RESUMO
Letermovir (MK-8228/AIC246) is a cytomegalovirus (CMV) DNA terminase complex inhibitor for CMV prophylaxis in adult patients undergoing hematopoietic stem cell transplant. It is cytochrome P450 (CYP) 3A inhibitor and inhibits organic anion transporting polypeptide 1B1/3 and breast cancer resistance protein transporters. Atorvastatin (ATV), a commonly used treatment for hypercholesterolemia, is a substrate of organic anion transporting polypeptide 1B1, potentially breast cancer resistance protein, and CYP3A. As letermovir may be coadministered with ATV, the effect of multiple-dose letermovir 480 mg once daily on the pharmacokinetics of single-dose ATV 20 mg and its metabolites (ortho-hydroxyatorvastatin [o-OH-ATV] and para-hydroxyatorvastatin [p-OH-ATV]) was evaluated in an open-label trial in healthy female adults (N = 14). ATV area under the plasma concentration-time curve from time 0 to infinity and maximum plasma concentration (Cmax ) increased ≈3-fold with letermovir coadministration. The time to ATV Cmax also increased, while apparent clearance decreased. The exposures of o-OH-ATV and p-OH-ATV were comparable in the presence versus absence of letermovir; however, o-OH-ATV Cmax decreased by 60% with coadministration, while p-OH-ATV Cmax was similar. Due to the increase in ATV exposure with letermovir coadministration, statin-associated adverse events such as myopathy should be closely monitored following coadministration. The dose of ATV should not exceed 20 mg daily when coadministered with letermovir.
Assuntos
Proteínas de Neoplasias , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Acetatos , Adulto , Atorvastatina , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , QuinazolinasRESUMO
The cytomegalovirus (CMV) viral terminase inhibitor letermovir is approved for prophylaxis of CMV infection and disease in adult CMV-seropositive allogeneic hematopoietic stem cell transplantation recipients. In a phase III trial (NCT02137772), letermovir significantly reduced clinically significant CMV infection (CS-CMVi) rate vs. placebo through Week 24 (primary end point) and Week 14 (secondary end point) post transplantation. Here, exposure-response relationships were investigated using efficacy and selected safety end points from the phase III trial to inform the proposed clinical dose. Post hoc exposure estimates were derived from a population pharmacokinetic model. No significant exposure dependencies were found for CS-CMVi through Week 24 or Week 14 among letermovir-treated participants. Evaluated covariates had no impact on exposure-efficacy relationships and letermovir plasma exposure did not affect time of CS-CMVi onset. There was no dependence between adverse event incidence and letermovir exposure. These results support current dosing recommendations in several countries and regions, including the United States and European Union.
Assuntos
Acetatos/administração & dosagem , Antivirais/administração & dosagem , Infecções por Citomegalovirus/prevenção & controle , Transplante de Células-Tronco Hematopoéticas , Quinazolinas/administração & dosagem , Acetatos/farmacocinética , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Idoso , Antivirais/farmacocinética , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Cálculos da Dosagem de Medicamento , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Quinazolinas/farmacocinética , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Leucine-rich repeat kinase 2 (LRRK2) inhibitors are currently in clinical development as interventions to slow progression of Parkinson's disease (PD). Understanding the rate of progression in PD as measured by both motor and nonmotor features is particularly important in assessing the potential therapeutic effect of LRRK2 inhibitors in clinical development. Using standardized data from the Critical Path for Parkinson's Unified Clinical Database, we quantified the rate of progression of the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part I (nonmotor aspects of experiences of daily living) in 158 participants with PD who were carriers and 598 participants with PD who were noncarriers of at least one of three different LRRK2 gene mutations (G2019S, R1441C/G, or R1628P). Age and disease duration were found to predict baseline disease severity, while presence of at least one of these three LRRK2 mutations was a predictor of the rate of MDS-UPDRS Part I progression. The estimated progression rate in MDS-UPDRS Part I was 0.648 (95% confidence interval: 0.544, 0.739) points per year in noncarriers of a LRRK2 mutation and 0.259 (95% confidence interval: 0.217, 0.295) points per year in carriers of a LRRK2 mutation. This analysis demonstrates that the rate of progression based on MDS-UPDRS Part I is ~ 60% lower in carriers as compared with noncarriers of LRRK2 gene mutations.
Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Doença de Parkinson/genética , Doença de Parkinson/fisiopatologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antiparkinsonianos/administração & dosagem , Antiparkinsonianos/uso terapêutico , Bases de Dados Factuais , Progressão da Doença , Feminino , Glucosilceramidase/genética , Heterozigoto , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Mutação/genética , Valor Preditivo dos Testes , Índice de Gravidade de Doença , alfa-Sinucleína/genéticaRESUMO
The development and application of quantitative systems pharmacology models in neuroscience have been modest relative to other fields, such as oncology and immunology, which may reflect the complexity of the brain. Technological and methodological advancements have enhanced the quantitative understanding of brain physiology and pathophysiology and the effects of pharmacological interventions. To maximize the knowledge gained from these novel data types, pharmacometrics modelers may need to expand their toolbox to include additional mathematical and statistical frameworks. A session was held at the 10th annual American Conference on Pharmacometrics (ACoP10) to highlight several recent advancements in quantitative and systems neuroscience. In this mini-review, we provide a brief overview of technological and methodological advancements in the neuroscience therapeutic area that were discussed during the session and how these can be leveraged with quantitative systems pharmacology modeling to enhance our understanding of neurological diseases. Microphysiological systems using human induced pluripotent stem cells (IPSCs), digital biomarkers, and large-scale imaging offer more clinically relevant experimental datasets, enhanced granularity, and a plethora of data to potentially improve the preclinical-to-clinical translation of therapeutics. Network neuroscience methodologies combined with quantitative systems models of neurodegenerative disease could help bridge the gap between cellular and molecular alterations and clinical end points through the integration of information on neural connectomics. Additional topics, such as the neuroimmune system, microbiome, single-cell transcriptomic technologies, and digital device biomarkers, are discussed in brief.
Assuntos
Encéfalo/metabolismo , Descoberta de Drogas , Modelos Biológicos , Farmacologia em Rede , Doenças Neurodegenerativas/tratamento farmacológico , Congressos como Assunto , HumanosRESUMO
Letermovir is indicated for prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Two-stage population pharmacokinetic (PK) modeling of letermovir was conducted to support dose rationale and evaluate the impact of intrinsic/extrinsic factors. Data from healthy phase I study participants over a wide dose range were modeled to evaluate the effects of selected intrinsic factors, including pharmacogenomics; next, phase III HSCT-recipient data at steady-state following clinical doses were modeled. The model in HSCT recipients adequately described letermovir PK following both oral or i.v. administration, and was consistent with the healthy participant model at steady-state clinical doses. Intrinsic factor effects were not clinically meaningful. These staged analyses indicate that letermovir PK in HSCT recipients and healthy participants differ only with respect to bioavailability and absorption rate. The HSCT recipient model was suitable for predicting exposure for exposure-response analysis supporting final dose selection.
Assuntos
Acetatos/farmacocinética , Antivirais/farmacocinética , Infecções por Citomegalovirus/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Quinazolinas/farmacocinética , Acetatos/administração & dosagem , Acetatos/uso terapêutico , Administração Intravenosa , Administração Oral , Adulto , Idoso , Antivirais/administração & dosagem , Antivirais/uso terapêutico , Disponibilidade Biológica , Estudos de Casos e Controles , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis/estatística & dados numéricos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Farmacogenética , Placebos/administração & dosagem , Quinazolinas/administração & dosagem , Quinazolinas/uso terapêutico , Transplantados/estatística & dados numéricosRESUMO
This work evaluates the performance of longitudinal item response (IR) theory models in shortened assessments using an existing model for part II and III of the MDS-UPDRS score. Based on the item information content, the assessment was reduced by removal of items in multiple increments and the models' ability to recover the item characteristics of the remaining items at each level was evaluated. This evaluation was done for both simulated and real data. The metric of comparison in both cases was the item information function. For real data, the impact of shortening on the estimated disease progression and drug effect was also studied. In the simulated data setting, the item characteristics did not differ between the full and the shortened assessments down to the lowest level of information remaining; indicating a considerable independence between items. In contrast when reducing the assessment in a real data setting, a substantial change in item information was observed for some of the items. Disease progression and drug effect estimates also decreased in the reduced assessments. These changes indicate a shift in the measured construct of the shortened assessment and warrant caution when comparing results from a partial assessment with results from the full assessment.
