RESUMO
Mitiperstat is a myeloperoxidase inhibitor in clinical development for treatment of patients with heart failure and preserved or mildly reduced ejection fraction, non-alcoholic steatohepatits and chronic obstructive pulmonary disease. We aimed to assess the risk of QT-interval prolongation with mitiperstat using concentration-QT (C-QT) modeling. Healthy male volunteers were randomized to receive single oral doses of mitiperstat 5, 15, 45, 135, or 405 mg (n = 6 per dose) or matching placebo (n = 10) in a phase 1 study (NCT02712372). Time-matched pharmacokinetic and digital electrocardiogram data were collected at the baseline (pre-dose) and at 11 time-points up to 48 h post-dose. C-QT analysis was prespecified as an exploratory objective. The prespecified linear mixed effects model used baseline-adjusted QT interval corrected for the heart rate by Fridericia's formula (ΔQTcF) as a dependent variable and plasma mitiperstat concentration as an independent variable. Initial exploratory analyses indicated that all model assumptions were met (no effect on heart rate; appropriate use of QTcF; no hysteresis; linear concentration-response relationship). Model-predicted mean baseline-corrected and placebo-adjusted ΔΔQTcF was +0.73 ms (90% confidence interval [CI]: -1.73, +3.19) at the highest anticipated clinical exposure (0.093 µmol/L) during treatment with mitiperstat 5 mg once daily. The upper 90% CI was below the established threshold of regulatory concern. The 16-fold margin to the highest observed exposure was high enough to mean that a positive control was not needed. Mitiperstat is not associated with risk of QT-interval prolongation at expected therapeutic concentrations.
Assuntos
Peroxidase , Pirimidinas , Pirróis , Humanos , Masculino , Eletrocardiografia , Voluntários SaudáveisRESUMO
Dapagliflozin was recently approved for use in adults with chronic heart failure with reduced ejection fraction (HFrEF) with/without type 2 diabetes mellitus (T2DM). The objectives of this analysis were to characterize dapagliflozin pharmacokinetics in patients with HFrEF and to compare dapagliflozin systemic exposure between adults with HFrEF with/without T2DM and adults with T2DM. A nonlinear mixed-effects modelling approach was applied; the population-pharmacokinetic model was developed using 9735 dapagliflozin plasma concentrations from 2744 patients. The final two-compartmental model adequately described the observed dapagliflozin concentrations, with a similar estimated apparent clearance compared with a previous estimate in patients with T2DM without HF and in healthy subjects (23.0 [95% CI: 22.6-23.9] L/h vs. 22.9 [95% CI: 22.1-23.7] L/h). The model-predicted median area under the dapagliflozin concentration-time profile was ≤1.2-fold higher in patients with HFrEF vs. those with T2DM without HFrEF, which is not considered clinically relevant. Dapagliflozin exposure was similar between patients with HFrEF with/without T2DM and T2DM patients without HFrEF.
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Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Disfunção Ventricular Esquerda , Adulto , Humanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/induzido quimicamente , Volume Sistólico , Glucosídeos/efeitos adversos , Compostos Benzidrílicos/efeitos adversos , Disfunção Ventricular Esquerda/induzido quimicamenteRESUMO
Despite the evidence that exercise is effective at mitigating common side effects in adults with cancer, it is rarely part of usual cancer care. One reason for this is the lack of economic evidence supporting the benefit of exercise. Economic evaluations often rely on the use of generic utility measures to assess cost effectiveness. This review identifies and synthesizes the literature on the use of generic utility measures used to evaluate exercise interventions for adults with cancer. A systematic search of the literature from January 2000 to February 2023 was conducted using four databases (Medline, EMBASE, CINAHL, Academic Search Complete). Exercise studies involving adults with any type of cancer that used a generic utility measure were eligible for inclusion. Of the 2780 citations retrieved, 10 articles were included in this review. Seven articles included economic evaluations, with varying results. Four studies reported on cost-effectiveness; however, detailed effectiveness data derived from the generic utility measure were often not reported. Generic utility measures help to compare baseline values of and changes in health utility weights across studies and to general population norms; however, to date, they are underutilized in exercise oncology studies. Consideration should be given to the identified research evidence, population, and methodological gaps.
