Método de Monte Carlo , Estudos de CoortesRESUMO
Polyarticular juvenile idiopathic arthritis (pJIA) is a pediatric chronic inflammatory arthritis, much like rheumatoid arthritis (RA) in adults. Drug development for pJIA can potentially be expedited by using extrapolation of efficacy from adult RA; however, the lack of understanding of the response and exposure relationship between pJIA and RA to therapeutic interventions has been a major roadblock. To address this, the objective of our analysis was to conduct a systematic response and exposure comparison between pJIA and RA trials for biologic products. Data from registration RA and pJIA clinical trials (parallel or withdrawal design) for infliximab, tocilizumab, golimumab, and adalimumab were utilized. First, exposure was compared between the pJIA trials and RA pivotal trials. Subsequently, the pJIA vs. RA response similarity was assessed by comparing similar individual subcomponents of the American College of Rheumatology (ACR) scores between the two populations. The exposure comparison demonstrated that at the pJIA trial dose, exposure in pediatric patients was similar to or higher than adults for all biologics evaluated except infliximab, where lower exposure was observed in pJIA patients ≤ 35 kg. Response comparison for individual subcomponents indicated that in a majority of the cases, pJIA response was similar or higher as compared with response from RA trials. Overall, this analysis suggests response similarity between pJIA and RA across the biologic products when exposures are matched between the two populations. These analyses provide support for the use of pharmacokinetic exposure-matching for extrapolation of efficacy from adult RA to pediatric pJIA for the products with established mechanism(s) of action.
Assuntos
Antirreumáticos/administração & dosagem , Artrite Juvenil/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/administração & dosagem , Adulto , Fatores Etários , Antirreumáticos/farmacocinética , Produtos Biológicos/farmacocinética , Criança , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Humanos , Resultado do TratamentoRESUMO
The introduction of novel, small-molecule Janus kinase inhibitors namely tofacitinib, baricitinib and upadacitinib has provided an alternative treatment option for patients with rheumatoid arthritis outside of traditional drugs and expensive biologics. This review aimed to critically assess the drug-drug interaction potential of tofacitinib, baricitinib and upadacitinib and provide a balanced perspective for choosing the most appropriate Janus kinase inhibitor based on the needs of patients with rheumatoid arthritis including co-medications and renal/hepatic impairment status. Based on the critical assessment, all three approved Janus kinase inhibitors generally provide a favourable opportunity for co-prescription with a plethora of drugs. While cytochrome P450 3A4-related inhibition or induction altered the exposures (area under the curve) of tofacitinib and upadacitinib, it did not impact the exposure of baricitinib. Transporter drug-drug interaction studies revealed that the disposition of baricitinib was altered with certain transporter inhibitors as compared with either tofacitinib or upadacitinib. Adjustment of tofacitinib or baricitinib dosages but not that of upadacitinib is required with the progression of renal impairment from a mild to a severe condition. While the dosage of tofacitinib needs to be adjusted for patients with moderate hepatic impairment status, it is not the case for either baricitinib or upadacitinib. Assessment of the drug-drug interaction potential suggests that tofacitinib, baricitinib and upadacitinib generally show a favourable disposition with no perpetrator activity; however, as victim drugs, they show subtle pharmacokinetic differences that may be considered during polypharmacy. Moreover, careful choice of the three drugs could be made in patients with rheumatoid arthritis with varying degrees of renal/hepatic impairments.
