RESUMO
BACKGROUND: Prusogliptin is a potent and selective DPP-4 inhibitor. In different animal models, Prusogliptin showed potential efficacy in the treatment of type 2 diabetes. However, the knowledge of its pharmacokinetics and safety in patients with liver dysfunction is limited. OBJECTIVES: The present study evaluated the pharmacokinetics and safety of Prusogliptin in subjects with mild or moderate hepatic impairment compared with healthy subjects. METHODS: According to the liver function of the subjects, we divided them into a mild liver dysfunction group, a moderate liver dysfunction group and a normal liver function group. All subjects in three groups received a single oral dose of Prusogliptin 100-mg tablets. Pharmacokinetics and safety index collection was carried out before and after taking the drug. Plasma pharmacokinetics of Prusogliptin were evaluated, and geometric least- -squares mean (GLSM) and associated 90% confidence intervals for insufficient groups versus the control group were calculated for plasma exposures. RESULTS: After a single oral administration of 100 mg of Prusogliptin tablets, the exposure level of Prusogliptin in subjects with mild liver dysfunction was slightly higher than that in healthy subjects. The exposure level of Prusogliptin was significantly increased in subjects with moderate liver dysfunction. There were no adverse events in this study. CONCLUSION: The exposure level of Prusogliptin in subjects with liver dysfunction was higher than that in healthy subjects. No participant was observed of adverse events. Prusogliptin tablets were safe and well tolerated in Chinese subjects with mild to moderate liver dysfunction and normal liver function.
Assuntos
Comprimidos , Humanos , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Insuficiência Hepática/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Uracila/análogos & derivados , Uracila/farmacocinética , Uracila/efeitos adversos , Uracila/administração & dosagem , Uracila/uso terapêutico , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Piperidinas/farmacocinética , Piperidinas/efeitos adversos , Piperidinas/administração & dosagem , Piperidinas/uso terapêutico , Adulto Jovem , Administração Oral , Fígado/metabolismo , Fígado/efeitos dos fármacos , PiperazinasRESUMO
Lemborexant, a dual orexin receptor antagonist, is approved in the United States, Japan, and Canada for the treatment of insomnia in adults. This phase I, multicenter, open-label, parallel-group study assessed the impact of mild or moderate hepatic impairment (HI) on lemborexant pharmacokinetics and metabolism. The pharmacokinetics, tolerability, and safety of lemborexant were evaluated in subjects with mild (Child-Pugh class A) or moderate (Child-Pugh class B) HI and healthy age-, sex-, and body mass index (BMI)-matched control subjects (n = 8 subjects/group). Subjects received a single oral dose of lemborexant 10 mg (LEM10). Blood samples were collected up to 312 hours post dosing for lemborexant pharmacokinetics assessments. Median time to maximum plasma concentration was similar across all groups. Compared with healthy subjects, exposure measures (maximum plasma concentration [Cmax ] and area under the curve extrapolated to infinity [AUC0-inf ]) increased by ~58% (Cmax ) and ~25% (AUC0-inf ) in subjects with mild HI and ~22% (Cmax ) and ~54% (AUC0-inf ) in subjects with moderate HI. Clearance decreased by 20% and 35% in subjects with mild and moderate HI, respectively, versus healthy subjects. Lemborexant unbound fraction was similar in all groups (range: 0.060-0.065). All treatment-emergent adverse events (TEAEs) were mild in severity; no serious TEAEs occurred. In conclusion, following a single LEM10 dose, lemborexant exposure was similar in subjects with mild HI and increased in subjects with moderate HI versus healthy subjects. No dose adjustment is required in subjects with mild HI. Dosing in subjects with moderate HI should be restricted to 5 mg. Lemborexant was well tolerated in all groups.
Assuntos
Insuficiência Hepática/metabolismo , Eliminação Hepatobiliar/fisiologia , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Medicamentos Indutores do Sono/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Área Sob a Curva , Feminino , Voluntários Saudáveis , Insuficiência Hepática/diagnóstico , Insuficiência Hepática/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Índice de Gravidade de Doença , Medicamentos Indutores do Sono/administração & dosagem , Medicamentos Indutores do Sono/efeitos adversos , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Adulto JovemRESUMO
Lorlatinib, a selective inhibitor of anaplastic lymphoma kinase (ALK) and c-ROS oncogene 1 (ROS1) tyrosine kinase, is indicated for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC) following progression on crizotinib and at least one other ALK inhibitor, or alectinib/ceritinib as the first ALK inhibitor therapy for metastatic disease. The population pharmacokinetics (PopPK) of lorlatinib was conducted by nonlinear mixed effects modeling of data from 330 patients with ALK-positive or ROS1-positive NSCLC and 95 healthy participants from six phase I studies in healthy volunteers; demographic, metabolizer phenotype, and patient prognostic factors were evaluated as covariates. Lorlatinib plasma PK was well-characterized by a two-compartment model with sequential zero-order and first-order absorption and a time-varying induction of clearance. Single dose clearance was estimated to be 9.04 L/h. Assuming that the metabolic auto-induction of lorlatinib reaches saturation in ~ 5 half-lives, clearance was estimated to approach a maximum of 14.5 L/h at steady-state after a period of ~ 7.25 days. The volume of distribution of the central compartment was estimated to be 121 L and the first-order absorption rate constant was estimated to be 3.1 h-1 . Baseline albumin and lorlatinib total daily dose were significant covariates on lorlatinib clearance. Use of proton pump inhibitors was found to be a significant covariate on the lorlatinib absorption rate constant. These factors were assessed to have no clinically meaningful impact on lorlatinib plasma exposure, and no dose adjustments are considered necessary based on the examined covariates.
