RESUMO
AIMS: Since the first approval for transthyretin amyloid polyneuropathy patients, new formulations and different strength of tafamidis have been developed and tested in a different population (transthyretin amyloid cardiomyopathy). The objective of this analysis was to develop a unified population pharmacokinetic (PK) model of tafamidis, which can describe the PK of various different formulations in healthy subjects as well as patients with TTR amyloidosis, and to understand effects of intrinsic and extrinsic factors on the PK variability. METHODS: Pooled data from 23 clinical studies (17 Phase 1 and 6 Phase 2/3 studies) were used for the analysis. The plasma concentration-time data were analysed using a nonlinear mixed effects modelling methodology. Covariate analysis was performed using a stepwise covariate model building procedure. RESULTS: The final model was a 2-compartment model with first-order absorption and elimination coupled with an absorption lag time for nonsolution formations. Body weight, food and tafamidis formulations were incorporated as structural covariates on PK parameters. Covariate analysis further identified age ≥65 years (14.5% decrease) and moderate hepatic impairment effects (57.6% increase) on apparent clearance and transthyretin amyloid polyneuropathy effect (17.3% decrease) on F. However, model-based clinical trial simulation results indicated that tafamidis steady-state exposure changes were not clinically meaningful under the tested conditions. CONCLUSIONS: The unified population PK model of tafamidis was developed based on 23 studies. Subsequent clinical trial simulations indicated that no significant changes in tafamidis exposure necessitating a dose modification are expected due to either extrinsic or intrinsic factors. The model was used to support labelling statements for dose recommendations in special populations.
Assuntos
Neuropatias Amiloides Familiares , Idoso , Neuropatias Amiloides Familiares/tratamento farmacológico , Benzoxazóis , Voluntários Saudáveis , HumanosRESUMO
BACKGROUND: It is unclear whether discharging patients from renal clinic to primary care is safe. AIM: To determine the characteristics, primary care monitoring and renal outcomes of patients discharged from renal clinic. DESIGN AND SETTING: A retrospective study of 2236 adults discharged from a tertiary renal clinic between 2013-2018. METHOD: Patient demographics, primary renal disease, laboratory results and timeline dates were collected from the renal IT system. Timing of blood tests, renal progression, needing dialysis and patient survival were analysed. Reasons for discharge and cause of disease progression were reviewed in patients developing new estimated glomerular filtration rate <20 ml/min/1.73 m2. RESULTS: Patients were older (median age 75; interquartile range 63-84) with non-progressive, seemingly non-proteinuric renal disease. Median time to repeat blood test post-discharge was 75 days with 90% tested within 12 months. Sixty-six percent saw an improvement in kidney function post-discharge and only 13% had a decline of >10 ml/min/1.73 m2. Only 132 patients (6%) developed new advanced chronic kidney disease (estimated glomerular filtration rate < 20 ml/min/1.73 m2) of whom 40% were palliative, 36% had developed acute kidney injury and 23% discharged for failing to attend clinic. One hundred and thirty-four patients (6%) were referred back to nephrology and eight started dialysis of whom six were discharged for failure to attend clinic. CONCLUSION: Most discharged patients are low risk of progressive renal disease and need infrequent monitoring. Non-adherent patients discharged for failing to attend appear to be at risk of poor outcomes and new strategies are needed to better support this population.
