RESUMO
Decitabine is a DNA methyltransferase inhibitor used in the treatment of acute myeloid leukemia and myelodysplastic syndrome. The notion that ongoing trials are presently exploring the combined use of decitabine, with or without the cytidine deaminase inhibitor cedazuridine, and other antileukemic drugs necessitates a comprehensive understanding of pharmacokinetic properties and an evaluation of drug-drug interaction liabilities. We report here the development and validation of a sensitive UHPLC-MS/MS method for quantifying decitabine in mouse plasma, which should be useful for such studies. The method involved a one-step protein precipitation extraction, and chromatographic separation on an XBridge HILIC column using gradient elution. The method was found to be robust, accurate, precise, and sufficiently sensitive (lower limit of quantitation, 0.4 ng/mL) to determine decitabine concentrations in microvolumes of plasma from mice receiving the agent orally or intravenously in the presence or absence of cedazuridine.
Assuntos
Decitabina , Espectrometria de Massas em Tandem , Animais , Espectrometria de Massas em Tandem/métodos , Decitabina/farmacocinética , Decitabina/sangue , Decitabina/administração & dosagem , Camundongos , Cromatografia Líquida de Alta Pressão/métodos , Reprodutibilidade dos Testes , Azacitidina/farmacocinética , Azacitidina/sangue , Azacitidina/análogos & derivados , Azacitidina/administração & dosagem , Azacitidina/química , Modelos Lineares , Uridina/farmacocinética , Uridina/sangue , Uridina/análogos & derivados , Sensibilidade e Especificidade , Limite de DetecçãoRESUMO
OBJECTIVE: To review the pharmacokinetic (PK)-pharmacodynamic (PD) profiles, disease setting, dosing, and safety of oral and parenteral hypomethylating agents (HMAs) for the treatment of myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML), and to provide a multidisciplinary perspective on treatment selection and educational needs relating to HMA use. DATA SOURCES: Clinical and real-world data for parenteral decitabine and azacitidine and two oral HMAs: decitabine-cedazuridine (DEC-C) for MDS and azacitidine (CC-486) for AML maintenance therapy. DATA SUMMARY: Differences in the PK-PD profiles of oral and parenteral HMA formulations have implications for their potential toxicities and planned use. Oral DEC-C (decitabine 35â mg and cedazuridine 100â mg) has demonstrated equivalent systemic area under the concentration-time curve (AUC) exposure to a 5-day regimen of intravenous (IV) decitabine 20â mg/m2 and showed no significant difference in PD. The AUC equivalence of oral DEC-C and IV decitabine means that these regimens can be treated interchangeably (but must not be substituted within a cycle). Oral azacitidine has a distinct PK-PD profile versus IV or subcutaneous azacitidine, and the formulations are not bioequivalent or interchangeable owing to differences in plasma time-course kinetics and exposures. Clinical trials are ongoing to evaluate oral HMA combinations and novel oral HMAs, such as NTX-301 and ASTX030. CONCLUSIONS: Treatment with oral HMAs has the potential to improve quality of life, treatment adherence, and disease outcomes versus parenteral HMAs. Better education of multidisciplinary teams on the factors affecting HMA treatment selection may help to improve treatment outcomes in patients with MDS or AML.