Assuntos
Aminopiridinas/farmacocinética , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Lactamas/farmacocinética , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Pirazóis/farmacocinética , Adulto , Aminopiridinas/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/secundário , Feminino , Voluntários Saudáveis/estatística & dados numéricos , Insuficiência Hepática/metabolismo , Humanos , Lactamas/administração & dosagem , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/farmacocinética , Pirazóis/administração & dosagem , Insuficiência Renal/metabolismo , Albumina Sérica/metabolismoRESUMO
Two open-label studies assessed the safety, tolerability, and pharmacokinetics of Oxbryta (voxelotor) in subjects with hepatic or renal impairment. Eight subjects with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2 ) and 8 healthy age-, sex-, and body mass index-matched controls were administered a single oral dose of voxelotor 900 mg. Seven patients with mild (Child-Pugh A), moderate (Child-Pugh B), and severe (Child-Pugh C) hepatic impairment and healthy age-, sex-, and body mass index-matched controls (7:7:7:7) were administered a single oral dose of voxelotor 1500 mg, except those with severe hepatic impairment (600 mg). There was no apparent effect of renal function on the excretion of voxelotor based on comparable half-life values between subjects with severe renal impairment and healthy matched controls. Mean area under the concentration-time curve from time 0 to infinity (AUC0-inf ) values were lower by approximately 50% (plasma) and 25% (whole blood) in subjects with severe renal impairment compared with controls. Accordingly, dose adjustment is not required in patients with severe renal impairment. Voxelotor plasma and whole-blood exposures were slightly increased in subjects with mild and moderate hepatic impairment. Mean AUC0-inf values were approximately 9% to 18% higher compared with those of healthy matched controls. Dose adjustment is therefore not required in patients with mild or moderate hepatic impairment. Voxelotor mean AUC0-inf values were approximately 90% higher in subjects with severe hepatic impairment. A lower voxelotor dose (1000 mg) is recommended for patients with severe hepatic impairment. Voxelotor was well tolerated in all treatment groups.
Assuntos
Benzaldeídos/farmacocinética , Fármacos Hematológicos/farmacocinética , Insuficiência Hepática/metabolismo , Pirazinas/farmacocinética , Pirazóis/farmacocinética , Insuficiência Renal/metabolismo , Adulto , Idoso , Área Sob a Curva , Índice de Massa Corporal , Relação Dose-Resposta a Droga , Feminino , Taxa de Filtração Glomerular , Meia-Vida , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The oral prodrug fostemsavir (GSK3684394, formerly BMS-663068) is an antiretroviral treatment for HIV-1. Fostemsavir is metabolized to its active moiety, temsavir, a first-in-class HIV-1 attachment inhibitor that binds to the viral envelope glycoprotein 120. Long-term antiretroviral therapy, the resulting longer life expectancy, and/or certain coinfections can increase the risk of chronic liver and kidney disease in HIV-1-infected individuals. Two studies were conducted to collectively evaluate the impact of renal and hepatic impairment on temsavir pharmacokinetics (PK) and safety following a single dose of a 600-mg extended-release fostemsavir tablet. There was no clinically meaningful effect of renal or hepatic impairment on temsavir PK, although renal clearance decreased with increasing renal impairment from moderate to severe, and exposure (maximum concentration and area under the plasma concentration-time curve from time 0 to infinity) tended to increase with increasing severity of hepatic impairment. No clinically meaningful effect of hemodialysis on temsavir PK parameters was observed. Fostemsavir was generally safe and well tolerated by treated subjects. Most adverse events (AEs) were mild, with the exception of 1 patient in the renal impairment study who discontinued due to 2 serious AEs unrelated to the study drug. No other treatment-emergent serious AEs occurred, and no other AEs leading to discontinuation were reported. Overall, these results suggest that fostemsavir can be used without dose modification in subjects with mild to severe renal impairment, including those with end-stage renal disease on hemodialysis, and in subjects with mild to severe hepatic impairment.