Assuntos
Continuidade da Assistência ao Paciente/normas , Testes de Função Renal/normas , Alta do Paciente , Atenção Primária à Saúde/normas , Insuficiência Renal Crônica/terapia , Injúria Renal Aguda/etiologia , Idoso , Idoso de 80 Anos ou mais , Continuidade da Assistência ao Paciente/organização & administração , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nefrologia/organização & administração , Nefrologia/normas , Ambulatório Hospitalar , Cuidados Paliativos/estatística & dados numéricos , Guias de Prática Clínica como Assunto , Atenção Primária à Saúde/organização & administração , Estudos Retrospectivos , Reino UnidoRESUMO
The International Council for Harmonisation (ICH) guidelines have been revised allowing for modeling of concentration-QT (C-QT) data from Phase I dose-escalation studies to be used as primary analysis for QT prolongation risk assessment of new drugs. This work compares three commonly used Phase I dose-escalation study designs regarding their efficiency to accurately identify drug effects on QT interval through C-QT modeling. Parallel group design and 4-period crossover designs with sequential or interleaving cohorts were evaluated. Clinical trial simulations were performed for each design and across different scenarios (e.g. different magnitudes of drug effect, QT variability), assuming a pre-specified linear mixed effect (LME) model for the relationship between drug concentration and change from baseline QT (ΔQT). Analyses suggest no systematic bias in either the predictions of placebo-adjusted ΔQT (ΔΔQT) or the LME model parameter estimates across all evaluated designs. Additionally, false negative rates remained similar and adequately controlled across all evaluated designs. However, compared to the crossover designs, the parallel design had significantly less power to correctly exclude a clinically significant QT effect, especially in the presence of substantial intercept inter-individual variability. In such cases, parallel design is associated with increased uncertainty around ΔΔQT prediction, mainly attributed to the uncertainty around the estimation of the treatment-specific intercept in the model. Throughout all the evaluated scenarios, the crossover design with interleaving cohorts had consistently the best performance characteristics. The results from this investigation will further facilitate informed decision-making during Phase I study design and the interpretation of the associated C-QT modeling output.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Eletrocardiografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Síndrome do QT Longo/induzido quimicamente , Preparações Farmacêuticas/administração & dosagem , Ensaios Clínicos como Assunto , Estudos de Coortes , Estudos Cross-Over , Relação Dose-Resposta a Droga , Humanos , Modelos Biológicos , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de RiscoRESUMO
Cardiac safety assessment is a key regulatory requirement for almost all new drugs. Until recently, one evaluation aspect was via a specifically designated, expensive, and resource intensive thorough QTc study, and a by-time-point analysis using an intersection-union test (IUT). ICH E14 Q&A (R3) (http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_Q_As_R3__Step4.pdf) allows for analysis of the PK-QTc relationship using early Phase I data to assess QTc liability. In this paper, we compared the cardiac risk assessment based on the early Phase I analysis with that from a thorough QTc study across eleven drug candidate programs, and demonstrate that the conclusions are largely the same. The early Phase I analysis is based upon a linear mixed effect model with known covariance structure (Dosne et al. in Stat Med 36(24):3844-3857, 2017). The treatment effect was evaluated at the supratherapeutic Cmax as observed in the thorough QTc study using a non-parametric bootstrap analysis to generate 90% confidence intervals for the treatment effect, and implementation of the standardized methodology in R and SAS software yielded consistent results. The risk assessment based on the concentration-response analysis on the early Phase I data was concordant with that based on the standard analysis of the thorough QTc study for nine out of the eleven drug candidates. This retrospective analysis is consistent with and supportive of the conclusion of a previous prospective analysis by Darpo et al. (Clin Pharmacol Ther 97(4):326-335, 2015) to evaluate whether C-QTc analysis can detect QTc effects in a small study with healthy subjects.
Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Eletrocardiografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Coração/efeitos dos fármacos , Preparações Farmacêuticas/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Estudos Cross-Over , Relação Dose-Resposta a Droga , Humanos , Estudos Prospectivos , Estudos Retrospectivos , Medição de Risco/métodosRESUMO
The International Council for Harmonisation revised the E14 guideline through the questions and answers process to allow concentration-QTc (C-QTc) modeling to be used as the primary analysis for assessing the QTc interval prolongation risk of new drugs. A well-designed and conducted QTc assessment based on C-QTc modeling in early phase 1 studies can be an alternative approach to a thorough QT study for some drugs to reliably exclude clinically relevant QTc effects. This white paper provides recommendations on how to plan and conduct a definitive QTc assessment of a drug using C-QTc modeling in early phase clinical pharmacology and thorough QT studies. Topics included are: important study design features in a phase 1 study; modeling objectives and approach; exploratory plots; the pre-specified linear mixed effects model; general principles for model development and evaluation; and expectations for modeling analysis plans and reports. The recommendations are based on current best modeling practices, scientific literature and personal experiences of the authors. These recommendations are expected to evolve as their implementation during drug development provides additional data and with advances in analytical methodology.
Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Preparações Farmacêuticas/administração & dosagem , Ensaios Clínicos Fase I como Assunto , Desenvolvimento de Medicamentos/métodos , Eletrocardiografia/métodos , Humanos , Modelos BiológicosRESUMO
The original version of this article unfortunately contained an error in Equation 1 under the section "Pre-specified linear mixed effects model". The correct equation has given below.
RESUMO
AIMS: The transthyretin (TTR) stabilizer, tafamidis, has demonstrated efficacy and safety in the treatment of TTR familial amyloid polyneuropathy (20 mg day(-1) ). Tafamidis use in TTR cardiomyopathy led to the study of the potential effect of tafamidis on the QTc interval in healthy subjects. METHODS: This randomized, three treatment, three period, six sequence crossover study with placebo, a positive control (moxifloxacin 400 mg) and tafamidis (400 mg, to achieve a supra-therapeutic Cmax of ~20 µg ml(-1) ) was conducted in healthy volunteers at three clinical research units. Oral dosing in each of the three treatment periods was separated by a washout period of ≥ 14 days. Serial triplicate 12-lead electrocardiograms were performed. QTc intervals were derived using the Fridericia correction method. Safety and tolerability were assessed by physical examination, vital signs measurement, laboratory analyses and monitoring of adverse events (AEs). RESULTS: A total of 42 subjects completed the study. The upper limit of the two-sided 90% confidence intervals (CIs) for the difference in baseline-adjusted QTc F between tafamidis 400 mg and placebo was <10 ms (non-inferiority criterion) for all time points. The lower limit of the two-sided 90% CI between moxifloxacin 400 mg and placebo exceeded 5 ms at the pre-specified moxifloxacin tmax of 3 h post-dose, confirming assay sensitivity. Cmax and AUC(0,24 h) for tafamidis were 20.36 µg ml(-1) and 305.4 µg ml(-1) h, respectively. There were no serious/severe AEs or treatment discontinuations due to AEs. CONCLUSIONS: This thorough QTc study suggests that a supra-therapeutic single 400 mg oral dose of tafamidis does not prolong the QTc interval and is well-tolerated in healthy volunteers.
Assuntos
Benzoxazóis/administração & dosagem , Benzoxazóis/efeitos adversos , Sistema de Condução Cardíaco/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Síndrome do QT Longo/induzido quimicamente , Potenciais de Ação , Administração Oral , Adulto , Bélgica , Benzoxazóis/farmacocinética , Estudos Cross-Over , Esquema de Medicação , Eletrocardiografia , Feminino , Voluntários Saudáveis , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Medição de Risco , Singapura , Estados Unidos , Adulto JovemRESUMO
The International Conference on Harmonization E14 guidance for the clinical evaluation of QT/QTc interval prolongation requires almost all new drugs to undergo a dedicated clinical study, primarily in healthy volunteers, the so-called TQT study. Since 2005, when the E14 guidance was implemented in United States and Europe, close to 400 TQT studies have been conducted. In February 2012, the Cardiac Safety Research Consortium held a think tank meeting at Food and Drug Administration's White Oak campus to discuss whether "QT assessment" can be performed as part of routine phase 1 studies. Based on these discussions, a group of experts convened to discuss how to improve the confidence in QT data from early clinical studies, for example, the First-Time-in-Human trial, through collection of serial electrocardiograms and pharmacokinetic samples and the use of exposure response analysis. Recommendations are given on how to design such "early electrocardiogram assessment," and the limitation of not having a pharmacologic-positive control in these studies is discussed. A research path is identified toward collecting evidence to replace or provide an alternative to the dedicated TQT study.