Assuntos
Azacitidina , Decitabina , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Humanos , Síndromes Mielodisplásicas/tratamento farmacológico , Leucemia Mieloide Aguda/tratamento farmacológico , Administração Oral , Azacitidina/farmacocinética , Azacitidina/administração & dosagem , Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Decitabina/farmacocinética , Decitabina/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/uso terapêutico , Uridina/farmacocinética , Uridina/análogos & derivados , Uridina/administração & dosagem , Uridina/uso terapêutico , Uridina/farmacologiaRESUMO
Oral hypomethylating agents (HMAs) represent a substantial potential boon for patients with myelodysplastic syndrome (MDS) who have previously required between 5 and 7 visits per month to an infusion clinic to receive therapy. For patients who respond to treatment, ongoing monthly maintenance visits represent a considerable burden to quality of life, and for those who are early in therapy, these sequential visits may tax transportation and financial resources that would be optimally distributed over the treatment cycle to facilitate transfusion support. The availability of oral HMAs may support the optimal application of these agents by contributing to adherence and lessening the burden of therapy, potentially encouraging patients to stay on longer-term treatment. Distinct pharmacokinetic profiles for the recently approved oral HMAs (oral azacitidine and decitabine-cedazuridine) result in differential toxicity profiles and have prompted their clinical trial development in lower- and higher-risk MDS, respectively.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Decitabina/uso terapêutico , Síndromes Mielodisplásicas/tratamento farmacológico , Uridina/análogos & derivados , Administração Oral , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Azacitidina/administração & dosagem , Azacitidina/farmacocinética , Decitabina/administração & dosagem , Decitabina/farmacocinética , Feminino , Humanos , Qualidade de Vida , Uridina/administração & dosagem , Uridina/farmacocinética , Uridina/uso terapêuticoRESUMO
Two oral hypomethylating agents, oral azacitidine (CC-486) and decitabine/cedazuridine (ASTX727), have recently entered the clinical domain. CC-486 has been shown to improve overall survival as maintenance therapy for older patients with acute myeloid leukemia in complete remission, whereas the combination of decitabine with cedazuridine, a cytidine deaminase inhibitor, is indicated for the treatment of adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia with intermediate-1, or higher, International Prognostic Scoring System risk. This article briefly summarizes the clinical development of both drugs, the pivotal studies that led to their approval and some of the issues faced in extending the use of these drugs to other indications.
Lay abstract One of the key challenges in treating acute myeloid leukemia is to prevent relapse after remission has been achieved. This means that developing an effective maintenance treatment is very important. Maintenance treatment is given for a prolonged period and so it needs to be easy to give and well tolerated. Oral azacitidine is an example of this type of treatment and is the first drug that has been shown to improve survival as maintenance therapy for acute myeloid leukemia patients. This article describes the key studies that led to the approval of this important therapy.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Decitabina/administração & dosagem , Aprovação de Drogas , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Uridina/análogos & derivados , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/farmacocinética , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/farmacocinética , Disponibilidade Biológica , Ensaios Clínicos Fase III como Assunto , Metilação de DNA/efeitos dos fármacos , Decitabina/efeitos adversos , Decitabina/farmacocinética , Combinação de Medicamentos , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão/métodos , Uridina/administração & dosagem , Uridina/efeitos adversos , Uridina/farmacocinéticaAssuntos
Antivirais/farmacocinética , Carbamatos/farmacocinética , Imidazóis/farmacocinética , Troca Materno-Fetal , Placenta/metabolismo , Pirrolidinas/farmacocinética , Uridina/análogos & derivados , Valina/análogos & derivados , Antivirais/metabolismo , Carbamatos/metabolismo , Feminino , Hepatite C/tratamento farmacológico , Humanos , Imidazóis/metabolismo , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , Pirrolidinas/metabolismo , Sofosbuvir/metabolismo , Sofosbuvir/farmacocinética , Uridina/metabolismo , Uridina/farmacocinética , Valina/metabolismo , Valina/farmacocinéticaRESUMO