Assuntos
Fármacos Anti-HIV/farmacocinética , Insuficiência Hepática/epidemiologia , Organofosfatos/farmacocinética , Piperazinas/farmacocinética , Insuficiência Renal/epidemiologia , Adulto , Fatores Etários , Idoso , Fármacos Anti-HIV/uso terapêutico , Índice de Massa Corporal , Creatinina/sangue , Feminino , Taxa de Filtração Glomerular , Infecções por HIV/tratamento farmacológico , Insuficiência Hepática/metabolismo , Humanos , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Organofosfatos/uso terapêutico , Gravidade do Paciente , Piperazinas/uso terapêutico , Pró-Fármacos , Grupos Raciais , Insuficiência Renal/metabolismo , Fatores SexuaisRESUMO
The non-vitamin K antagonist oral anticoagulant rivaroxaban is used in several thromboembolic disorders. Rivaroxaban is eliminated via both metabolic degradation and renal elimination as unchanged drug. Therefore, renal and hepatic impairment may reduce rivaroxaban clearance, and medications inhibiting these clearance pathways could lead to drug-drug interactions. This physiologically based pharmacokinetic (PBPK) study investigated the pharmacokinetic behavior of rivaroxaban in clinical situations where drug clearance is impaired. A PBPK model was developed using mass balance and bioavailability data from adults and qualified using clinically observed data. Renal and hepatic impairment were simulated by adjusting disease-specific parameters, and concomitant drug use was simulated by varying enzyme activity in virtual populations (n = 1000) and compared with pharmacokinetic predictions in virtual healthy populations and clinical observations. Rivaroxaban doses of 10 mg or 20 mg were used. Mild to moderate renal impairment had a minor effect on area under the concentration-time curve and maximum plasma concentration of rivaroxaban, whereas severe renal impairment caused a more pronounced increase in these parameters vs normal renal function. Area under the concentration-time curve and maximum plasma concentration increased with severity of hepatic impairment. These effects were smaller in the simulations compared with clinical observations. AUC and Cmax increased with the strength of cytochrome P450 3A4 and P-glycoprotein inhibitors in simulations and clinical observations. This PBPK model can be useful for estimating the effects of impaired drug clearance on rivaroxaban pharmacokinetics. Identifying other factors that affect the pharmacokinetics of rivaroxaban could facilitate the development of models that approximate real-world pharmacokinetics more accurately.
Assuntos
Anticoagulantes/farmacocinética , Insuficiência Hepática/metabolismo , Insuficiência Renal/metabolismo , Rivaroxabana/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/antagonistas & inibidores , Anticoagulantes/administração & dosagem , Área Sob a Curva , Simulação por Computador , Inibidores do Citocromo P-450 CYP3A/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Taxa de Depuração Metabólica , Modelos Biológicos , Gravidade do Paciente , Rivaroxabana/administração & dosagemRESUMO
Cirrhosis is a primary cause of liver-related mortality and morbidity. The basic process driving chronic liver disease to cirrhosis is accelerated fibrogenesis. Although the pathogenesis of liver cirrhosis is a multifactorial process, the essential step in the evolution of liver fibrosis is the activation of hepatic stellate cells, which are the main source of collagen produced in the extracellular matrix. This activation process is mediated by multiple growth factors, cytokines, and chemokines. One of the hepatic stellate cell-activating signaling molecules (and also one associated with cell injury and fibrosis) is osteopontin (OPN). OPN concentration in the plasma has been found to be predictive of liver fibrosis in various liver diseases. OPN concentrations correlate significantly with the stage of fibrosis, liver insufficiency, portal hypertension, and the presence of hepatocellular cancer. However, due to its versatile signaling functions, OPN not only contributes to the development of liver cirrhosis, but is also implicated in the pathogenesis of other chronic hepatic diseases such as viral hepatitis, both alcoholic and non-alcoholic steatohepatitis, drug-induced liver injury, and hepatocellular cancer. Thus, the targeting of OPN pathways seems to be a promising approach in the treatment of chronic liver diseases.