Assuntos
Antiarrítmicos/uso terapêutico , Avaliação Pré-Clínica de Medicamentos/métodos , Eletrocardiografia , Sistema de Condução Cardíaco/efeitos dos fármacos , Síndrome do QT Longo/diagnóstico , Antiarrítmicos/farmacocinética , Antiarrítmicos/farmacologia , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/diagnóstico , Avaliação Pré-Clínica de Medicamentos/normas , Humanos , Síndrome do QT Longo/prevenção & controle , Técnicas de Patch-Clamp , Projetos de PesquisaRESUMO
A collaboration between the Consortium for Innovation and Quality in Pharmaceutical Development and the Cardiac Safety Research Consortium has been formed to design a clinical study in healthy subjects demonstrating that the thorough QT (TQT) study can be replaced by robust ECG monitoring and exposure-response (ER) analysis of data generated from First-in-Man single ascending dose (SAD) studies. Six marketed drugs with well-characterized QTc effects were identified in discussions with FDA; five have caused QT prolongation above the threshold of regulatory concern. Twenty healthy subjects will be enrolled in a randomized, placebo-controlled study designed with the intent to have similar power to exclude small QTc effects as a SAD study. Two doses (low and high) of each drug will be given on separate, consecutive days to 9 subjects. Six subjects will receive placebo. Data will be analyzed using linear mixed-effects ER models. Criteria for QT-positive drugs will be the demonstration of an upper bound (UB) of the 2-sided 90% confidence interval (CI) of the projected QTc effect at the peak plasma level of the lower dose above the threshold of regulatory concern (currently 10 ms) and a positive slope of ER relationship. The criterion for QT-negative drug will be an UB of the CI of the projected QTc effect of the higher dose <10 ms. It is expected that a successful outcome in this study will provide evidence supporting replacement of the TQT study with ECG assessments in standard early clinical development studies for a new chemical entity.
Assuntos
Ensaios Clínicos Fase I como Assunto/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Eletrocardiografia/efeitos dos fármacos , Eletrocardiografia/métodos , Estudos Prospectivos , Projetos de Pesquisa/estatística & dados numéricos , Relação Dose-Resposta a Droga , Eletrocardiografia/estatística & dados numéricos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Valores de ReferênciaRESUMO
In 2012, the Quality-by-Design and Product Performance Focus Group of AAPS conducted a survey to assess the state of adoption and perception of Quality-by-Design (QbD). Responses from 149 anonymous individuals from industry-including consultants-(88%), academia (7%), and regulatory body (4%), were collected. A majority of respondents (54% to 76%) reported high frequency of utilization of several tools and most QbD elements outlined by International Conference on Harmonization Q8, with design of experiments, risk assessment, and the quality target product profile ranked as the top three. Over two thirds of respondents agreed that the benefits of QbD included both the positive impact it can have on the patient (78%), as well as on internal processes such as knowledge management (85%), decision making (79%), and lean manufacture (71%). However, more than 50% from industry were neutral about or disagreed with QbD leading to a better return on investment. This suggests that, despite the recognized scientific, manufacture, and patient-related benefits, there is not yet a clearly articulated business case for QbD available. There was a difference of opinion between industry and regulatory agency respondents as to whether a QbD-based submission resulted in increased efficiency of review. These contrasting views reinforce the idea that QbD implementation can benefit from further dialog between industry and regulatory authorities. A majority of respondents from academia indicated that QbD has influenced their research. In total, the results indicate the broad adoption of QbD but also suggest we are yet in a journey and that the process of gathering all experience and metrics required for connecting and demonstrating QbD benefits to all stakeholders is still in progress.
Assuntos
Desenho de Fármacos , Indústria Farmacêutica , Controle de Qualidade , Tomada de Decisões , HumanosRESUMO
The ICH E14/S7B Questions and Answers (Q&As) guideline introduces the concept of a "double negative" nonclinical scenario (negative hERG assay and negative in vivo QTc study) to demonstrate that a drug does not produce a clinically relevant QT prolongation (i.e., no QT liability). This nonclinical "double negative" data package, along with negative Phase 1 clinical QTc data, may be sufficient to substitute for a clinical Thorough QT (TQT) study in some specific cases. While standalone GLP in vivo cardiovascular studies in non-rodent species are standard practice during nonclinical drug development for small molecule programs, a variety of approaches to the design, conduct, analysis and interpretation are utilized across pharmaceutical companies and contract research organizations (CROs) that may, in some cases, negatively impact the stringent sensitivity needed to fulfill the new Q&As. Subject matter experts from both Pharma and CROs have collaborated to recommend best practices for more robust nonclinical cardiovascular telemetry studies in non-rodent species, with input from clinical and regulatory experts. The aim was to increase consistency and harmonization across the industry and to ensure delivery of high quality nonclinical QTc data to meet the proposed sensitivities defined within the revised ICH E14/S7B Q&As guideline (Q&As 5.1 and 6.1). The detailed best practice recommendations presented here cover the design and execution of the safety pharmacology cardiovascular study, including optimal methods for acquiring, analyzing, reporting, and interpreting the resulting QTc and pharmacokinetic data to allow for direct comparison to clinical exposures and assessment of safety margin for QTc prolongation.