This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage and then as a single fixed-dose combination (FDC) tablet. Primary end points: mean decitabine systemic exposure (geometric least-squares mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), percentage long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1-106.5) and 97.6% (80.5-118.3) for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35 mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar efficacy. This study is registered at www.clinicaltrials.gov as #NCT02103478.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mielomonocítica Crônica/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Cápsulas , Estudos Cross-Over , Metilação de DNA/efeitos dos fármacos , DNA-Citosina Metilases/antagonistas & inibidores , Decitabina/administração & dosagem , Decitabina/efeitos adversos , Decitabina/farmacocinética , Decitabina/farmacologia , Progressão da Doença , Combinação de Medicamentos , Monitoramento de Medicamentos , Feminino , Gastroenteropatias/induzido quimicamente , Doenças Hematológicas/induzido quimicamente , Humanos , Estimativa de Kaplan-Meier , Análise dos Mínimos Quadrados , Leucemia Mieloide Aguda/prevenção & controle , Elementos Nucleotídeos Longos e Dispersos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Comprimidos , Uridina/administração & dosagem , Uridina/efeitos adversos , Uridina/análogos & derivados , Uridina/farmacocinética , Uridina/farmacologiaRESUMO
Despite being in routine for onco-diagnostics for years, the applicability of nucleosidic molecular imaging probes is severely restricted in neurological applications due to their low permeability across blood-brain-barrier (BBB). For extending nucleoside tracers utility for neuro-onco early diagnostics, suitable modification which enhances their BBB permeation needs investigation. Among various modifications, lipidization of nucleosides has been reported to enhance cellular permeability. Extending the concept, the aim was to exemplify the possibility of lipidized nucleosides as potential brain tracer with capability to cross intact BBB and evaluate as metal based neuro-imaging SPECT agent. Uridine based non-lipidic (NSDAU) and di-C15-ketal appended lipidic (NLDPU) ligands were conjugated to chelator, DTPA (DTPA-NSDAU and DTPA-NLDPU) using multi-step chemistry. The ligands were evaluated in parallel for comparative physical and biological parameters. Additionally, effects of enhanced lipophilicity on UV-absorption, acid strength, fluorescence and non-specific protein binding were evaluated. Fluorescence quenching of BSA indicated appreciable interaction of DTPA-NLDPU with protein only above 10â¯mM without inducing conformational changes. In addition, DTPA-NLDPU was found to be haematocompatible and cytocompatible with low dose-dependent toxicity in HEK-cells. The chelator DTPA was used for 99mTc-complexation for SPECT imaging. Optimized 99mTc-radiolabeling parameters resulted in quantitative (≥97%) labeling with good stability parameters in in-vitro serum and cysteine challenge studies. We demonstrate that the nucleolipid radiotracer (99mTc-DTPA-NLDPU) was successfully able to permeate the BBB with brain uptake of 0.2% ID/g in normal mice as compared to 0.06% ID/g uptake of 99mTc-DTPA-NSDAU at 5â¯min. Blood kinetics indicate biphasic profile and t1/2(distribution) 46â¯min for 99mTc-DTPA-NLDPU. The preferential accumulation of 99mTc-DTPA-NLDPU in brain tumor intracranial xenograft indicate the targeting capability of the nucleoside. We conclude that as first-of-its-kind, this work presents the potential of the biocompatible nucleolipidic system for brain targeting and early diagnostics.
Assuntos
Barreira Hematoencefálica/metabolismo , Hidrocarbonetos/administração & dosagem , Cetonas/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Pentetato de Tecnécio Tc 99m/administração & dosagem , Uridina/administração & dosagem , Animais , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Hidrocarbonetos/farmacocinética , Cetonas/farmacocinética , Camundongos Endogâmicos BALB C , Permeabilidade , Coelhos , Compostos Radiofarmacêuticos/farmacocinética , Pentetato de Tecnécio Tc 99m/farmacocinética , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único , Uridina/farmacocinéticaRESUMO
Sofosbuvir is an NS5B nucleotide inhibitor for the treatment of hepatitis C viral infection. In this study the pharmacokinetics (PK) and safety of single and multiple doses of generic sofosbuvir were investigated in healthy Chinese subjects. Twelve subjects (6 male and 6 female) were enrolled in this study. The PK parameters of sofosbuvir and its metabolite (GS-331007) in both blood and urine samples were analyzed after dosing by the established liquid chromatography tandem mass spectrometry analytical method. The safety/tolerability assessment consisted of documenting adverse events, vital signs, electrocardiogram, and laboratory test results. Sofosbuvir was well tolerated. Major PK parameters of the generic formulation of sofosbuvir were similar to those found in previous reports. These data support further clinical evaluation of this generic formulation of sofosbuvir.