Assuntos
Hepatopatias/metabolismo , Osteopontina/metabolismo , Biomarcadores , Carcinoma Hepatocelular , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Insuficiência Hepática/metabolismo , Células Estreladas do Fígado/metabolismo , Humanos , Hipertensão Portal/metabolismo , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: Multidisciplinary treatment for colorectal liver metastases (CLMs) often includes major hepatectomy for preoperative chemotherapy-related hepatic injury, although the safety limit for resection extent is unclear. We investigated this parameter using the estimated indocyanine green clearance rate (ICG-K) of liver remnants, focusing on postoperative subclinical hepatic insufficiency (PHI). METHODS: Altogether, 225 patients who underwent resection of CLMs were studied. The predictive power of estimated ICG-K of liver remnant (ICG-Krem) for subclinical PHI (peak bilirubin ≥3 mg/dL or refractory ascites) was compared with those of other potential predictors. The suggested safety limit of ICG-Krem ≥0.05 was also assessed. RESULTS: Receiver-operating curve analysis revealed that ICG-Krem [area under the curve (AUC) 0.752, cutoff 0.102] was the best predictor of subclinical PHI (AUC range for others was 0.632-0.668). Makuuchi's criteria corresponded to ICG-Krem 0.10. Subclinical PHI incidence was significantly elevated at ICG-Krem <0.10 (26% vs 8%, p = 0.002), while potentially fatal PHI (peak bilirubin >7 mg/dL) was not observed until down to ICG-Krem of 0.05. CONCLUSIONS: ICG-Krem sensitively predicts subclinical PHI. Liver failure-related death could be avoided so long as ICG-Krem remains at ≥0.05. However, patients with ICG-Krem 0.05-0.10 are at high risk of subclinical PHI and require intensive care postoperatively.
Assuntos
Neoplasias Colorretais/patologia , Corantes/farmacocinética , Insuficiência Hepática/diagnóstico , Verde de Indocianina/farmacocinética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bilirrubina/sangue , Feminino , Hepatectomia , Insuficiência Hepática/etiologia , Insuficiência Hepática/metabolismo , Humanos , Testes de Função Hepática , Neoplasias Hepáticas/secundário , Masculino , Metastasectomia , Pessoa de Meia-Idade , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/metabolismo , Valor Preditivo dos Testes , Curva ROC , Estudos RetrospectivosRESUMO
Purpose: Revefenacin, a long-acting muscarinic antagonist for nebulization, has been shown to improve lung function in patients with chronic obstructive pulmonary disease. Here we report pharmacokinetic (PK) and safety results from two multicenter, open-label, single-dose trials evaluating revefenacin in subjects with severe renal impairment (NCT02578082) and moderate hepatic impairment (NCT02581592). Subjects and methods: The renal impairment trial enrolled subjects with normal renal function and severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2). The hepatic impairment trial enrolled subjects with normal hepatic function and moderate hepatic impairment (Child-Pugh class B). Subjects received a single 175-µg dose of revefenacin through nebulization. PK plasma samples and urine collections were obtained at multiple time points for 5 days following treatment; all subjects were monitored for adverse events. Results: In the renal impairment study, the maximum observed plasma revefenacin concentration (Cmax) was up to 2.3-fold higher and area under the concentration-time curve from time 0 to infinity (AUCinf) was up to 2.4-fold higher in subjects with severe renal impairment compared with those with normal renal function. For THRX-195518, the major metabolite of revefenacin, the corresponding changes in Cmax and AUCinf were 1.8- and 2.7-fold higher, respectively. In the hepatic impairment study, revefenacin Cmax and AUCinf were 1.03- and 1.18-fold higher, respectively, in subjects with moderate hepatic impairment compared with those with normal hepatic function. The corresponding changes in THRX-195518 Cmax and AUCinf were 1.5- and 2.8-fold higher, respectively. Conclusion: Systemic exposure to revefenacin increased modestly in subjects with severe renal impairment but was similar between subjects with moderate hepatic impairment and normal hepatic function. The increase in plasma exposure to THRX-195518 in subjects with severe renal or moderate hepatic impairment is unlikely to be of clinical consequence given its low antimuscarinic potency, low systemic levels after inhaled revefenacin administration, and favorable safety profile.
Assuntos
Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Carbamatos/efeitos adversos , Carbamatos/farmacocinética , Insuficiência Hepática/metabolismo , Antagonistas Muscarínicos/efeitos adversos , Antagonistas Muscarínicos/farmacocinética , Insuficiência Renal/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Clinical development of lesinurad, a selective uric acid reabsorption inhibitor, required analysis of lesinurad in plasma from special patient populations. METHODS: EMA and FDA bioanalytical method validation guidance have recommended studying matrix effects on quantitation if samples from special patient populations are to be analyzed. In addition to lesinurad (plasma protein binding 98.2%), the matrix effects from special population plasma on the quantitation of verapamil (PPB 89.6%), allopurinol and oxypurinol (PPB negligible) were also investigated. RESULTS: The plasma from special population patients had no matrix effects on the three quantification methods with stable isotope labeled internal standard, protein precipitation extraction, and LC-MS/MS detection. The validated lesinurad plasma quantification method was successfully applied for the pharmacokinetic evaluations to support the clinical studies in renal impaired patients. CONCLUSION: Special population plasma did not affect quantitation of drugs with a wide range of plasma protein binding levels in human plasma. With the confirmation that there is no impact on quantification from the matrix, the bioanalytical method can be used to support the pharmacokinetic evaluations for clinical studies in special populations.