Assuntos
Antirreumáticos/efeitos adversos , Azetidinas/efeitos adversos , Interações Medicamentosas , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Janus Quinases/antagonistas & inibidores , Farmacocinética , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Purinas/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Sulfonamidas/efeitos adversos , Animais , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Azetidinas/farmacocinética , Azetidinas/toxicidade , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Piperidinas/farmacocinética , Piperidinas/toxicidade , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Purinas/farmacocinética , Purinas/toxicidade , Pirazóis/farmacocinética , Pirazóis/toxicidade , Pirimidinas/farmacocinética , Pirimidinas/toxicidade , Sulfonamidas/farmacocinética , Sulfonamidas/toxicidadeRESUMO
BACKGROUND: Infliximab (INX) and other tumour necrosis factor inhibitors (TNFi) have revolutionised the treatment of several immune mediated inflammatory diseases. Still, many patients do not respond sufficiently to therapy or lose efficacy over time. The large interindividual variation in serum drug concentrations on standard doses and the development of anti-drug antibodies are thought to be major reasons for treatment failures. Therapeutic drug monitoring (TDM), an individualised treatment strategy based on systematic assessments of serum drug concentrations, has been proposed as a clinical tool to optimise efficacy of INX treatment. TDM seems reasonable both from a clinical and an economical point of view, but the effectiveness of this treatment strategy has not yet been demonstrated in randomised clinical trials. The NORwegian DRUg Monitoring study (NOR-DRUM) aims to assess the effectiveness of TDM, both with regard to the achievement of remission in patients starting INX treatment (part A) as well as to maintain disease control in patients on INX treatment (part B). METHODS: The NOR-DRUM study is a randomised, open, controlled, parallel-group, comparative, multi-centre, national, superiority, phase IV study with two separate parts, NOR-DRUM A and NOR-DRUM B. Patients with rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, ulcerative colitis, Crohn's disease and psoriasis are included. In both study parts participants are randomised 1:1 to either TDM of infliximab (intervention group) or to standard treatment with infliximab without knowledge of drug levels or ADAb status (control group). NOR-DRUM A will include 400 patients starting INX therapy. The primary outcome is remission at 30 weeks. In NOR-DRUM B, 450 patients on maintenance treatment with INX will be included. The primary endpoint is occurrence of disease worsening during the 52-week study period. DISCUSSION: As the first trial to assess the effectiveness, safety and cost-effectiveness of TDM in patients receiving TNFi for a range of immune mediated inflammatory diseases, we hope that the NOR-DRUM study will contribute to the advancement of evidence based personalised treatment with biological medicines. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03074656. Registered on 090317.
Assuntos
Antirreumáticos/uso terapêutico , Monitoramento de Medicamentos , Infliximab/uso terapêutico , Adulto , Idoso , Antirreumáticos/farmacocinética , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Ensaios Clínicos Fase IV como Assunto , Colite Ulcerativa/sangue , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/sangue , Doença de Crohn/tratamento farmacológico , Feminino , Humanos , Infliximab/farmacocinética , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Noruega , Psoríase/sangue , Psoríase/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Espondilite Anquilosante/sangue , Espondilite Anquilosante/tratamento farmacológico , Resultado do Tratamento , Adulto JovemRESUMO
Available evidence indicates that a therapeutic drug monitoring strategy leads to major cost savings related to the anti-tumour necrosis factor-α therapy in both inflammatory bowel disease and rheumatoid arthritis (RA) patients, with no negative impact on efficacy. However, although the systematic use of therapeutic drug monitoring could potentially be beneficial and economically acceptable to drug dose optimization, it is not justifiable for all drugs. Infliximab (IFX) is a chimeric monoclonal immunoglobulin G1 targeting tumour necrosis factor. It has been approved for the treatment of immuno-inflammatory diseases, including RA, ankylosing spondylitis, psoriatic arthritis, Crohn's disease and ulcerative colitis. IFX's pharmacokinetics is highly variable and influences clinical response in chronic inflammatory diseases. Clinical response increases with IFX trough concentrations in RA, ankylosing spondylitis, inflammatory bowel disease and psoriatic patients. Target concentrations predictive of good clinical response were proposed in RA, Crohn's disease and ulcerative colitis. The purpose of this article is to review the current literature surrounding IFX serum concentrations and their related parameters with disease activity in patients with spondyloarthritis. Gathering information about the efficacy of IFX in patients with spondyloarthritis and relating IFX serum concentrations to disease activity were the main goals of this study.