Assuntos
Antivirais/farmacocinética , Medicamentos Genéricos/farmacocinética , Sofosbuvir/farmacocinética , Uridina/análogos & derivados , Administração Oral , Adulto , Antivirais/efeitos adversos , Antivirais/sangue , Antivirais/urina , Área Sob a Curva , Relação Dose-Resposta a Droga , Medicamentos Genéricos/efeitos adversos , Feminino , Voluntários Saudáveis , Hepacivirus/efeitos dos fármacos , Humanos , Masculino , Taxa de Depuração Metabólica , Sofosbuvir/efeitos adversos , Sofosbuvir/sangue , Sofosbuvir/urina , Uridina/efeitos adversos , Uridina/sangue , Uridina/farmacocinética , Uridina/urinaRESUMO
BACKGROUND: Limited data exist on the pharmacokinetic profile of novel direct-acting antivirals in kidney transplant recipients. Daclatasvir is primarily eliminated through the biliary route and sofosbuvir through the renal route; here, we report the pharmacokinetic profile of combined treatment with these compounds in a prospective study of hepatitis C virus (HCV)-positive kidney transplant recipients (EudraCT: 2014-004551-32). METHODS: In this study, plasma samples of 16 HCV-positive kidney transplant recipients receiving daclatasvir and sofosbuvir were collected at 4 time points at days 1, 7, 14, 21, 56, and 84 after start of treatment. Inclusion criteria were stable graft function and an estimated glomerular filtration rate (eGFR) >30 mL/min/1.73 m. Daclatasvir, sofosbuvir, and GS-331007 (inactive metabolite of sofosbuvir) plasma concentrations were determined using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry. RESULTS: All patients showed a rapid virological response with HCV RNA below the detection limit 21 days after the start of therapy (medium time to viral clearance). No difference of the areas under the concentration-time curve (AUC) of daclatasvir, sofosbuvir, and GS-331007 was observed between patients with an eGFR below or ≥60 mL/min. For GS-331007, no relevant changes of trough levels were observed over time. Mean GS-331007 trough levels were 339.5 ± 174.9 ng/mL in patients with an eGFR ≥60 mL/min and 404.3 ± 226 ng/mL in patients with an eGFR <60 mL/min at day 7 (P = 0.52). At day 84, GS-331007 trough levels were 357.8 ± 200.8 and 404.2 ± 70.2 ng/mL in patients with an eGFR ≥60 mL/min and in patients with an eGFR <60 mL/min, respectively (P = 0.51). The accumulation ratios of renally eliminated GS-331007 for AUC and Cmax did not significantly differ between the 2 eGFR groups at day 7. CONCLUSIONS: An impaired eGFR (30-60 mL/min) does not lead to a dose accumulation of daclatasvir, sofosbuvir, and GS-331007. This study provides the rationale for future studies investigating the pharmacokinetic profile of sofosbuvir-based HCV treatment in kidney transplant recipients with an eGFR <30 mL/min.
Assuntos
Antivirais/farmacocinética , Hepatite C Crônica/metabolismo , Imidazóis/farmacocinética , Sofosbuvir/farmacocinética , Uridina/análogos & derivados , Antivirais/uso terapêutico , Carbamatos , Estudos de Coortes , Quimioterapia Combinada/métodos , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/sangue , Hepatite C Crônica/tratamento farmacológico , Humanos , Imidazóis/uso terapêutico , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Pirrolidinas , Sofosbuvir/uso terapêutico , Transplantados , Uridina/farmacocinética , Uridina/uso terapêutico , Valina/análogos & derivadosRESUMO
The aim of the current study was to characterize the time course of plasma concentrations of AL-335 and its main metabolites (ALS-022399 and ALS-022227) after oral administration in healthy and hepatitis C virus (HCV)-infected subjects, in monotherapy as well as in combination with simeprevir and/or odalasvir. AL-335, ALS-022399, and ALS-022227 plasma concentrations from subjects receiving 800 mg of AL-335 orally once daily (qd) as monotherapy or in combination were pooled and analyzed using a nonlinear mixed effect modeling approach. The typical values (between subject variability) of AL-335 and ALS-022399 apparent linear clearances were 3300 L/h (33.9%) and 1910 L/h (30.0%), respectively. ALS-022227 elimination was characterized as a nonlinear process, with typical values of Vmax,ALS-022227 and Km,ALS-022227 estimated to be 84,799 ng/h (14.9%) and 450.2 ng/mL, respectively. AL-335 and ALS-022399 plasma concentrations were increased more than 2-fold in presence of simeprevir and/or odalasvir, while the effect on ALS-022227 plasma concentrations was limited. The effect of simeprevir and/or odalasvir might be explained by their capacity to inhibit P-glycoprotein. Internal evaluation confirmed that the population pharmacokinetic model developed was deemed appropriate to describe the time course of AL-335, ALS-022399, and ALS-022227 plasma concentrations and their associated variability in both healthy and HCV-infected subjects, as well as the interaction effect of simeprevir and/or odalasvir over AL-335 and its metabolites in healthy subjects. This model can be used as a starting point to evaluate drug-drug interaction processes in HCV-infected patients and support the development of a direct-acting antiviral (DAA) combination.