Assuntos
Antiparkinsonianos/farmacologia , Monitoramento de Medicamentos/métodos , Modelos Biológicos , Atividade Motora/efeitos dos fármacos , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/uso terapêutico , Simulação por Computador , Progressão da Doença , Humanos , Estudos Longitudinais , Doença de Parkinson/diagnóstico , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Alzheimer's disease (AD) is the leading cause of dementia worldwide. With 35 million people over 60 years of age with dementia, there is an urgent need to develop new treatments for AD. To streamline this process, it is imperative to apply insights and learnings from past failures to future drug development programs. In the present work, we focus on how modeling and simulation tools can leverage open data to address drug development challenges in AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Simulação por Computador/tendências , Coleta de Dados/tendências , Desenvolvimento de Medicamentos/tendências , Descoberta de Drogas/tendências , Animais , Ensaios Clínicos como Assunto/métodos , Coleta de Dados/métodos , Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Humanos , Pesquisa Translacional Biomédica/métodos , Pesquisa Translacional Biomédica/tendênciasRESUMO
A quantitative assessment of Parkinson's disease (PD) progression is critical for optimizing clinical trials design. Disease progression model was developed using pooled data from the Progression Marker Initiative study and the Incidence of Cognitive Impairment in Cohorts with Longitudinal Evaluation in Parkinson's Disease study. Age, gender, concomitant medication, and study arms were predictors of baseline. A mutation in the leucine-rich repeat kinase 2 (LRRK2) encoding gene was associated with the disease progression rate. The progression rate in subjects with PD who carried LRRK2 mutation was slightly slower (~0.170 points/month) than that in PD subjects without the mutation (~0.222 points/month). For a nonenriched placebo-controlled clinical trial, approximately 70 subjects/arm would be required to detect a drug effect of 50% reduction in the progression rate with 80% probability, whereas 85, 93, and 100 subjects/arm would be required for an enriched clinical trial with 30%, 50%, and 70% subjects with LRRK2 mutations, respectively.
Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Modelos Teóricos , Doença de Parkinson/fisiopatologia , Projetos de Pesquisa , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto/métodos , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Doença de Parkinson/genéticaRESUMO
OBJECTIVE: Letermovir is an inhibitor of the terminase complex of cytomegalovirus (CMV) used as prophylactic therapy in CMV-seropositive allogeneic hematopoietic stem cell transplant recipients. As the combination oral contraceptive (COC) levonorgestrel/ethinyl estradiol (LNG/EE) may be coadministered in this target transplant population, the effects of letermovir on the pharmacokinetics (PK) of LNG and EE were investigated. MATERIALS AND METHODS: This was a phase I, open-label, fixed-sequence, two-period study conducted in healthy women (18 - 65 years old) of non-childbearing potential (protocol number: MK-8228 035). On day 1 of period 1, participants received a single dose of COC (LNG 0.15 mg/EE 0.03 mg). Following a 7-day washout, oral letermovir 480 mg was administered once-daily on days 1 - 12 of period 2, with a single dose of COC coadministered on day 8. Blood samples were collected to determine LNG and EE PK, and safety was assessed. RESULTS: The AUC0-∞ geometric mean ratios (90% confidence intervals) for COC + letermovir/COC alone were 1.36 (1.30, 1.43) for LNG and 1.42 (1.32, 1.52) for EE, indicating that letermovir coadministration increased COC exposure. Coadministration had no clinically-meaningful effect on Cmax, tmax, or apparent terminal T1/2 for either LNG or EE. All treatments were generally well tolerated. CONCLUSION: Letermovir coadministration with COC resulted in an increase in LNG and EE exposure in healthy adult women; however, levels were within the established safety margins. There was no decrease in LNG or EE exposure with no apparent risk of contraceptive failure on coadministration of letermovir and COC.â©.