Assuntos
Sistema Cardiovascular , Síndrome do QT Longo , Humanos , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnóstico , Telemetria , EletrocardiografiaRESUMO
This single-center, randomized, 3-way crossover thorough QT study evaluated the effect of steady-state supratherapeutic venlafaxine (Effexor) on cardiac repolarization. Fifty-four healthy adults received double-blinded extended-release venlafaxine 450 mg/d and placebo and open-label positive-control moxifloxacin 400 mg. The postdose QT intervals corrected for heart rate using the Fridericia formula (QTcF) were assessed on day 14 with an analysis of covariance using a mixed-effects model. At each time, the upper bound of the 2-sided 90%CI for time-matched least-squares (LS) mean difference between venlafaxine and placebo did not exceed the predefined cutoff of 10 milliseconds; the highest 90%CI upper bound was 5.8 milliseconds 24 hours postdose, demonstrating the lack of effect of venlafaxine on the QTc interval (primary objective). Assay sensitivity was established because the lower bound of the 2-sided 90%CI for LS mean difference in QTcF between moxifloxacin and placebo was 7.413 milliseconds on day 14 (postdose 3 hours). The exposure-response analysis demonstrated no evidence of increase in QTcF with increase in venlafaxine and desvenlafaxine concentrations. Also, supratherapeutic venlafaxine was found to be safe and well tolerated. Overall, the results demonstrated the lack of significant prolongation of the QTc interval with supratherapeutic venlafaxine 450 mg/d.
Assuntos
Síndrome do QT Longo , Adulto , Método Duplo-Cego , Eletrocardiografia , Fluoroquinolonas/efeitos adversos , Voluntários Saudáveis , Humanos , Síndrome do QT Longo/induzido quimicamente , Cloridrato de Venlafaxina/efeitos adversosRESUMO
A double-blind, placebo-controlled, four-way crossover study was conducted in 40 subjects to assess the effect of linezolid on corrected QT (QTc) interval prolongation. Time-matched, placebo-corrected QT intervals were determined predose and at 0.5, 1 (end of infusion), 2, 4, 8, 12, and 24 h after intravenous dosing of linezolid 600 and 1,200 mg. Oral moxifloxacin at 400 mg was used as an active control. The pharmacokinetic profile of linezolid was also evaluated. At each time point, the upper bound of the 90% confidence interval (CI) for placebo-corrected QTcF values (i.e., QTc values adjusted for ventricular rate using the correction methods of Fridericia) for linezolid 600 and 1,200-mg doses were <10 ms, which indicates an absence of clinically significant QTc prolongation. At 2 and 4 h after the moxifloxacin dose, corresponding to the population T(max), the lower bound of the two-sided 90% CI for QTcF when comparing moxifloxacin to placebo was >5 ms, indicating that the study was adequately sensitive to assess QTc prolongation. The pharmacokinetic profile of linezolid at 600 mg was consistent with previous observations. Systemic exposure to linezolid increased in a slightly more than dose-proportional manner at supratherapeutic doses, but the degree of nonlinearity was small. At a supratherapeutic single dose of 1,200 mg of linezolid, no treatment-related increase in adverse events was seen compared to 600 mg of linezolid, and no clinically meaningful effects on vital signs and safety laboratory evaluations were noted.