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Exercício Físico , Neoplasias , Adulto , Humanos , Análise Custo-Benefício , Neoplasias/terapia , Análise de Custo-EfetividadeRESUMO
Background: Approaches to screening, assessment, and treatment of breast cancer-related lymphedema (BCRL) vary widely. We evaluated overall quality of clinical practice guidelines (CPGs) for managing BCRL using the Appraisal of Guidelines for REsearch and Evaluation II (AGREE II) tool, and relevance of consensus recommendations for the Canadian health context. Methods and Results: We searched electronic databases, gray literature, national lymphedema frameworks, and expert opinions, to identify lymphedema CPGs, printed/published from January 2013 to October 2021. Using AGREE II, six health care professionals reviewed CPGs for consensus. Domain-specific AGREE II quality consensus scores were required (≥70% for Rigor of Development; ≥ 60% for Stakeholder Involvement and Editorial Independence; and ≥50% for Clarity of Presentation, Applicability, Scope, and Purpose). Results and overall recommendations from the CPGs were summarized and synthesized. Nine CPGs met inclusion criteria for review. Wide variability of evidence-based recommendations, and limited clinical considerations were found. Scope and Purpose, and Clarity of Presentation were adequate in six of nine CPGs; Stakeholder Involvement in seven of nine CPGs; and Editorial Independence in three of nine CPGs. Across all CPGs, Applicability was minimally reported. Only the Queensland Health CPG met quality consensus scores for Rigor and Development; however, the focus was limited to compression therapy. Conclusions: No CPG reviewed could be adopted for the Canadian health context. The proposed Canadian BCRL CPG will focus on stakeholder engagement, methodology, and implementation/evaluation. Using AGREE II allowed for assessment of quality of methods used to develop identified CPGs from other countries before consideration of adoption in a Canadian Context.
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Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by abnormally high blood glucose concentrations due to dysfunction of the insulin-producing beta-cells in the pancreas. Dapagliflozin, an inhibitor of renal glucose reabsorption, has the potential to improve often suboptimal glycemic control in patients with T1DM through insulin-independent mechanisms and to partially mitigate the adverse effects associated with long-term insulin administration. In this work, we have adapted a systems pharmacology model of type 2 diabetes mellitus to describe the T1DM condition and characterize the effect of dapagliflozin on short- and long-term glycemic markers under various treatment scenarios. The developed platform serves as a quantitative tool for the in silico evaluation of the insulin-glucose-dapagliflozin crosstalk, optimization of the treatment regimens, and it can be further expanded to include additional therapies or other aspects of the disease.
Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Glicemia , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Transportador 2 de Glucose-Sódio/uso terapêutico , Glucose/uso terapêutico , InsulinaRESUMO
AIM: This thorough QT/QTc (TQT) study was conducted to evaluate the risk of QT prolongation for verinurad when combined with allopurinol. Verinurad is a novel, urate anion exchanger 1 inhibitor that reduces serum urate levels by promoting urinary excretion of uric acid. It is co-administered with a xanthine oxidase inhibitor. METHODS: The TQT study (NCT04256629) was a randomized, placebo-controlled, double-blind, three-period, crossover study, conducted in healthy volunteers. A total of 24 participants received single doses of verinurad 24 mg extended release, 40 mg immediate release formulation (both co-administered with allopurinol 300 mg), and matching placebos. The primary endpoint was baseline- and placebo-adjusted Fridericia-corrected QTcF interval (ΔΔQTcF) at the concentration of interest. A prespecified linear mixed-effects concentration-QTc model was used to estimate the primary endpoint. Time-matched 12-lead digital electrocardiograms and plasma concentrations were measured at baseline and up to 48 h after dose in each participant. RESULTS: Estimated ΔΔQTcF at the highest clinically relevant scenario (76 ng/mL) was -2.7 msec (90% confidence interval [CI]: -4.6, -0.8). Furthermore, the upper 90% ΔΔQTcF CI was estimated to be below 10 msec at all observed verinurad concentrations. Supratherapeutic verinurad dose was used to achieve exposures eightfold higher than the highest clinically relevant exposure, thus waiving the need for positive control. CONCLUSIONS: As the effect on ΔΔQTcF was below the threshold for regulatory concern (10 msec) at the supratherapeutic exposure, it can be concluded that verinurad and allopurinol treatment does not induce QTcF prolongation at the highest clinically relevant exposures.