Assuntos
Acetatos/farmacologia , Anticoncepcionais Orais Combinados/farmacocinética , Etinilestradiol/farmacocinética , Levanogestrel/farmacocinética , Quinazolinas/farmacologia , Adolescente , Adulto , Idoso , Interações Medicamentosas , Feminino , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
Letermovir (AIC246, MK-8228) is a human cytomegalovirus terminase inhibitor indicated for the prophylaxis of cytomegalovirus infection and disease in allogeneic hematopoietic stem cell transplant recipients that is also being investigated for use in other transplant settings. Many transplant patients receive immunosuppressant drugs, of which several have narrow therapeutic ranges. There is a potential for the coadministration of letermovir with these agents, and any potential effect on their pharmacokinetics (PK) must be understood. Five phase 1 trials were conducted in 73 healthy female participants to evaluate the effect of letermovir on the PK of cyclosporine, tacrolimus, sirolimus, and mycophenolic acid (active metabolite of mycophenolate mofetil [MMF]), as well as the effect of cyclosporine and MMF on letermovir PK. Safety and tolerability were also assessed. Coadministration of letermovir with cyclosporine, tacrolimus, and sirolimus resulted in 1.7-, 2.4-, and 3.4-fold increases in area under the plasma concentration-time curve and 1.1-, 1.6-, and 2.8-fold increases in maximum plasma concentration, respectively, of the immunosuppressants. Coadministration of letermovir and MMF had no meaningful effect on the PK of mycophenolic acid. Coadministration with cyclosporine increased letermovir area under the plasma concentration-time curve by 2.1-fold and maximum plasma concentration by 1.5-fold, while coadministration with MMF did not meaningfully affect the PK of letermovir. Given the increased exposures of cyclosporine, tacrolimus, and sirolimus, frequent monitoring of concentrations should be performed during administration and at discontinuation of letermovir, with dose adjustment as needed. These data support the reduction in clinical dosage of letermovir (to 240 mg) upon coadministration with cyclosporine.
Assuntos
Acetatos/farmacocinética , Ciclosporina/farmacocinética , Interações Medicamentosas/fisiologia , Imunossupressores/farmacocinética , Ácido Micofenólico/farmacocinética , Quinazolinas/farmacocinética , Sirolimo/farmacocinética , Tacrolimo/farmacocinética , Adolescente , Adulto , Idoso , Antivirais/farmacocinética , Área Sob a Curva , Método Duplo-Cego , Feminino , Humanos , Transplante de Rim/métodos , Pessoa de Meia-Idade , Adulto JovemRESUMO
The Critical Path for Parkinson's (CPP) Imaging Biomarker and Modeling and Simulation working groups aimed to achieve qualification opinion by the European Medicines Agency (EMA) Committee for Medical Products for Human Use (CHMP) for the use of baseline dopamine transporter neuroimaging for patient selection in early Parkinson's disease clinical trials. This paper describes the regulatory science strategy to achieve this goal. CPP is an international consortium of three Parkinson's charities and nine pharmaceutical partners, coordinated by the Critical Path Institute.