Assuntos
Acetamidas/efeitos adversos , Anti-Infecciosos/efeitos adversos , Arritmias Cardíacas/induzido quimicamente , Oxazolidinonas/efeitos adversos , Acetamidas/uso terapêutico , Adulto , Compostos Aza/efeitos adversos , Compostos Aza/uso terapêutico , Estudos Cross-Over , Método Duplo-Cego , Esquema de Medicação , Feminino , Fluoroquinolonas , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Humanos , Linezolida , Masculino , Pessoa de Meia-Idade , Moxifloxacina , Oxazolidinonas/uso terapêutico , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Adulto JovemRESUMO
INTRODUCTION: ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial) demonstrated the efficacy and safety of tafamidis in transthyretin amyloid cardiomyopathy (ATTR-CM). Model-based analyses from ATTR-ACT can examine predictor effects on dose-response/exposure-response relationships. METHODS: Parametric hazard distributions were developed for all-cause mortality and frequency of cardiovascular-related hospitalization. Time-to-event models were fitted to survival data, and repeated time-to-event models were fitted to hospitalization data. Disease-specific characteristics were assessed as baseline predictors of event hazards. RESULTS: There were 441 patients in this analysis. At month 30, 70.5% (tafamidis) and 57.1% (placebo) of patients were alive, with 154/441 deaths reported; 495 cardiovascular-related hospitalizations occurred. The cumulative risk of death was 42.1% (95% confidence interval [CI] 24.2-58.0) lower with tafamidis than with placebo, regardless of New York Heart Association (NYHA) class; significant predictors of decreased risk were genotype (wild-type), greater 6-Minute Walk Test (6MWT) distance, higher left ventricular ejection fraction (LVEF), and lower blood urea nitrogen (BUN) and N-terminal pro-B-type natriuretic peptide concentrations. The average cumulative risk of cardiovascular-related hospitalization up to 30 months was 40.8% (95% CI 31.0-49.7) lower with tafamidis in NYHA class I/II patients. Significant predictors of reduced risk were greater 6MWT distance, higher LVEF, and lower BUN and troponin I concentrations. CONCLUSIONS: Tafamidis reduced cumulative mortality and hospitalization risk versus placebo in patients with ATTR-CM. Baseline predictors of outcome were consistent with the cardiovascular nature of the disease and suggested that earlier treatment may improve outcomes. CLINICAL TRIALS. GOV IDENTIFIER: NCT01994889 (date of registration: November 26, 2013).
Assuntos
Neuropatias Amiloides Familiares , Benzoxazóis , Cardiomiopatias , Neuropatias Amiloides Familiares/tratamento farmacológico , Benzoxazóis/uso terapêutico , Cardiomiopatias/tratamento farmacológico , Hospitalização/estatística & dados numéricos , Humanos , Modelos Estatísticos , Análise de SobrevidaRESUMO
Rare diseases are increasingly recognized as a global public health priority. Governments worldwide currently provide important incentives to stimulate the discovery and development of orphan drugs for the treatment of these conditions, but substantial scientific, clinical, and regulatory challenges remain. Tafamidis is a first-in-class, disease-modifying transthyretin (TTR) kinetic stabilizer that represents a major breakthrough in the treatment of transthyretin amyloidosis (ATTR amyloidosis). ATTR amyloidosis is a rare, progressive, and fatal systemic disorder caused by aggregation of misfolded TTR and extracellular deposition of amyloid fibrils in various tissues and organs, including the heart and nervous systems. In this review, we present the successful development of tafamidis spanning 3 decades, marked by meticulous laboratory research into disease mechanisms and natural history, and innovative clinical study design and implementation. These efforts established the safety and efficacy profile of tafamidis, leading to its regulatory approval, and enabled post-approval initiatives that further support patients with ATTR amyloidosis.
Assuntos
Benzoxazóis/uso terapêutico , Descoberta de Drogas , Doenças Raras/tratamento farmacológico , Benzoxazóis/síntese química , Benzoxazóis/química , HumanosRESUMO
Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis. Results from 2 randomized, double-blind, vehicle-controlled phase 3 studies showed that twice-daily crisaborole in children and adults with mild to moderate atopic dermatitis was efficacious and well tolerated. Initial pharmacokinetics (PK) studies of crisaborole indicated absorption with measurable systemic levels of crisaborole. The current analysis was conducted to correlate steady-state systemic exposure parameters with ointment dose and identify covariates impacting PK parameters in healthy participants and patients with atopic dermatitis or psoriasis. A nonlinear regression analysis was conducted using ointment dose and noncompartmental PK parameters at steady state (area under the curve [AUCss ] and maximum concentration [Cmax,ss ]). PK data were available from 244 participants across 6 clinical studies (AUCss , N = 239; Cmax,ss , N = 241). Disease condition had the greatest impact on slope in both models, corresponding to 2.5-fold higher AUCss and Cmax,ss values at a given ointment dose in patients with atopic dermatitis or psoriasis relative to healthy participants. Disease severity, race/ethnicity, and sex had marginal effects on AUCss and Cmax,ss . Systemic exposures were similar across age groups ≥2 years of age when the same percentage of body surface area (%BSA) was treated. Predictive performance plots for AUCss and Cmax,ss for different age groups demonstrated that the models adequately describe the observed data. Model predictions indicated that systemic exposure to crisaborole in pediatric patients (2-17 years) is unlikely to exceed systemic exposure in adults (≥18 years), even at the highest possible ointment dose corresponding to a %BSA of 90.