Assuntos
Antirreumáticos/administração & dosagem , Infliximab/administração & dosagem , Espondilartrite/tratamento farmacológico , Antirreumáticos/farmacocinética , Monitoramento de Medicamentos/economia , Monitoramento de Medicamentos/métodos , Humanos , Infliximab/farmacocinética , Espondilartrite/fisiopatologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) are recommended for the medium- to long-term management of knee osteoarthritis (OA) due to their abilities to control pain, improve function and delay joint structural changes. Among SYSADOAs, evidence is greatest for the patented crystalline glucosamine sulfate (pCGS) formulation (Mylan). Glucosamine is widely available as glucosamine sulfate (GS) and glucosamine hydrochloride (GH) preparations that vary substantially in molecular form, pharmaceutical formulation and dose regimen. Only pCGS is given as a highly bioavailable once-daily dose (1500 mg), which consistently delivers the plasma levels of around 10 µmol/L required to inhibit interleukin-1-induced expression of genes involved in the pathophysiology of joint inflammation and tissue destruction. Careful consideration of the evidence base reveals that only pCGS reliably provides a moderate effect size on pain that is higher than paracetamol and equivalent to non-steroidal anti-inflammatory drugs (NSAIDs), while non-crystalline GS and GH fail to reach statistical significance for pain reduction. Chronic administration of pCGS has disease-modifying effects, with a reduction in need for total joint replacement lasting for 5 years after treatment cessation. Pharmacoeconomic studies of pCGS demonstrate long-term reduction in additional pain analgesia and NSAIDs, with a 50% reduction in costs of other OA medication and healthcare consultations. Consequently, pCGS is the logical choice, with demonstrated medium-term control of pain and lasting impact on disease progression. Physician and patient education on the differentiation of pCGS from other glucosamine formulations will help to improve treatment selection, increase treatment adherence, and optimize clinical benefit in OA.
Assuntos
Antirreumáticos/uso terapêutico , Glucosamina/uso terapêutico , Osteoartrite/tratamento farmacológico , Patentes como Assunto , Animais , Antirreumáticos/efeitos adversos , Antirreumáticos/economia , Antirreumáticos/farmacocinética , Análise Custo-Benefício , Cristalização , Composição de Medicamentos , Custos de Medicamentos , Glucosamina/efeitos adversos , Glucosamina/economia , Glucosamina/farmacocinética , Humanos , Osteoartrite/diagnóstico , Osteoartrite/economia , Educação de Pacientes como Assunto , Resultado do TratamentoRESUMO
BACKGROUND: A standard low-dosing schedule of rituximab (RTX; 2 × 500 mg or 1 × 1000 mg) is as effective for active rheumatoid arthritis (RA) as the registered dose (2 × 1000 mg). Moreover, several small uncontrolled studies suggest that even lower-dosed treatment with RTX also leads to good treatment response in patients with RA. Retreatment with such an 'ultra-low' dose RTX in patients who responded well to RTX induction treatment is of special interest, as long-term use of lower RTX doses may lead to shorter infusion duration, lower risk of adverse events and lower costs. However, the effect of ultra-low dose of RTX has not been investigated using a controlled trial of proper design and dimensions. METHODS/DESIGN: REDO is an investigator driven six-month pragmatic, double-blind, randomised controlled non-inferiority trial on the effects of ultra-low-dose RTX (1 × 500 or 1 × 200 mg) compared to standard low dose (1 × 1000 mg) in RA patients who are being retreated with RTX. A total of 140 RA patients, having reached low disease activity (DAS28CRP < 2.9) after the previous RTX infusion and DAS28CRP < 3.5 at moment of retreatment, are randomised in a ratio of 1:2:2 to 1 × 1000 mg, 1 × 500 mg or 1 × 200 mg. The primary objective is testing non-inferiority of the ultra-low-dose vs. standard low-dose RTX, by comparing mean change in DAS28CRP from baseline to six months to the non-inferiority margin of 0.6. Secondary outcomes over the same period are: function; quality of life; safety; costs; and pharmacokinetics and dynamics as process measures. DISCUSSION: This study protocol shares characteristics of both early dose finding trials as well as late pragmatic clinical studies. Several choices in the design of this trial are described and possible consequences for RA treatment and expected biosimilar introduction are discussed. TRIAL REGISTRATION: Dutch Trial Register, NTR6117 . Registered on 15 November 2016 (CMO NL57520.091.16 , 8 November 2016).
Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Rituximab/administração & dosagem , Antirreumáticos/efeitos adversos , Antirreumáticos/economia , Antirreumáticos/farmacocinética , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/economia , Protocolos Clínicos , Análise Custo-Benefício , Avaliação da Deficiência , Custos de Medicamentos , Humanos , Infusões Parenterais , Países Baixos , Qualidade de Vida , Projetos de Pesquisa , Rituximab/efeitos adversos , Rituximab/economia , Rituximab/farmacocinética , Fatores de Tempo , Resultado do TratamentoRESUMO
Population pharmacokinetic/pharmacodynamic (PK/PD) models were developed to quantitate the exposure-response relationships using continuous longitudinal data on American College of Rheumatology (ACR) subcomponents, that is, tender-joint count (TJC), swollen-joint count (SJC), C-reactive protein, patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, and patient's assessment of physical function for 5 biologics approved for use in rheumatoid arthritis. The models were then used to simulate the time courses of clinical outcomes following different treatment regimens. The relative sensitivity of the 7 subcomponents was assessed using Monte Carlo simulation-based power analysis. The developed population PK/PD models adequately described the relationship between serum concentrations and changes in ACR subcomponents. The trial simulation and subsequent power analysis showed that SJC and TJC appeared to be more sensitive than the other 5 ACR subcomponents to detect treatment effect over placebo/methotrexate. These 7 ACR subcomponents had similar power in detecting the treatment difference between different doses. In addition, the continuous measures of ACR subcomponents did not appear to be more sensitive than binary measures.
Assuntos
Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Modelos Biológicos , Antirreumáticos/administração & dosagem , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Produtos Biológicos/administração & dosagem , Produtos Biológicos/farmacocinética , Produtos Biológicos/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Articulações/efeitos dos fármacos , Articulações/patologia , Metotrexato/administração & dosagem , Metotrexato/farmacocinética , Metotrexato/uso terapêutico , Método de Monte Carlo , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
American College of Rheumatology (ACR) response criteria is used to assess improvement in tender and swollen joint counts and in 3 of the 5 core measures (acute-phase reactant, physician global assessment, patient global assessment, pain, and physical function). From the clinical trial data on 5 approved biological products for the treatment of rheumatoid arthritis, population pharmacokinetic/pharmacodynamic models were developed to quantitatively describe the relationship between exposure and response rates of 3 individual components of ACR response criteria. The models were then used to simulate the clinical outcomes at various time points following different treatment regimens. The relative sensitivity of these criteria components was assessed using power analysis. As compared to the composite endpoints (ACR20/ACR50/ACR70), the individual ACR criteria components had adequate power and higher sensitivity in distinguishing treatment effects over placebo/methotrexate control. The 3 individual ACR criteria components appeared to have similar powers at different dose levels after long-term treatment. This research provides a unique approach to assess the relative sensitivity of the 3 binary components of ACR response criteria which would be useful to support future dose selection and trial design in the treatment of rheumatoid arthritis.
Assuntos
Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Modelos Biológicos , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Produtos Biológicos/farmacocinética , Produtos Biológicos/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Articulações/efeitos dos fármacos , Articulações/patologia , Metotrexato/farmacocinética , Metotrexato/uso terapêutico , Método de Monte Carlo , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
The use of biologics has significantly changed the management of rheumatoid arthritis over the last decade, becoming the cornerstone treatment for many patients. The current therapeutic arsenal consists of just under 10 biologic agents, with four different mechanisms of action. Several studies have demonstrated a large interindividual pharmacokinetic variability, which translates to unpredictability in clinical response among individuals. The present review focuses on the pharmacokinetics and pharmacodynamics of biologic agents approved for rheumatoid arthritis. The literature relating to their concentration-effect relationship and the use of pharmacokinetic-pharmacodynamic modelling to optimize drug regimens is analysed. Due to the scarcity and complexity of these studies, the current dosing strategy is based on clinical indexes/aspects. In general, dose individualization for biologics should be implemented increasingly in clinical practice as there is a direct benefit for treated rheumatoid arthritis patients. Moreover, there is an indirect benefit in terms of cost-effectiveness.