Assuntos
Biomarcadores/metabolismo , Ensaios Clínicos como Assunto , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neuroimagem , Doença de Parkinson/metabolismo , Progressão da Doença , Humanos , Modelos Biológicos , Atividade Motora , Doença de Parkinson/fisiopatologiaRESUMO
Letermovir is a human cytomegalovirus terminase inhibitor for cytomegalovirus infection prophylaxis in hematopoietic stem cell transplant recipients. Posaconazole (POS), a substrate of glucuronosyltransferase and P-glycoprotein, and voriconazole (VRC), a substrate of CYP2C9/19, are commonly administered to transplant recipients. Because coadministration of these azoles with letermovir is expected, the effect of letermovir on exposure to these antifungals was investigated. Two trials were conducted in healthy female subjects 18 to 55 years of age. In trial 1, single-dose POS 300 mg was administered alone, followed by a 7-day washout; then letermovir 480 mg once daily was given for 14 days with POS 300 mg coadministered on day 14. In trial 2, on day 1 VRC 400 mg was given every 12 hours; on days 2 and 3, VRC 200 mg was given every 12 hours, and on day 4 VRC 200 mg. On days 5 to 8, letermovir 480 mg was given once daily. Days 9 to 12 repeated days 1 to 4 coadministered with letermovir 480 mg once daily. In both trials, blood samples were collected for the assessment of the pharmacokinetic profiles of the antifungals, and safety was assessed. The geometric mean ratios (90%CIs) for POS+letermovir/POS area under the curve and peak concentration were 0.98 (0.83, 1.17) and 1.11 (0.95, 1.29), respectively. Voriconazole+letermovir/VRC area under the curve and peak concentration geometric mean ratios were 0.56 (0.51, 0.62) and 0.61 (0.53, 0.71), respectively. All treatments were generally well tolerated. Letermovir did not affect POS pharmacokinetics to a clinically meaningful extent but decreased VRC exposure. These results suggest that letermovir may be a perpetrator of CYP2C9/19-mediated drug-drug interactions.
Assuntos
Acetatos/farmacocinética , Antifúngicos/farmacocinética , Antivirais/farmacocinética , Quinazolinas/farmacocinética , Triazóis/farmacocinética , Voriconazol/farmacocinética , Acetatos/administração & dosagem , Acetatos/sangue , Administração Oral , Adulto , Antifúngicos/administração & dosagem , Antivirais/administração & dosagem , Área Sob a Curva , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Voluntários Saudáveis , Humanos , Pessoa de Meia-Idade , Quinazolinas/administração & dosagem , Quinazolinas/sangue , Triazóis/administração & dosagem , Triazóis/sangue , Voriconazol/administração & dosagem , Voriconazol/sangueRESUMO
Given the recognition that disease-modifying therapies should focus on earlier Parkinson's disease stages, trial enrollment based purely on clinical criteria poses significant challenges. The goal herein was to determine the utility of dopamine transporter neuroimaging as an enrichment biomarker in early motor Parkinson's disease clinical trials. Patient-level longitudinal data of 672 subjects with early-stage Parkinson's disease in the Parkinson's Progression Markers Initiative (PPMI) observational study and the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) clinical trial were utilized in a linear mixed-effects model analysis. The rate of worsening in the motor scores between subjects with or without a scan without evidence of dopamine transporter deficit was different both statistically and clinically. The average difference in the change from baseline of motor scores at 24 months between biomarker statuses was -3.16 (90% confidence interval [CI] = -0.96 to -5.42) points. Dopamine transporter imaging could identify subjects with a steeper worsening of the motor scores, allowing trial enrichment and 24% reduction of sample size.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/análise , Modelos Biológicos , Imagem Molecular/métodos , Neuroimagem/métodos , Doença de Parkinson/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Progressão da Doença , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Método de Monte Carlo , Atividade Motora/fisiologia , Doença de Parkinson/fisiopatologia , Pacientes Desistentes do Tratamento , Ensaios Clínicos Controlados Aleatórios como Assunto , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
Inhibition of sodium glucose cotransporter 2 with empagliflozin results in caloric loss by increasing urinary glucose excretion and has a mild diuretic effect. Diuretic effects are usually associated with reflex-mediated increases in sympathetic tone, whereas caloric loss is associated with decreased sympathetic tone. In an open-label trial, muscle sympathetic nerve activity (MSNA) (burst frequency, burst incidence, and total MSNA) was assessed using microneurography performed off-treatment and on day 4 of treatment with empagliflozin 25 mg once daily in 22 metformin-treated patients with type II diabetes (mean [range] age 54 [40-65] years). Systolic and diastolic blood pressure (BP), heart rate, urine volume, and body weight were assessed before and on day 4 (BP, heart rate), day 5 (urine volume), or day 6 (body weight) of treatment with empagliflozin. After 4 days of treatment with empagliflozin, no significant changes in MSNA were apparent despite a numerical increase in urine volume, numerical reductions in BP, and significant weight loss. There were no clinically relevant changes in heart rate. Empagliflozin is not associated with clinically relevant reflex-mediated sympathetic activation in contrast to increases observed with diuretics in other studies. Our study suggests a novel mechanism through which sodium glucose cotransporter 2 inhibition affects human autonomic cardiovascular regulation.