Assuntos
Alopurinol , Síndrome do QT Longo , Humanos , Moxifloxacina/farmacologia , Estudos Cross-Over , Alopurinol/farmacologia , Ácido Úrico , Frequência Cardíaca , Relação Dose-Resposta a Droga , Eletrocardiografia , Método Duplo-Cego , Síndrome do QT Longo/induzido quimicamente , Síndrome do QT Longo/diagnósticoRESUMO
Dapagliflozin improves glycemic control in patients with type 2 diabetes mellitus (T2DM) and is approved in Japanese patients with type 1 diabetes mellitus (T1DM) with inadequate glycemic control. The objectives of this work were to characterize the dapagliflozin pharmacokinetics (PK) in patients with T1DM, assess the influence of covariates on dapagliflozin PK, and compare dapagliflozin systemic exposure between patients with T1DM and T2DM. Population PK analysis was performed using a nonlinear mixed-effect modeling approach. The analysis included 5793 dapagliflozin plasma concentrations from 1150 adult patients with T1DM (global population), who were on routine insulin therapy, collected from 1 phase 2 (NCT01498185) and 2 phase 3 (DEPICT-1, NCT02268214; DEPICT-2, NCT02460978) studies. Covariate effects were investigated using stepwise covariate modeling. Model-derived area under the concentration-time curve (AUC) in patients with T1DM was compared to AUC in patients with T2DM (using data from historical dapagliflozin studies). The final 2-compartmental model adequately described the dapagliflozin concentrations in patients with T1DM. The estimated apparent clearance was 20.5 L/h. Renal function (measured as estimated glomerular filtration rate), sex, and body weight were identified as covariates, where patients with better renal function, male patients, and heavier patients had lower dapagliflozin systemic exposure. Among the covariates studied, none of the covariates affected dapagliflozin systemic exposure >1.4-fold compared to a reference individual and were therefore deemed to be not clinically relevant. Dapagliflozin systemic exposure was comparable between patients with T1DM and T2DM.
Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Adulto , Compostos Benzidrílicos/farmacocinética , Glicemia/análise , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Relação Dose-Resposta a Droga , Feminino , Glucosídeos , Humanos , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , MasculinoRESUMO
BACKGROUND: One of the more frequent complications following treatment for breast cancer, lymphedema is a substantial swelling of the arm, breast and chest wall that occurs on the side where lymph nodes were removed. The aim of this work is to update recommendations on the prevention, diagnosis and management of lymphedema related to breast cancer. METHODS: We present the protocol for an update of the 2001 clinical practice guideline on lymphedema from the Steering Committee for Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. We will use a patient-oriented research approach with a focus on self-management and the positive health model to inform the updated guideline development. The methods proposed will be undertaken with consideration of the standards outlined in the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. The literature will be appraised by evaluating existing guidelines from other countries, the evidence from systematic reviews and meta-analyses and direct evidence from clinical studies. We will manage competing interests according to Guidelines International Network principles. Recommendations will be presented using an actionable statement format and will be linked to the level of evidence along with any relevant considerations used in formulation. A draft of the guideline will be produced by the steering committee then sent out to international experts and stakeholder groups for feedback. INTERPRETATION: The primary benefit of this clinical guideline will be to improve the quality of care of women with breast cancer-related lymphedema. Findings will be disseminated at national and international conferences and through webinars and educational videos hosted on the websites of the supporting organizations.