Assuntos
Insuficiência Hepática/metabolismo , Insuficiência Renal/metabolismo , Tioglicolatos/sangue , Triazóis/sangue , Uricosúricos/sangue , Alopurinol/farmacocinética , Calibragem , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida de Alta Pressão/normas , Ensaios Clínicos como Assunto , Insuficiência Hepática/sangue , Insuficiência Hepática/fisiopatologia , Humanos , Rim/metabolismo , Rim/fisiopatologia , Fígado/metabolismo , Fígado/fisiopatologia , Oxipurinol/sangue , Oxipurinol/farmacocinética , Padrões de Referência , Insuficiência Renal/sangue , Insuficiência Renal/fisiopatologia , Reabsorção Renal , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Espectrometria de Massas em Tandem/normas , Tioglicolatos/farmacocinética , Triazóis/farmacocinética , Uricosúricos/farmacocinética , Verapamil/sangue , Verapamil/farmacocinéticaRESUMO
Statins reduce cardiovascular risk. However, "real-life" data on statin use in patients with chronic liver disease and its impact on overall and liver-related survival are limited. Therefore, we assessed 1265 CLD patients stratified as advanced (ACLD) or non-advanced (non-ACLD) stage. Statin indication was evaluated according to the 2013 ACC/AHA guidelines and survival-status was verified by national death registry data. Overall, 122 (9.6%) patients had an indication for statin therapy but did not receive statins, 178 (14.1%) patients were on statins and 965 (76.3%) patients had no indication for statins. Statin underutilization was 34.2% in non-ACLD and 48.2% in ACLD patients. In non-ACLD patients, survival was worse without a statin despite indication as compared to patients on statin or without indication (log-rank p = 0.018). In ACLD patients, statin use did not significantly impact on survival (log-rank p = 0.264). Multivariate cox regression analysis confirmed improved overall survival in patients with statin as compared to patients with indication but no statin (HR 0.225; 95%CI 0.053-0.959; p = 0.044) and a trend towards reduced liver-related mortality (HR 0.088; 95%CI 0.006-1.200; p = 0.068). This was not observed in ACLD patients. In conclusion, guideline-confirm statin use is often withhold from patients with liver disease and this underutilization is associated with impaired survival in non-ACLD patients.
Assuntos
Anticolesterolemiantes/uso terapêutico , Dislipidemias/tratamento farmacológico , Insuficiência Hepática/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Adulto , Idoso , Doença Crônica , Dislipidemias/metabolismo , Dislipidemias/mortalidade , Dislipidemias/patologia , Feminino , Insuficiência Hepática/metabolismo , Insuficiência Hepática/mortalidade , Insuficiência Hepática/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Modelos de Riscos Proporcionais , Sistema de RegistrosRESUMO
INTRODUCTION: Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on venetoclax pharmacokinetics. METHODS: A phase I study was carried out in 24 women with normal hepatic function or mild, moderate, or severe hepatic impairment (based on Child-Pugh scores), who received a single 50 mg dose of venetoclax with a low-fat meal. Blood samples were collected up to 120 h after venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods. RESULTS: Venetoclax maximum observed plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) in subjects with mild or moderate hepatic impairment were similar to subjects with normal hepatic function. Mean venetoclax AUC in subjects with severe hepatic impairment was 2.3- to 2.7-fold higher than in subjects with normal hepatic function. The half-life of venetoclax in subjects with severe hepatic impairment was approximately two-fold longer than in subjects with normal hepatic function and subjects with mild or moderate hepatic impairment. Unbound fractions of venetoclax in subjects with mild, moderate, and severe hepatic impairment were similar to the subjects with normal hepatic function. No significant adverse safety events were reported. CONCLUSIONS: No venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of venetoclax is recommended to account for higher exposures and the longer half-life.
Assuntos
Antineoplásicos/farmacocinética , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Insuficiência Hepática/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Sulfonamidas/farmacocinética , Administração Oral , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/sangue , Estudos de Casos e Controles , Feminino , Meia-Vida , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pessoa de Meia-Idade , Segurança , Sulfonamidas/administração & dosagem , Sulfonamidas/sangueRESUMO
Renal or hepatic impairment is a common comorbidity for patients with cancer either because of the disease itself, toxicity of previous anticancer treatments, or because of other factors affecting organ function, such as increased age. Because renal and hepatic function are among the main determinants of drug exposure, the pharmacokinetic profile might be altered for patients with cancer who have renal or hepatic impairment, necessitating dose adjustments. Most anticancer drugs are dosed near their maximum tolerated dose and are characterised by a narrow therapeutic index. Consequently, selecting an adequate dose for patients who have either hepatic or renal impairment, or both, is challenging and definitive recommendations on dose adjustments are scarce. In this Review, we discuss the effect of renal and hepatic impairment on the pharmacokinetics of anticancer drugs. To guide clinicians in selecting appropriate dose adjustments, information from available drug labels and from the published literature were combined to provide a practical set of recommendations for dose adjustments of 160 anticancer drugs for patients with hepatic and renal impairment.