Assuntos
Compostos Benzidrílicos/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/farmacologia , Hipoglicemiantes/farmacologia , Músculo Esquelético/inervação , Inibidores do Transportador 2 de Sódio-Glicose , Sistema Nervoso Simpático/efeitos dos fármacos , Adulto , Compostos Benzidrílicos/uso terapêutico , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Estudos Cross-Over , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/urina , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Glucose/metabolismo , Glucosídeos/uso terapêutico , Frequência Cardíaca/efeitos dos fármacos , Humanos , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Músculo Esquelético/efeitos dos fármacos , Eliminação Renal/efeitos dos fármacos , Transportador 2 de Glucose-Sódio , Sistema Nervoso Simpático/fisiopatologiaRESUMO
PURPOSE: Our aim was to investigate the effects of the sodium glucose cotransporter 2 inhibitor empagliflozin on urinary and serum glucose and electrolytes, urinary volume, osmolality, and the renin-angiotensin system in patients with type 2 diabetes. METHODS: In an open-label study, 22 patients receiving metformin (median age 56 years; range 40-65 years) received empagliflozin 25 mg once daily for 5 days. Food, fluid, and sodium intake were standardized for 3 days before and during treatment. FINDINGS: Twenty patients completed treatment. After single and multiple doses of empagliflozin, mean (SE) changes from baseline in 24-hour urinary glucose excretion were 463.3 (57.3) mmol/d and 599.5 (60.0) mmol/d, respectively (83.5 [10.3] g/d and 108.0 [10.8] g/d, respectively) (both P < 0.001), and in fasting serum glucose concentration were -1.8 (0.4) mmol/L and -1.1 (0.3) mmol/L, respectively (both P < 0.001). After a single dose, mean (SE) change from baseline in urine sodium excretion was 45.3 (9.6) mmol/d (P < 0.001), and in urine volume was 341.0 (140.5) g/d (P = 0.025), but there were no changes compared with baseline in either parameter after multiple doses. There were no changes in plasma renin or serum aldosterone with single or multiple doses of empagliflozin. There was a nonsignificant reduction in weight after a single dose of empagliflozin and a mean (SE) change of -1.4 (0.5) kg after multiple doses (P = 0.020). IMPLICATIONS: Empagliflozin 25 mg increased urinary glucose excretion and decreased serum glucose and weight with transient natriuresis and increases in urine volume, without significant changes in the renin-angiotensin system. Clinicaltrials.gov Identifier: NCT01276288.