Assuntos
Absorção Fisiológica , Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Fármacos Dermatológicos/farmacocinética , Fármacos Dermatológicos/uso terapêutico , Inibidores da Fosfodiesterase 4/farmacocinética , Inibidores da Fosfodiesterase 4/uso terapêutico , Administração Tópica , Adolescente , Adulto , Idoso , Área Sob a Curva , Compostos de Boro/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Criança , Pré-Escolar , Ensaios Clínicos Fase I como Assunto , Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/sangue , Relação Dose-Resposta a Droga , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Dinâmica não Linear , Pomadas , Inibidores da Fosfodiesterase 4/sangue , Psoríase/tratamento farmacológico , Análise de Regressão , Adulto JovemRESUMO
PF-05251749 is a dual inhibitor of casein kinase 1 δ/ε, key regulators of circadian rhythm. As a result of its mechanism of action, PF-05251749 may also change the heart rate corrected QT (QTc) circadian rhythm, which may confound detection of drug-induced QTc prolongation. In this analysis, a nonlinear mixed effect model including a multioscillator function was developed in addition to fitting the prespecified linear mixed effect concentration-QTc model, to identify QTc liability of PF-05251749 in the presence of potential circadian rhythm change. The modeling results suggested lack of clinically meaningful QTc prolongation (upper bound of 90% confidence interval for ∆∆QTc < 10 milliseconds) and that the drug-induced QTc circadian rhythm change was not present. However, simulation results indicated that inference of drug-induced QTc prolongation could be misleading if the drug effect on QTc circadian rhythm is not properly addressed. The modeling and simulation results suggest that prespecification of the concentration-QTc model should be reconsidered for drugs with circadian rhythm modulation potential.
Assuntos
Ritmo Circadiano/efeitos dos fármacos , Síndrome do QT Longo/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Caseína Quinase 1 épsilon/antagonistas & inibidores , Caseína Quinase Idelta/antagonistas & inibidores , Eletrocardiografia , Humanos , Modelos Lineares , Dinâmica não LinearRESUMO
The effect of steady-state supratherapeutic sertraline (Zoloft) on QT interval was assessed in a single-center, randomized, 3-way crossover, double-blind, placebo- and moxifloxacin-controlled thorough QT study. Healthy adults received sertraline 400 mg/day, moxifloxacin 400 mg, and placebo, with a washout period (≥14 days) between treatments. A 12-lead electrocardiogram was recorded in triplicate before dosing and at selected time points up to 72 hours after dosing. Analysis of covariance using a mixed-effect model with sequence, period, treatment, time, and treatment-by-time interaction as fixed effects; subject within sequence as a random effect; and baseline QT corrected for heart rate using Fridericia formula (QTcF) as a covariate was conducted. A 90% confidence interval for the least squares (LS) mean difference in QTcF between active treatment and placebo was computed for each postdose time point. Exposure-response was assessed using linear mixed-effect modeling. Fifty-four subjects were enrolled. Over 24 hours after dosing, the LS mean difference in QTcF for sertraline versus placebo ranged from 5.597 milliseconds to 9.651 milliseconds. The upper bound of the 90% confidence interval for the LS mean difference exceeded a predefined 10-millisecond significance threshold at the 4-hour postdose time point only (LS mean, 9.651 milliseconds [90% confidence interval, 7.635-11.666]). In the exposure-response analysis, QTcF values increased significantly with increasing sertraline concentration (slope = 0.036 milliseconds/ng/mL; P < .0001). Predicted change from baseline in QTcF at therapeutic maximum plasma sertraline concentration was 3.57 milliseconds. This thorough QTc study demonstrated a positive signal for QTc prolongation for sertraline at the steady-state 400-mg/day dose.