Assuntos
Neoplasias da Mama , Linfedema , Gerenciamento da Prática Profissional , Neoplasias da Mama/complicações , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapia , Canadá/epidemiologia , Feminino , Humanos , Linfedema/diagnóstico , Linfedema/etiologia , Linfedema/terapia , Guias de Prática Clínica como AssuntoRESUMO
AIMS: Concentration-QT modelling (C-QTc) of first-in-human data has been rapidly adopted as the primary evaluation of QTc interval prolongation risk. Here, we evaluate the performance of C-QTc in early oncology settings (i.e., patients, no placebo or supratherapeutic dose, 3 + 3 designs). METHODS: C-QTc performance was evaluated across three oncology scenarios using a simulation-estimation approach: (scen1) typical dose-escalation testing six dose levels (n = 21); (scen2) small dose-escalation testing two dose levels (n = 9); (scen3) expansion cohorts at one dose level (n = 6-140). True ΔΔQTc effects ranged from 3 ms ("no effect") to 20 ms ("large effect"). Performance was assessed based on the upper limit of the ΔQTc two-sided 90% CI against a threshold of 10 or 20 ms. RESULTS: The performance against the 10 ms threshold was limited based on C-QTc data from typical dose escalation (scen1) and acceptable performance was observed only for relatively large expansions (n ≥ 45; scen3). Performance against the 20 ms threshold was acceptable based on C-QTc data from a typical dose escalation (scen1) or dose expansion cohort n > 10 (scen3). In general, pooling C-QTc data from dose escalation and expansion cohorts substantially improved the performance and reduced the ΔQTc 90% CI width. CONCLUSION: C-QTc performance appeared limited using a 10 ms threshold, but acceptable against a 20 ms threshold. Selection of threshold may be informed by the benefit-risk balance in a specific disease area. Acceptable precision (i.e., confidence intervals) of the estimated ΔQTc, regardless of its magnitude, can be facilitated by pooling data from dose escalation and expansion cohorts.
Assuntos
Eletrocardiografia , Síndrome do QT Longo , Simulação por Computador , Relação Dose-Resposta a Droga , Frequência Cardíaca , Humanos , Síndrome do QT Longo/induzido quimicamente , OncologiaRESUMO
Pharmacokinetics-matched digital electrocardiogram data (n = 503 measurements from 180 patients) collected in a first-in-human, multi-part, dose-escalation (from 80 to 800 mg) and dose expansion (at 480 mg) phase 1 study in patients with advanced solid malignancies, were used to assess potential risk of QT prolongation associated with the AKT inhibitor capivasertib. The relationship between plasma drug concentrations and baseline-adjusted Fridericia-corrected QT (ΔQTcF) values was estimated using a prespecified linear mixed-effects model. The model provided an unbiased reproduction of the experimental data set, estimating a small but positive correlation between capivasertib concentration and ΔQTcF. At the expected therapeutic dose (400 mg twice daily) the predicted mean ΔQTcF at the steady state maximum concentration was 3.97 ms with an upper limit of the 90% CI of 5.07 ms; below the 10 ms limit proposed by ICH E14 guidance. This analysis suggests that capivasertib is not expected to present a clinically significant risk for QT prolongation that is associated with pro-arrhythmic effects.
Assuntos
Síndrome do QT Longo , Neoplasias , Relação Dose-Resposta a Droga , Eletrocardiografia , Frequência Cardíaca , Humanos , Síndrome do QT Longo/induzido quimicamente , Neoplasias/tratamento farmacológico , Pirimidinas , PirróisRESUMO
Verinurad, a uric acid transporter 1 (URAT1) inhibitor, lowers serum uric acid by promoting its urinary excretion. Co-administration with a xanthine oxidase inhibitor (XOI) to simultaneously reduce uric acid production rate reduces the potential for renal tubular precipitation of uric acid, which can lead to acute kidney injury. The combination is currently in development for chronic kidney disease and heart failure. The aim of this work was to apply and extend a previously developed semi-mechanistic exposure-response model for uric acid kinetics to include between-subject variability to verinurad and its combinations with XOIs, and to provide predictions to support future treatment strategies. The model was developed using data from 12 clinical studies from a total of 434 individuals, including healthy volunteers, patients with hyperuricemia, and renally impaired subjects. The model described the data well, taking into account the impact of various patient characteristics such as renal function, baseline fractional excretion of uric acid, and race. The potencies (EC50s) of verinurad (reducing uric acid reuptake), febuxostat (reducing uric acid production), and oxypurinol (reducing uric acid production) were: 29, 128, and 13,030 ng/mL, respectively. For verinurad, symptomatic hyperuricemic (gout) subjects showed a higher EC50 compared with healthy volunteers (37 ng/mL versus 29 ng/mL); while no significant difference was found for asymptomatic hyperuricemic patients. Simulations based on the uric acid model were performed to assess dose-response of verinurad in combination with XOI, and to investigate the impact of covariates. The simulations demonstrated application of the model to support dose selection for verinurad.