Assuntos
Compostos Benzidrílicos/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/administração & dosagem , Hipoglicemiantes/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose , Adulto , Idoso , Glicemia/efeitos dos fármacos , Peso Corporal , Estudos Cross-Over , Jejum , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
PURPOSE: The goal of this study was to investigate the pharmacodynamic effects of co-administration of empagliflozin, a sodium glucose cotransporter 2 inhibitor, with diuretic agents. METHODS: In a randomized, open-label cross-over study, 22 patients with type 2 diabetes mellitus received empagliflozin 25 mg for 5 days and either hydrochlorothiazide 25 mg for 4 days followed by hydrochlorothiazide 25 mg plus empagliflozin 25 mg for 5 days, or torasemide 5 mg for 4 days followed by torasemide 5 mg plus empagliflozin 25 mg for 5 days; 20 completed treatment. Food, fluid, and sodium intake were standardized for 3 days before and during treatment. FINDINGS: At baseline, the median age of the treated patients was 56 years (range, 40-65 years), body mass index was 26.8 kg/m2 (range, 20.1-34.4 kg/m2), fasting plasma glucose was 8.6 mmol/L (range, 6.0-12.9 mmol/L), and glycosylated hemoglobin level was 7.6% (range, 7%-10%). Empagliflozin significantly increased 24-hour urinary glucose excretion and reduced fasting serum glucose levels. These effects were maintained after co-administration with either diuretic. Urinary sodium excretion did not significantly change with empagliflozin or diuretic administration alone, but seemed to increase compared with either diuretic alone when empagliflozin was co-administered with either diuretic. Plasma renin and serum aldosterone levels were unaltered with empagliflozin or torasemide alone, but tended to increase with hydrochlorothiazide alone, and tended to increase when empagliflozin was co-administered with a diuretic compared with either diuretic alone. Urinary volume did not increase with empagliflozin or diuretics alone, but increased when empagliflozin was co-administered with either diuretic. IMPLICATIONS: Empagliflozin alone for 5 days increased urinary glucose excretion but did not seem to have a relevant impact on urine volume or electrolytes. When empagliflozin was co-administered with a diuretic agent, urinary glucose excretion remained increased, and the renin-angiotensin system was activated. Clinicaltrials.gov identifier: NCT01276288.
Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diuréticos/administração & dosagem , Glucosídeos/uso terapêutico , Hidroclorotiazida/administração & dosagem , Adulto , Idoso , Estudos Cross-Over , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores do Transportador 2 de Sódio-Glicose , Sulfonamidas/administração & dosagem , TorasemidaRESUMO
INTRODUCTION: The aim of the analysis was to characterize the population pharmacokinetics (PKs) and exposure-response (E-R) for efficacy (fasting plasma glucose, glycated hemoglobin) and safety/tolerability [hypoglycemia, genital infections, urinary tract infection (UTI), and volume depletion] of the sodium glucose cotransporter 2 inhibitor, empagliflozin, in patients with type 2 diabetes mellitus. This study extends the findings of previous analyses which described the PK and pharmacodynamics (PD) using early clinical studies of up to 12 weeks in duration. METHODS: Population pharmacokinetic and E-R models were developed based on two Phase I, four Phase II, and four Phase III studies. RESULTS: Variability in empagliflozin exposure was primarily affected by estimated glomerular filtration rate (eGFR) (less than twofold increase in exposure in patients with severe renal impairment). Consistent with its mode of action, the efficacy of empagliflozin was increased with elevated baseline plasma glucose levels and attenuated with decreasing renal function, but was still maintained to nearly half the maximal effect with eGFR as low as 30 mL/min/1.73 m(2). All other investigated covariates, including sex, body mass index, race, and age did not alter the PK or efficacy of empagliflozin to a clinically relevant extent. Compared with placebo, empagliflozin administration was associated with an exposure-independent increase in the incidence of genital infections and no significant change in the risk of UTI, hypoglycemia, or volume depletion. CONCLUSION: Based on the results from the PK and E-R analysis, no dose adjustment is required for empagliflozin in the patient population for which the drug is approved. FUNDING: Boehringer Ingelheim.