Assuntos
Artrite Reumatoide/tratamento farmacológico , Fatores Biológicos/uso terapêutico , Monitoramento de Medicamentos/métodos , Antirreumáticos/economia , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Artrite Reumatoide/economia , Fatores Biológicos/economia , Fatores Biológicos/farmacocinética , Análise Custo-Benefício , Relação Dose-Resposta a Droga , HumanosRESUMO
AIMS: To evaluate potential differences between PF-05280586 and rituximab sourced from the European Union (rituximab-EU) and USA (rituximab-US) in clinical response (Disease Activity Score in 28 Joints [DAS28] and American College of Rheumatology [ACR] criteria), as part of the overall biosimilarity assessment of PF-05280586. METHODS: A randomised, double-blind, pharmacokinetic similarity trial was conducted in patients with active rheumatoid arthritis refractory to anti-tumour necrosis factor therapy on a background of methotrexate. Patients were treated with 1000 mg of PF-05280586, rituximab-EU or rituximab-US on days 1 and 15 and followed over 24 weeks for pharmacokinetic, clinical response and safety assessments. Key secondary end points were the areas under effect curves for DAS28 and ACR responses. Mean differences in areas under effect curves were compared against respective reference ranges established by observed rituximab-EU and rituximab-US responses using longitudinal nonlinear mixed effects models. RESULTS: The analysis included 214 patients. Demographics were similar across groups with exceptions in some baseline disease characteristics. Baseline imbalances and group-to-group variation were accounted for by covariate effects in each model. Predictions from the DAS28 and ACR models tracked the central tendency and distribution of observations well. No point estimates of mean differences were outside the reference range for DAS28 or ACR scores. The probabilities that the predicted differences between PF-05280586 vs. rituximab-EU or rituximab-US lie outside the reference ranges were low. CONCLUSIONS: No clinically meaningful differences were detected in DAS28 or ACR response between PF-05280586 and rituximab-EU or rituximab-US as the differences were within the pre-specified reference ranges. TRIAL REGISTRATION NUMBER: NCT01526057.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Medicamentos Biossimilares/uso terapêutico , Modelos Biológicos , Rituximab/uso terapêutico , Antirreumáticos/farmacocinética , Medicamentos Biossimilares/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Rituximab/farmacocinética , Resultado do TratamentoRESUMO
Biological drugs and their originated biosimilars are large, highly complex molecules derived from living cells or organisms. Traditional medicines, by contrast, are usually simple molecules of low molecular weight, synthesised by chemical means. The distinct complexities and methods of manufacture create an important difference between biosimilars and conventional generic drugs: while chemical generics can be fully characterised as identical to the originator product, biosimilars cannot. In addition, biological therapies are inherently variable, creating unavoidable differences between even subsequent batches of the same product. An expiring patent does not necessarily mean that the manufacturing process of the originator product becomes available to the biosimilar developers (for instance, the relevant cell line clone and growth medium). Therefore, it cannot be guaranteed that biosimilar products are identical to their reference product on a molecular level. This difference has important implications for the regulation and licensing of biosimilars. While conventional generic drugs require only a limited comparison and demonstration of identical chemical structure to the reference product, biosimilars require far more rigorous testing. In general, there must be a thorough comparison of structural and functional characteristics between biosimilar and originator drug. Stepwise nonclinical in vitro and in vivo approaches are recommended to evaluate the similarity of both drugs and any identified micro-heterogeneities must then be assessed for their impact on safety and clinical performance. Subsequently, clinical pharmacokinetic (PK) studies need to be performed in order to demonstrate a similar PK profile, prior to conducting clinical efficacy trials.
Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Medicamentos Biossimilares/uso terapêutico , Aprovação de Drogas/métodos , Medicamentos Genéricos/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Reumáticas/tratamento farmacológico , Animais , Anti-Inflamatórios/efeitos adversos , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/normas , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacocinética , Antirreumáticos/normas , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/farmacocinética , Medicamentos Biossimilares/normas , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Medicamentos Genéricos/efeitos adversos , Medicamentos Genéricos/normas , Fármacos Gastrointestinais/efeitos adversos , Fármacos Gastrointestinais/farmacocinética , Fármacos Gastrointestinais/normas , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/imunologia , Patentes como Assunto , Segurança do Paciente , Controle de Qualidade , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/imunologia , Medição de Risco , Equivalência Terapêutica , Resultado do TratamentoRESUMO
Despite major advances in the treatment of rheumatoid arthritis (RA) led by the success of biologic therapies, the lack of response to therapy in a proportion of patients, as well as therapy discontinuation owing to systemic toxicity, are still unsolved issues. Unchecked RA might develop into progressive structural joint damage, loss of function and long-term disability, disorders which are associated with a considerable health-economic burden. Therefore, new strategies are required to actively target and deliver therapeutic agents to disease sites in order to promote in situ activity and decrease systemic toxicity. Polymer-drug conjugates can improve the pharmacokinetics of therapeutic agents, conferring desirable properties such as increased solubility and tissue penetration at sites of active disease. Additionally, nanotechnology is an exciting modality in which drugs are encapsulated to protect them from degradation or early activation in the circulation, as well as to reduce systemic toxicity. Together with the targeting capacity of antibodies and site-specific peptides, these approaches will facilitate selective accumulation of therapeutic agents in the inflamed synovium, potentially improving drug efficacy at disease sites without affecting healthy tissues. This Review aims to summarize key developments in the past 5 years in polymer conjugation, nanoparticulate drug delivery and antibody or peptide-based targeting--strategies that might constitute the platform for the next generation of RA therapeutics.
Assuntos
Antirreumáticos/administração & dosagem , Antirreumáticos/farmacocinética , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Animais , Artrite Reumatoide/economia , Sistemas de Liberação de Medicamentos , Desenho de Fármacos , Humanos , Terapia de Alvo Molecular , Nanoestruturas/administração & dosagem , Polímeros/administração & dosagem , Polímeros/farmacocinéticaRESUMO
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
BACKGROUND AND OBJECTIVES: Therapeutic drug monitoring in patients with rheumatoid arthritis (RA) receiving methotrexate (MTX, MTXGlu1) has not been established. In this study, we aim to explore the relationship between red blood cell (RBC) concentrations of MTX and its polyglutamate metabolites (MTXGlu(n); n = 2, 3, 4, 5) and clinical response in RA patients commencing MTX. METHODS: The binding activity of MTXGlu(n) to three putative enzymes involved in the MTX mechanism of actiondihydrofolate reductase, thymidylate synthase, and 5-aminoimidazole-4-carboxamide ribonucleotide transformylasewas simulated. RBC MTXGlu(n) concentrations that gave the highest inhibition activity across all three enzymes were linked with the disease activity score DAS28-3v (C-reactive protein [CRP]). A population pharmacokinetic-pharmacodynamic model was developed to describe the relationship between RBC MTX polyglutamate concentrations and clinical response in 12 RA patients commencing MTX. RESULTS: The highest inhibition activity was with RBC MTXGlu(3-5). These polyglutamates were further evaluated for their relationship with DAS28-3v (CRP). Three of the 12 patients had a high DAS28-3v (CRP) at baseline (mean = 6.1) and showed a delayed response to MTX treatment. The remaining nine patients with a lower DAS28-3v (CRP) baseline (mean = 3.6) showed an immediate response. The developed MTX pharmacokinetic-pharmacodynamic model provided an acceptable description of the observed DAS28-3v (CRP) across all patients. CONCLUSIONS: The developed model describes a longitudinal relationship between RBC MTXGlu(3-5) concentrations and DAS28-3v (CRP) in patients with RA commencing MTX. Further work is required to determine whether measurement of RBC MTX polyglutamates might be useful for dose individualisation in patients with RA.