Assuntos
Hiperuricemia/tratamento farmacológico , Naftalenos/uso terapêutico , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Propionatos/uso terapêutico , Piridinas/uso terapêutico , Ácido Úrico/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Feminino , Humanos , Hiperuricemia/sangue , Hiperuricemia/urina , Rim/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Naftalenos/administração & dosagem , Naftalenos/farmacologia , Propionatos/administração & dosagem , Propionatos/farmacologia , Piridinas/administração & dosagem , Piridinas/farmacologia , Ácido Úrico/urina , Xantina Oxidase/antagonistas & inibidores , Adulto JovemRESUMO
The International Conference on Harmonisation (ICH) E14 guidance provides recommendations to assess the potential of a drug to delay cardiac repolarization (QT prolongation), including general guidelines for cases in which a conventional thorough QT study (TQT) might not be feasible. These guidelines have been updated through the ICH question-and-answer process, with the last revision in 2015. We conducted a comprehensive analysis of QT prolongation evaluation of small-molecule new drug applications (NDAs) approved in oncology between 2011 and 2019 to extract learning experience. The following information was analysed: (1) methods to assess QT prolongation, (2) electrocardiogram data collection, (3) QT-related label language, and (4) postmarketing requirements. Overall, every NDA included a QT assessment. The concentration-QTc modeling approach (studies in which QT was not the primary objective) was the most common approach (59%), followed by the TQT and the dedicated QT studies (20% and 21%, respectively). The quality and quantity of the QT assessments were different across NDAs, which suggested relatively large flexibility in the designs and approaches to characterizing QT liability. The QT-related label language reflected the QT results, but also the safety events and the study design limitations because of the oncology settings. There was no delay in approval because of less robust QTc studies as long as the benefit-to-risk ratio of the drug was acceptable, and the implications were reflected in the label. This work offers a structured understanding of the QT evaluation criteria by the Food and Drug Administration and can assist in planning QT prolongation assessments in oncology settings.
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Antineoplásicos/efeitos adversos , Aprovação de Drogas/estatística & dados numéricos , Síndrome do QT Longo/induzido quimicamente , Relação Dose-Resposta a Droga , Eletrocardiografia , Europa (Continente) , Humanos , Vigilância de Produtos Comercializados/estatística & dados numéricos , Projetos de PesquisaRESUMO
This analysis reports a quantitative modeling and simulation approach for oral dapagliflozin, a primarily uridine diphosphate-glucuronosyltransferase (UGT)-metabolized human sodium-glucose cotransporter 2 selective inhibitor. A mechanistic dapagliflozin physiologically based pharmacokinetic (PBPK) model was developed using in vitro metabolism and clinical pharmacokinetic (PK) data and verified for context of use (e.g., exposure predictions in pediatric subjects aged 1 month to 18 years). Dapagliflozin exposure is challenging to predict in pediatric populations owing to differences in UGT1A9 ontogeny maturation and paucity of clinical PK data in younger age groups. Based on the exposure-response relationship of dapagliflozin, twofold acceptance criteria were applied between model-predicted and observed drug exposures and PK parameters (area under the curve and maximum drug concentration) in various scenarios, including monotherapy in healthy adults (single/multiple dose), monotherapy in hepatically or renally impaired patients, and drug-drug interactions with UGT1A9 modulators, such as mefenamic acid and rifampin. The PBPK model captured the observed exposure within twofold of the observed monotherapy data in adults and adolescents and in special population. As a guide to determining dosing regimens in pediatric studies, the verified PBPK model, along with UGT enzyme ontogeny maturation understanding, was used for predictions of dapagliflozin monotherapy exposures in pediatric subjects aged 1 month to 18 years that best matched exposure in adult patients with a 10-mg single dose of dapagliflozin.