RESUMO
OBJECTIVE: To compare the pharmacokinetics of fixed-dose combination (FDC) tablets of empagliflozin/metformin with individual tablets taken together. METHODS: In 3 randomized, open-label studies, healthy subjects received a single FDC tablet of empagliflozin/metformin in 1 of 6 dose combinations (empagliflozin 12.5 mg or 5 mg; metformin 500 mg, 850 mg, or 1,000 mg) in 1 period and the individual tablets taken together under fed conditions in another period. Empagliflozin 12.5 mg/metformin 1,000 mg FDC and individual tablets were also given under fasted conditions. RESULTS: Adjusted geometric mean ratios (GMRs) of empagliflozin area under the plasma concentration-time curve (AUC(0-∞)) for the FDCs vs. individual tablets ranged from 97.92 to 106.00%, and 90% CIs ranged from 93.53 to 109.39%. Adjusted GMRs of empagliflozin maximum plasma concentrations (C(max)) for the FDCs vs. individual tablets ranged from 100.97 to 106.52%, and 90% CIs ranged from 95.86 to 118.35%. Adjusted GMRs of metformin AUC(0-∞) for the FDCs vs. individual tablets ranged from 96.25 to 101.61%, and 90% CIs ranged from 88.54 to 106.62%. Adjusted GMRs of metformin C(max) for the FDCs vs. individual tablets ranged from 93.83 to 102.95%, and 90% CIs ranged from 88.01 to 109.08%. Bioequivalence was also established under fasted conditions for empagliflozin 12.5 mg/metformin 1,000 mg FDC vs. individual tablets taken together. All treatments were well tolerated. CONCLUSION: Empagliflozin/metformin FDC tablets were found to be bioequivalent to individual tablets taken together at all tested dose strengths.
Assuntos
Compostos Benzidrílicos/farmacocinética , Glucosídeos/farmacocinética , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Adulto , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/efeitos adversos , Estudos Cross-Over , Combinação de Medicamentos , Feminino , Glucosídeos/administração & dosagem , Glucosídeos/efeitos adversos , Humanos , Masculino , Metformina/administração & dosagem , Metformina/efeitos adversos , Pessoa de Meia-Idade , ComprimidosRESUMO
PURPOSE: This study was undertaken to compare the steady-state pharmacokinetic and pharmacodynamic properties of empagliflozin 5 mg twice daily (BID) and 10 mg once daily (QD) in healthy subjects. METHODS: In an open-label, 2-way crossover study, subjects (n = 16) received empagliflozin 5 mg BID for 5 days and empagliflozin 10 mg QD for 5 days in a randomized order, with a washout period of ≥6 days between each treatment. The primary objective was the comparison of the overall exposure during a 24-hour period at steady state (AUC0-24,ss) for empagliflozin, based on standard bioequivalence criteria, with BID and QD dose regimens. FINDINGS: The study population comprised 7 (43.8%) men and 9 (56.3%) women with a baseline median age of 38.0 years (range, 23-47 years) and a median body mass index of 23.3 kg/m(2) (range, 19.8-27.8 kg/m(2)). Based on standard bioequivalence criteria, there was no difference in the overall exposure of empagliflozin between BID and QD dose regimens (geometric mean ratio of AUC0-24,ss for empagliflozin 5 mg BID compared with empagliflozin 10 mg QD = 99.36%; 90% CI, 94.29-104.71). For empagliflozin 10 mg QD, mean (%CV) AUC during the dosing interval was 1900 nmol · h/L (20.6%), mean (%CV) Cmax,ss was 330 nmol/L (25.3%), and median (range) Tmax,ss was 1.0 hour (0.7-2.0 hours). For empagliflozin 5 mg BID, mean (%CV) AUC during the dosing interval was 1010 nmol · h/L (15.1%) and 867 nmol · h/L (18.6%) after the morning and evening dose, respectively, mean (%CV) Cmax,ss was 193 nmol/L (16.5%) and 120 nmol/L (21.0%), respectively, and median Tmax,ss was 1.0 hour (range, 0.7-2.0 hours) and 2.0 hours (range, 1.0-4.0 hours), respectively. The mean (%CV) cumulative amount of glucose excreted in urine during 24 hours was 52.1 g (32.1%) with empagliflozin 5 mg BID and 43.9 g (30.3%) with empagliflozin 10 mg QD. Adverse events were reported in six subjects (37.5%) receiving empagliflozin 5 mg BID and four (25.0%) receiving empagliflozin 10 mg QD. Headache was the most frequent AE. No severe, serious, or drug-related AEs were reported. IMPLICATIONS: There were no clinically relevant differences in pharmacokinetic or pharmacodynamic properties between BID and QD dose regimens of empagliflozin in healthy subjects. Both dose regimens were well tolerated. EU Clinical Trials Register (EudraCT) number: 2009-012524-90.