Assuntos
Antineoplásicos/farmacocinética , Insuficiência Hepática/metabolismo , Neoplasias/metabolismo , Insuficiência Renal/metabolismo , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Tomada de Decisão Clínica , Relação Dose-Resposta a Droga , Insuficiência Hepática/fisiopatologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/fisiopatologia , Guias de Prática Clínica como Assunto , Insuficiência Renal/fisiopatologiaRESUMO
Cabotegravir is an investigational integrase inhibitor in development for the treatment and pre-exposure prophylaxis of HIV-1 infection. Liver disease is a major cause of morbidity and mortality in HIV-infected individuals and can impact the pharmacokinetics (PK) of HIV medications. This phase 1 study evaluated the PK of cabotegravir in individuals with moderate hepatic impairment (n = 8) versus healthy controls (n = 8). Participants received a single oral cabotegravir 30-mg tablet and underwent PK sampling to determine total and unbound plasma cabotegravir concentrations. Calculated geometric least-squares mean ratios (90% confidence intervals) for individuals with hepatic impairment versus healthy controls were 0.73 (0.50-1.06) for AUC0-∞ , 0.69 (0.51-0.93) for Cmax , 1.40 (0.80-2.46) for unbound concentration (CU) 2 hours postdose, 1.55 (0.82-2.94) for CU at 24 hours, 2.14 (1.57-2.90) for unbound fraction (FU) at 2 hours, and 1.90 (1.14-3.18) for FU at 24 hours. Adverse events (AEs) occurred in 2 individuals with hepatic impairment and 3 healthy controls and were grade 1/2 in severity. No participant discontinued because of AEs. Increased FU resulted in a modest decrease in total plasma exposure not considered clinically relevant. We conclude that cabotegravir may be administered without dose adjustment in patients with mild to moderate hepatic impairment.
Assuntos
Fármacos Anti-HIV/farmacocinética , Insuficiência Hepática/metabolismo , Piridonas/farmacocinética , Administração Oral , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/sangue , Feminino , Insuficiência Hepática/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Piridonas/efeitos adversos , Piridonas/sangueRESUMO
AIMS: Remote ischemic conditioning (RIC) protects against organ ischemia/reperfusion injury in experimental and clinical settings. We have demonstrated that RIC prevents liver and lung inflammation/injury after hemorrhagic shock/resuscitation (S/R). In this study, we used a murine model of S/R to investigate the role of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in mediating hepatoprotection. RESULTS: The combination of RIC with S/R caused a synergistic rise in Nrf2 and its translocation to the nucleus in the liver. Increased activation of Nrf2 by RIC augmented heme oxygenase-1 (HO-1) and autophagy and exerted hepatoprotection, concurrent with reductions in S/R-induced TNF-α (tumor necrosis factor alpha) and IL-6 (interleukin-6). In Nrf2 knockout (KO) animals, RIC did not exert hepatoprotection, and it failed to upregulate HO-1 and autophagy. Further, resuscitating wildtype (WT) animals with blood from donor WT animals undergoing RIC was hepatoprotective, but not in Nrf2 KO recipient animals. Interestingly, RIC blood from Nrf2 KO donor animals was also not protective when used to resuscitate WT animals, suggesting a role for Nrf2 both in the afferent arm of RIC where protective factors are generated and also in the efferent arm where organ protection is exerted. Finally, RIC plasma prevented oxidant-induced zebrafish mortality, but not in Nrf2a morpholino knockdown fish. INNOVATION: Activation of Nrf2 is an essential mechanism underlying the hepatoprotective effects of RIC. Nrf2 appears to play a role in the afferent limb of RIC protection, as its absence precludes the generation of the protective humoral factors induced by RIC. CONCLUSION: Our studies demonstrate the critical role of Nrf2 in the ability of RIC to prevent organ injury after S/R.