Assuntos
Compostos Benzidrílicos/farmacocinética , Glucosídeos/farmacocinética , Glucuronosiltransferase/metabolismo , Ácido Mefenâmico/farmacocinética , Rifampina/farmacocinética , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , UDP-Glucuronosiltransferase 1A/metabolismo , Administração Oral , Adolescente , Antibióticos Antituberculose/administração & dosagem , Antibióticos Antituberculose/efeitos adversos , Antibióticos Antituberculose/farmacocinética , Área Sob a Curva , Criança , Pré-Escolar , Simulação por Computador , Inibidores de Ciclo-Oxigenase/administração & dosagem , Inibidores de Ciclo-Oxigenase/efeitos adversos , Inibidores de Ciclo-Oxigenase/farmacocinética , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Voluntários Saudáveis/estatística & dados numéricos , Insuficiência Hepática/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Masculino , Ácido Mefenâmico/administração & dosagem , Ácido Mefenâmico/efeitos adversos , Modelos Biológicos , Valor Preditivo dos Testes , Insuficiência Renal/tratamento farmacológico , Rifampina/administração & dosagem , Rifampina/efeitos adversosRESUMO
CONTEXT: Combining a sodium-glucose cotransporter 2 inhibitor with a xanthine oxidase inhibitor (XOI) and a urate transporter 1 (URAT1) inhibitor may enhance serum uric acid (sUA) lowering. However, concerns exist regarding high urinary UA (uUA) excretion rates and subsequent crystallization in renal tubules. OBJECTIVE: To assess whether dapagliflozin added to verinurad, a selective URAT1 inhibitor, and febuxostat, an XOI, increases uUA excretion. DESIGN: Randomized, placebo-controlled, 2-way crossover study (NCT03316131). PATIENTS: Adults with asymptomatic hyperuricemia. INTERVENTIONS: Subjects (N = 36) were randomized to oral once-daily 9 mg verinurad plus 80 mg febuxostat plus 10 mg dapagliflozin for 7 days and 7 days of oral once-daily 9 mg verinurad plus 80 mg febuxostat plus placebo with an intervening 7- to 21-day washout period. MAIN OUTCOME MEASURE: Difference in peak uUA excretion between groups from baseline to day 7. Secondary outcomes included changes in sUA levels and 24-h uUA excretion. RESULTS: Both regimens lowered mean peak uUA excretion (least squares mean changes from baseline: -12.9 mg/h [95% confidence interval (CI): -21.0 to -4.7], dapagliflozin; -13.2 mg/h [95% CI -21.3 to -5.0], placebo). sUA concentrations were lower with dapagliflozin (mean treatment difference -62.3 µmol/L [95% CI -82.8 to -41.8]). Dapagliflozin did not impact verinurad pharmacokinetics, its main metabolites, or febuxostat or fasting plasma glucose levels vs verinurad plus febuxostat. There were no clinically relevant changes in safety parameters. CONCLUSIONS: Dapagliflozin further reduced sUA without influencing uUA excretion, suggesting that its combination with verinurad and febuxostat at the doses tested does not adversely affect kidney function. CLINICAL TRIAL REGISTRATION NUMBER: NCT03316131.