Assuntos
Síndrome do QT Longo/induzido quimicamente , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Sertralina/efeitos adversos , Adulto , Estudos Cross-Over , Método Duplo-Cego , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Moxifloxacina/administração & dosagem , Moxifloxacina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Sertralina/administração & dosagem , Fatores de Tempo , Adulto JovemRESUMO
Tafamidis, a non-nonsteroidal anti-inflammatory benzoxazole derivative, acts as a transthyretin (TTR) stabilizer to slow progression of TTR amyloidosis (ATTR). Tafamidis meglumine, available as 20-mg capsules, is approved in more than 40 countries worldwide for the treatment of adults with early-stage symptomatic ATTR polyneuropathy. This agent, administered as an 80-mg, once-daily dose (4 × 20-mg capsules), is approved in the United States, Japan, Canada, and Brazil for the treatment of hereditary and wild-type ATTR cardiomyopathy in adults. An alternative single solid oral dosage formulation (tafamidis 61-mg free acid capsules) was developed and introduced for patient convenience (approved in the United States, United Arab Emirates, and European Union). In this single-center, open-label, randomized, 2-period, 2-sequence, crossover, multiple-dose phase 1 study, the rate and extent of absorption were compared between tafamidis 61-mg free acid capsules (test) and tafamidis meglumine 80-mg (4 × 20-mg) capsules (reference) after 7 days of repeated oral dosing under fasted conditions in 30 healthy volunteers. Ratios of adjusted geometric means (90%CI) for the test/reference formulations were 102.3 (98.0-106.8) for area under the concentration-time profile over the dosing interval and 94.1 (89.1-99.4) for the maximum observed concentration, satisfying prespecified bioequivalence acceptance criteria (90%CI, 80-125). Both tafamidis regimens had an acceptable safety/tolerability profile in this population.
Assuntos
Neuropatias Amiloides/tratamento farmacológico , Benzoxazóis/farmacocinética , Cardiomiopatias/prevenção & controle , Pré-Albumina/efeitos dos fármacos , Administração Oral , Adulto , Neuropatias Amiloides Familiares/complicações , Benzoxazóis/administração & dosagem , Benzoxazóis/efeitos adversos , Brasil , Canadá , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Estudos Cross-Over , Progressão da Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Composição de Medicamentos/métodos , Jejum/sangue , Feminino , Voluntários Saudáveis/estatística & dados numéricos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Pré-Albumina/metabolismo , Segurança , Equivalência Terapêutica , Estados UnidosRESUMO
The JTpeak interval has been proposed as a new biomarker to demonstrate mixed ion channel effects, potentially leading to reduced late-stage electrocardiogram (ECG) monitoring for mildly QT-prolonging drugs. ECG waveforms from the IQ-CSRC study were used. Twenty healthy subjects were enrolled with 6 subjects on placebo and 9 subjects on each of 5 mildly QT-prolonging drugs - moxifloxacin, dofetilide, ondansetron, dolasetron, and quinine - and 1 negative drug, levocetirizine. A vector magnitude lead was derived from 12-lead ECGs, and measurements were made on a median beat from three 10-second replicates. Data were analyzed using a linear concentration-response model with QTcF and heart rate corrected JTpeak (JTpeak_c) as dependent variables. For moxifloxacin, dofetilide, and ondansetron, all pure hERG blockers, slopes of the concentration (C)-QTcF and C-JTpeak_c relationships were positive and statistically significant. With the prespecified linear model, the predicted effects on ΔΔQTcF and ΔΔJTpeak_c were 11.4 and 9.4 milliseconds for moxifloxacin at the geometric mean Cmax on day 1, 9.0 and 11.7 milliseconds for dofetilide and 11.5, and 7.9 milliseconds for ondansetron, respectively. In contrast, dolasetron and quinine, both with additional ion channel effects, prolonged QTcF with a positive C-ΔQTcF slope and predicted ΔΔQTcF effect on day 1 of 6.2 and 11.4 milliseconds, whereas the C-ΔJTpeak_c slope and the predicted ΔΔJTpeak on day 1 were negative (-0.3 and -7.5 milliseconds per ng/mL). Pure hERG-blocking drugs prolonged both the QTc and the JTpeak_c intervals, whereas drugs with mixed ion channel effects, including peak sodium inhibition, prolonged QTcF but not the JTpeak_c interval.