Assuntos
Precondicionamento Isquêmico , Fígado/irrigação sanguínea , Fígado/metabolismo , Fator 2 Relacionado a NF-E2/genética , Choque Hemorrágico/metabolismo , Animais , Autofagia/genética , Modelos Animais de Doenças , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Insuficiência Hepática/etiologia , Insuficiência Hepática/metabolismo , Insuficiência Hepática/patologia , Peróxido de Hidrogênio/metabolismo , Peróxido de Hidrogênio/farmacologia , Imuno-Histoquímica , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Fígado/patologia , Fígado/ultraestrutura , Lesão Pulmonar/etiologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Camundongos , Camundongos Knockout , Fator 2 Relacionado a NF-E2/metabolismo , Choque Hemorrágico/complicações , Choque Hemorrágico/etiologia , Transdução de SinaisRESUMO
Background Patients with impaired liver function ( ILF ) were excluded from clinical trials that investigated non-vitamin K antagonist oral anticoagulants ( NOAC s) for stroke prevention in patients with atrial fibrillation. The aim of this study was to evaluate the efficacy and safety of NOAC s in atrial fibrillation patients with ILF . Methods and Results A cohort study based on electronic medical records was conducted from 2009 to 2016 at a multicenter healthcare provider in Taiwan and included 6451 anticoagulated atrial fibrillation patients (aged 76.7±7.0 years, 52.5% male). Patients were classified into 2 subgroups: patients with normal liver function (n=5818) and patients with ILF (n=633, 9.8%). Cox regression analysis was performed to investigate the risks of thromboembolism, bleeding, and death associated with use of NOAC s and warfarin in patients with normal liver function and ILF , respectively. In patients with normal liver function, compared with warfarin therapy (n=2928), NOAC therapy (n=4048) was associated with significantly lower risks of stroke or systemic embolism (adjusted hazard ratio: 0.75; 95% confidence interval, 0.65-0.88; P<0.001) and death (adjusted hazard ratio: 0.69; 95% confidence interval, 0.60-0.80; P<0.001) with no difference in major bleeding or gastrointestinal bleeding. In patients with ILF , compared with warfarin therapy (n=394), NOAC therapy (n=342) was associated with significantly lower risk of death (adjusted hazard ratio: 0.64; 95% confidence interval, 0.49-0.83; P<0.001), but no difference in stroke or systemic embolism, major bleeding, or gastrointestinal bleeding. Conclusions In atrial fibrillation patients with ILF , NOAC therapy and warfarin therapy were associated with similar risks of stroke or systemic embolism, major bleeding, and gastrointestinal bleeding.
Assuntos
Fibrilação Atrial/tratamento farmacológico , Inibidores do Fator Xa/uso terapêutico , Hemorragia/induzido quimicamente , Insuficiência Hepática/metabolismo , Acidente Vascular Cerebral/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Antitrombinas/uso terapêutico , Fibrilação Atrial/complicações , Estudos de Coortes , Dabigatrana/uso terapêutico , Feminino , Hemorragia Gastrointestinal/induzido quimicamente , Hemorragia Gastrointestinal/epidemiologia , Hemorragia/epidemiologia , Insuficiência Hepática/complicações , Humanos , Masculino , Modelos de Riscos Proporcionais , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Piridonas/uso terapêutico , Estudos Retrospectivos , Rivaroxabana/uso terapêutico , Acidente Vascular Cerebral/etiologia , Tiazóis/uso terapêutico , Tromboembolia/etiologia , Tromboembolia/prevenção & controle , Varfarina/uso terapêuticoRESUMO
BACKGROUND Effects of liver dysfunction on target-controlled infusion (TCI) with Marsh parameters of propofol remain poorly documented. The purpose of this study was to evaluate the performance of propofol TCI in a cohort of Chinese patients with severe hepatic insufficiency. MATERIAL AND METHODS We assigned 32 patients who underwent liver transplantation to 3 groups according to Child-Turcotte-Pugh (CTP) score. Anesthesia, preceding liver transplantation, was induced and maintained with TCI of 3 µg/mL propofol. Plasma propofol concentration was assessed. Propofol TCI system performance was analyzed in terms of error size, bias, and divergence. Data on plasma propofol concentrations were analyzed, and population pharmacokinetic parameters of propofol were fitted by NONMEM software. RESULTS In the CTP C group, measured concentrations of propofol were much higher than those of predictive concentrations, with significantly higher overshoots compared to CTP A patients. Overall, TCI system performance was significantly lower in CTP C patients. Linear regression equations of Cm vs. Cp and a regression model of pharmacokinetics were obtained. CONCLUSIONS Propofol TCI device performance with Marsh parameters was clinically acceptable in CTP A patients but may not be suitable for patients with severe hepatic impairment.