Assuntos
Compostos Benzidrílicos/administração & dosagem , Febuxostat/administração & dosagem , Glucosídeos/administração & dosagem , Hiperuricemia/tratamento farmacológico , Naftalenos/administração & dosagem , Propionatos/administração & dosagem , Piridinas/administração & dosagem , Adulto , Compostos Benzidrílicos/efeitos adversos , Estudos Cross-Over , Quimioterapia Combinada , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Febuxostat/efeitos adversos , Feminino , Glucosídeos/efeitos adversos , Supressores da Gota/administração & dosagem , Supressores da Gota/efeitos adversos , Humanos , Hiperuricemia/sangue , Masculino , Pessoa de Meia-Idade , Naftalenos/efeitos adversos , Propionatos/efeitos adversos , Piridinas/efeitos adversos , Resultado do Tratamento , Estados Unidos , Ácido Úrico/sangue , Uricosúricos/administração & dosagem , Uricosúricos/efeitos adversos , Adulto JovemRESUMO
RATIONALE & OBJECTIVE: Hyperuricemia has been implicated in the development and progression of chronic kidney disease. Verinurad is a novel, potent, specific urate reabsorption inhibitor. We evaluated the effects on albuminuria of intensive urate-lowering therapy with verinurad combined with the xanthine oxidase inhibitor febuxostat in patients with hyperuricemia and type 2 diabetes mellitus (T2DM). STUDY DESIGN: Phase 2, multicenter, prospective, randomized, double-blind, parallel-group, placebo-controlled trial. SETTING & PARTICIPANTS: Patients 18 years or older with hyperuricemia, albuminuria, and T2DM. INTERVENTION: Patients randomly assigned 1:1 to verinurad (9mg) plus febuxostat (80mg) or matched placebo once daily for 24 weeks. OUTCOMES: The primary end point was change in urinary albumin-creatinine ratio (UACR) from baseline after 12 weeks' treatment. Secondary end points included safety and tolerability and effect on glomerular filtration. RESULTS: 60 patients were enrolled (n=32, verinurad and febuxostat; n=28, placebo). UACRs after treatment with verinurad plus febuxostat were lower than after placebo at 1, 12, and 24 weeks: -38.6% (90% CI, -60.9% to-3.6%), -39.4% (90% CI, -61.8% to-3.8%), and-49.3% (90% CI, -68.2% to-19.0%), respectively. Serum urate levels after treatment with verinurad plus febuxostat were 59.6% and 63.7% lower than after placebo at 12 and 24 weeks, respectively. No clinically meaningful changes were observed in estimated glomerular filtration rate or serum creatinine or serum cystatin C concentrations. Verinurad plus febuxostat was well tolerated. LIMITATIONS: Sample size and study duration were insufficient to evaluate definitive effects of verinurad plus febuxostat on UACR and glomerular filtration. Generalizability was limited by exclusion of patients with stages 4 and 5 chronic kidney disease. CONCLUSIONS: Verinurad plus febuxostat reduced albuminuria and lowered serum urate concentrations in patients with T2DM, albuminuria, and hyperuricemia. Definitive assessment of their combined impact on preservation of kidney function awaits larger clinical studies. FUNDING: This study was supported by AstraZeneca. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT03118739.
Assuntos
Albuminúria/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Febuxostat/administração & dosagem , Supressores da Gota/administração & dosagem , Naftalenos/administração & dosagem , Propionatos/administração & dosagem , Piridinas/administração & dosagem , Ácido Úrico , Idoso , Albuminúria/sangue , Albuminúria/epidemiologia , Biomarcadores/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Taxa de Filtração Glomerular/efeitos dos fármacos , Taxa de Filtração Glomerular/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Ácido Úrico/sangueRESUMO
AIMS: To develop a quantitative systems pharmacology model to describe the effect of dapagliflozin (a sodium-glucose co-transporter-2 [SGLT2] inhibitor) on glucose-insulin dynamics in type 2 diabetes mellitus (T2DM) patients, and to identify key determinants of treatment-mediated glycated haemoglobin (HbA1c) reduction. MATERIALS AND METHODS: Glycaemic control during dapagliflozin treatment was mechanistically characterized by integrating components representing dapagliflozin pharmacokinetics (PK), glucose-insulin homeostasis, renal glucose reabsorption, and HbA1c formation. The model was developed using PK variables, glucose, plasma insulin, and urinary glucose excretion (UGE) from a phase IIa dapagliflozin trial in patients with T2DM (NCT00162305). The model was used to predict dapagliflozin-induced HbA1c reduction; model predictions were compared to actual data from phase III trials (NCT00528879, NCT00683878, NCT00680745 and NCT00673231). RESULTS: The integrated glucose-insulin-dapagliflozin model successfully described plasma glucose and insulin levels, as well as UGE in response to oral glucose tolerance tests and meal intake. HbA1c reduction was also well predicted. The results show that dapagliflozin-mediated glycaemic control is anticorrelated to steady-state insulin concentration and insulin sensitivity. CONCLUSIONS: The developed model framework is the first to integrate SGLT2 inhibitor mechanism of action with both short-term glucose-insulin dynamics and long-term glucose control (HbA1c). The results suggest that dapagliflozin treatment is beneficial in patients with inadequate glycaemic control from insulin alone and this benefit increases as insulin control diminishes.