Assuntos
Antirreumáticos/farmacocinética , Artrite Reumatoide/sangue , Metotrexato/análogos & derivados , Modelos Biológicos , Ácido Poliglutâmico/análogos & derivados , Adulto , Idoso , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Eritrócitos/metabolismo , Feminino , Humanos , Masculino , Metotrexato/farmacocinética , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Ácido Poliglutâmico/farmacocinética , Ácido Poliglutâmico/uso terapêutico , Resultado do TratamentoRESUMO
Obesity, particularly abdominal obesity, is currently considered a chronic low-grade inflammatory condition that plays an active role in the development of the pathophysiologic phenomena responsible for metabolic syndrome and cardiovascular disease through the secretion of proinflammatory adipokines and cytokines. In recent years clear genetic, pathogenic, and epidemiologic links have been established between psoriasis and obesity, with important implications for health. The relationship between the 2 conditions is probably bidirectional, with obesity predisposing to psoriasis and psoriasis favoring obesity. Obesity also has important implications in the treatment of psoriasis, such as a greater risk of adverse effects with conventional systemic drugs and reduced efficacy and/or increased cost with biologic agents, for which dosage should be adjusted to the patient's weight.
Assuntos
Inflamação/complicações , Obesidade/imunologia , Psoríase/imunologia , Adipócitos/metabolismo , Adipócitos/patologia , Adipocinas/metabolismo , Adipocinas/fisiologia , Tecido Adiposo/metabolismo , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/economia , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/uso terapêutico , Antirreumáticos/administração & dosagem , Antirreumáticos/economia , Antirreumáticos/farmacocinética , Antirreumáticos/uso terapêutico , Peso Corporal/efeitos dos fármacos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Causalidade , Moléculas de Adesão Celular/metabolismo , Comunicação Celular , Citocinas/metabolismo , Citocinas/fisiologia , Suscetibilidade a Doenças , Relação Dose-Resposta a Droga , Ácidos Graxos não Esterificados/metabolismo , Hormônios/fisiologia , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/economia , Fatores Imunológicos/farmacocinética , Fatores Imunológicos/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Linfócitos/patologia , Síndrome Metabólica/etiologia , Síndrome Metabólica/fisiopatologia , Modelos Biológicos , Obesidade/complicações , Obesidade/fisiopatologia , Terapia PUVA , Psoríase/complicações , Psoríase/tratamento farmacológicoRESUMO
INTRODUCTION: Rheumatoid arthritis (RA) is a chronic painful and debilitating autoimmune disease. Although the outcome for patients with RA has improved markedly in the past decades, driven largely by the advent of biological disease-modifying antirheumatic drugs (DMARDs) and updated management strategies, adequate disease control cannot be achieved in a substantial proportion of patients. Since RA is a syndrome with different biological subsets, DMARDs, with a novel mechanism of action, may represent a valuable addition to the current armamentarium. Tofacitinib is a novel synthetic DMARD that selectively inhibits Janus kinases (JAKs), particularly JAK1 and JAK3. AREAS COVERED: This review describes the pharmacokinetics of tofacitinib. Furthermore, the article summarizes and comments the drug's efficacy and safety profile in RA patients. The authors furthermore assess data derived from the FDA's RA development program. EXPERT OPINION: Tofacitinib is an oral synthetic DMARD displaying linear pharmacokinetics. Metabolism, primarily mediated by CYP3A4, accounts for 70% of the total clearance of the drug; the remaining 30% are renally excreted. Tofacitinib monotherapy, or in combination with traditional DMARDs, has demonstrated its efficacy while having an acceptable safety profile in RA patients who have responded inadequately to current DMARDs, including TNF antagonists. In view of its undetermined benefit to risk ratio, in the real-world population, tofacitinib should, for now, only be prescribed to selected patients.