Assuntos
Insuficiência Hepática/metabolismo , Propofol/administração & dosagem , Propofol/farmacocinética , Adulto , Anestésicos Intravenosos/administração & dosagem , Anestésicos Intravenosos/farmacocinética , Povo Asiático , China , Estudos de Coortes , Feminino , Insuficiência Hepática/sangue , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Propofol/sangueRESUMO
Caspofungin is an echinocandin antifungal agent licensed as a first-line therapy for invasive candidiasis in patients with moderate to severe illness or recent exposure to azoles. In this study we developed a whole-body physiology-based pharmacokinetics (WB-PBPK) model to predict the pharmacokinetics (PK) of caspofungin, and combined with Monte Carlo simulation (MCS) to optimize clinical dosage regimens of caspofungin in different kinds of patients. A WB-PBPK model of caspofungin was built and validated with raw data from 4 previous trials of general patients, intensive care unit (ICU) patients with Child-Pugh B, ICU patients on continuous renal replacement therapy, mild and moderate hepatic insuffciency (HI) patients. MCS was used to optimize clinical dosage regimens of caspofungin in these patients. A cumulative fraction of response (CFR) value of ≥90% was considered to be the minimum for achieving optimal empirical therapy. The simulated results of the WB-PBPK model were in good agreement with observed values of all trials. For general and ICU patients with caspofungin 70/50 mg, AUC and Cmax were decreased with the increase of body weight (BW) and showed great variation. MCS showed all general patients achieved CFR≥90% regardless of BW. But not all ICU patients with higher BW (≥70 kg) could achieve CFR≥90%. Compared with standard dosage regimens in general patients, caspofungin 70/35 mg in ICU patients with Child-Pugh B achieved significantly decreased AUC and Cmax, but obtained similar AUC and Cmax in moderate HI patients with Child-Pugh B. The WB-PBPK model of caspofungin is able to predict PK of all populations correctly. The combined WB-PBPK model with MCS can successfully optimize clinical dosage regimens of caspofungin in all patient populations.
Assuntos
Antifúngicos/farmacocinética , Caspofungina/farmacocinética , Modelos Biológicos , Adulto , Antifúngicos/administração & dosagem , Caspofungina/administração & dosagem , Insuficiência Hepática/metabolismo , Humanos , Unidades de Terapia Intensiva , Masculino , Método de Monte Carlo , Adulto JovemRESUMO
The aim of this study is to assess a potential mechanism by which the serotonergic system can control the expression and activity of cytochrome (CYP) 2C11 and CYP3A isoforms during liver insufficiency. A rat model of diethylnitrosamine (DEN)-induced liver insufficiency was developed by administering 50â¯mg/kg of DEN twice a week for 7 weeks. Dysfunction of the serotonergic system was evoked by feeding the rats with a tryptophan-free diet for three weeks. Dysfunction of the serotonergic system during liver insufficiency decreased the level of proinflammatory cytokines (TGF-ß and IL-1ß) and increased the level of an anti-inflammatory cytokine (IL-4). Simultaneously, activation of the repressive mechanism IL-4/JAK1/STAT6/SOCS1 of the JAK2/STAT5b-mediated signal transduction pathway and the pERK1/2/GR/STAT6 signal transduction pathway resulted in the suppression of the CYP2C11 and CYP3A isoforms. Moreover, dysfunction of the serotonergic system during liver insufficiency equalized the level of testosterone to the basal level, did not change the steady state of the corticosterone level and significantly enhanced the reduced level of growth hormone. An altered cytokine profile under control of the serotonergic system determines the regulation of CYP2C11 and CYP3A isoforms during liver insufficiency through mechanisms based on posttranscriptional and posttranslational processes.
Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Citocromo P-450 CYP3A/metabolismo , Família 2 do Citocromo P450/metabolismo , Citocinas/sangue , Insuficiência Hepática/enzimologia , Serotonina/fisiologia , Esteroide 16-alfa-Hidroxilase/metabolismo , Animais , Biomarcadores/metabolismo , Peso Corporal , Dietilnitrosamina/toxicidade , Modelos Animais de Doenças , Insuficiência Hepática/induzido quimicamente , Insuficiência Hepática/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-4/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Tamanho do Órgão , Processamento de Proteína Pós-Traducional , Processamento Pós-Transcricional do RNA , Ratos Wistar , Transdução de Sinais , Testosterona/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
BACKGROUND: Necrotizing enterocolitis (NEC) is a disease known to cause injury to multiple organs including the liver. Liver regeneration is essential for the recovery after NEC-induced liver injury. Our aim was to investigate hepatic proliferation and progenitor cell marker expression in experimental NEC. METHODS: Following ethical approval (#32238), NEC was induced in mice by hypoxia, gavage feeding of hyperosmolar formula, and lipopolysaccharide. Breastfed pups were used as control. We analyzed serum ALT level, liver inflammatory cytokines, liver proliferation markers, and progenitor cell marker expression. Comparison was made between NEC and controls. RESULTS: Serum ALT level was higher in NEC (p<0.05). The mRNA expression of inflammatory cytokines in the liver was also higher in NEC (IL6: p<0.05, TNF-α: p<0.01). Conversely, mRNA expression of proliferation markers in the liver was lower in NEC (Ki67; p<0.01, PCNA: p<0.01). LGR5 expression was also significantly decreased in NEC as demonstrated by mRNA (p<0.05) and protein (p<0.01) levels. CONCLUSIONS: Inflammatory injury was present in the liver during experimental NEC. Proliferation and LGR5 expression were impaired in the NEC liver. Modulation of progenitor cell expressing LGR5 may result in stimulation of liver regeneration in NEC-induced liver injury and improved clinical outcome. LEVEL OF EVIDENCE: Level IV.