Assuntos
Diabetes Mellitus Tipo 2 , Compostos Benzidrílicos , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose , Glucosídeos , Humanos , Hipoglicemiantes/uso terapêutico , Insulina , Resultado do TratamentoRESUMO
AIMS: To quantitatively compare pharmacokinetics (PK) and the exposure-response (ER) relationship of the sodium-glucose cotransporter-2 inhibitor, dapagliflozin, between adolescents/young adults and adults with type 1 diabetes mellitus (T1DM). METHODS: Data from 2 clinical studies for dapagliflozin were analysed using a non-linear mixed-effects approach. The PK and the relationship between dapagliflozin exposure and response (24-hour urinary glucose excretion) were characterized. PK was evaluated using a 2-compartment model with first-order absorption while the exposure response-relationship was analysed using a sigmoidal maximal-effect model. The 24-hour median blood glucose, estimated glomerular filtration rate (eGFR), sex, age and body weight were evaluated as covariates. RESULTS: A 2-compartment model with first order absorption provided a reasonable fit to the dapagliflozin PK data. Body weight was found to be a significant covariate on dapagliflozin exposure. The ER relationship was best described by a sigmoidal maximal effect model with 24-hour median blood glucose and eGFR as significant covariates on maximal effect. In accordance with the observed data, model-predicted urinary glucose excretion response following 10 mg dapagliflozin dose was higher in the study in adolescents/young adults (138.0 g/24 h) compared to adults (70.5 g/24 h) with T1DM. This is linked to higher eGFR and 24-hour median blood glucose in this trial. CONCLUSIONS: Dapagliflozin PK and ER relationship were similar in the 2 analysed studies after accounting for covariate effects. These results suggest that no dose adjustment is required for adolescent patients with T1DM.
Assuntos
Compostos Benzidrílicos/administração & dosagem , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucosídeos/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/administração & dosagem , Adolescente , Fatores Etários , Compostos Benzidrílicos/farmacocinética , Glicemia/análise , Criança , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Diabetes Mellitus Tipo 1/sangue , Relação Dose-Resposta a Droga , Feminino , Taxa de Filtração Glomerular , Glucosídeos/farmacocinética , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/farmacocinética , Adulto JovemRESUMO
AIMS: To quantitatively describe the relationship between dapagliflozin systemic exposure and HbA1c response among patients with type 1 diabetes mellitus (T1DM) and assess the potential impact of covariate effects. MATERIALS AND METHODS: Individual longitudinal HbA1c data from two phase 3 studies in patients with T1DM (24-week treatment with once-daily dapagliflozin 5 or 10 mg or placebo, with adjustable insulin) were analyzed using a non-linear mixed effect modeling approach. Area under the concentration curve was used to measure dapagliflozin systemic exposure. Baseline HbA1c, estimated glomerular filtration rate, reduction in total insulin dose, baseline glucose concentrations, age, sex, race (Asian vs. non-Asian), and insulin administration method (multiple daily injections vs. insulin pump) were assessed as covariates. RESULTS: A maximum effect (Emax ) model identified a positive exposure-response relationship. Model-predicted placebo-corrected HbA1c reductions after 24 weeks for dapagliflozin 5- and 10-mg doses were - 0.42% [95% confidence interval (CI) -0.47 to -0.36) and - 0.45% (95% CI -0.50 to -0.40), respectively; baseline HbA1c was ~8.4%. This was in good agreement with actual observations from both studies. Baseline HbA1c was a significant covariate: patients with higher baseline HbA1c were predicted to have greater HbA1c reductions. CONCLUSIONS: The relationship between dapagliflozin systemic exposure and HbA1c response was successfully described in patients with T1DM. None of the tested covariates affected the efficacy of dapagliflozin to a clinically relevant extent. Therefore, no dose adjustment of dapagliflozin is required in patients with T1DM based on the tested covariates. ClinicalTrials.gov, NCT02268214; NCT02460978.