Assuntos
Alanina/análogos & derivados , Antivirais/farmacocinética , Variação Biológica da População , Hepatite C Crônica/tratamento farmacológico , Uridina/análogos & derivados , Administração Oral , Alanina/administração & dosagem , Alanina/farmacocinética , Antivirais/administração & dosagem , Antivirais/metabolismo , Benzimidazóis/administração & dosagem , Carbamatos/administração & dosagem , Esquema de Medicação , Interações Medicamentosas , Quimioterapia Combinada/métodos , Voluntários Saudáveis , Humanos , Indóis/administração & dosagem , Fosforamidas , Simeprevir/administração & dosagem , Uridina/administração & dosagem , Uridina/farmacocinéticaRESUMO
BACKGROUND: The nucleotide analog AL-335 is a pangenotypic hepatitis C virus (HCV) nonstructural protein (NS)5B inhibitor being evaluated as treatment for chronic HCV infection. METHODS: This three-part randomized, double-blind study evaluated the safety and pharmacokinetics of single and multiple ascending oral doses of AL-335. Healthy volunteers (HVs) received single doses of AL-335 (100-1,200 mg) or placebo in a fasted or fed (400 mg) state. Non-cirrhotic subjects (HCV genotype [GT]1-4) and GT1-infected subjects with Child Pugh A cirrhosis received multiple doses of AL-335 (400, 800, 1,200 mg) or placebo once daily (QD) for 7 days. RESULTS: Forty-eight HVs and 64 subjects with HCV GT1-4 were randomized and received treatment. AL-335 was well tolerated in HVs and HCV-infected subjects with/without cirrhosis. AL-335 was rapidly absorbed and converted to the metabolites ALS-022399 and ALS-022227. ALS-022227 exposure increased less than dose-proportionally and was unaffected by food, while AL-335 and ALS-022399 exposure increased with food by 85% and 50%, respectively, in HVs. Rapid and dose-dependent reductions in HCV-RNA were observed in GT1-infected subjects. In non-cirrhotic, GT1-4-infected subjects receiving AL-335 800 mg QD, potent antiviral activity was observed, regardless of genotype (mean maximum reductions in HCV-RNA of 4.0-4.8 log10 IU/mL). The same dose in GT1-infected cirrhotic subjects resulted in a 3.5 log10 IU/mL mean maximum reduction in HCV-RNA. CONCLUSIONS: AL-335 was well tolerated when administered as single and multiple doses, with an acceptable pharmacokinetic profile. The drug also demonstrated potent antiviral activity in HCV GT1-4-infected subjects, including GT1-infected subjects with cirrhosis.
Assuntos
Alanina/análogos & derivados , Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Uridina/análogos & derivados , Adulto , Alanina/efeitos adversos , Alanina/farmacocinética , Alanina/uso terapêutico , Antivirais/efeitos adversos , Antivirais/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Genótipo , Meia-Vida , Hepacivirus/genética , Hepatite C/complicações , Humanos , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Fosforamidas , Efeito Placebo , RNA Viral/sangue , Uridina/efeitos adversos , Uridina/farmacocinética , Uridina/uso terapêuticoRESUMO
PURPOSE: The purpose of this study was to investigate the safety, tolerability, and pharmacokinetic profile of sofosbuvir and its metabolites after a single dose of sofosbuvir 400mg and once daily dosing of sofosbuvir 400mg for 7days in healthy Chinese subjects. METHODS: This Phase I, open-label, single- and multiple-dose study enrolled 14 Chinese subjects aged 18 to 45years with an approximately even distribution of healthy male (nâ¯=â¯9) and nonpregnant, nonlactating female subjects (nâ¯=â¯5). Subjects received a single oral dose of sofosbuvir 400mg (one tablet) (morning, fasted conditions; single-dose treatment). After a 3-day washout, subjects received oral sofosbuvir 400mg (one tablet) (morning, fasted) for 7days (multiple dose treatment). FINDINGS: No significant accumulation of sofosbuvir, GS-566500, or GS-331007 was observed. Steady state of the major metabolite GS-331007 was achieved after 4days of consecutive dosing with sofosbuvir 400mg once daily. Sofosbuvir was generally well tolerated. IMPLICATIONS: Overall, this study supports the further evaluation of sofosbuvir 400mg in the Chinese population. The pharmacokinetic properties of sofosbuvir, GS-556500, and GS-311007 were found to be broadly similar in healthy Chinese subjects compared with non-Chinese subjects in previous sofosbuvir studies. ChinaDrugTrials.org.cn identifier: CTR20150249.
Assuntos
Antivirais/efeitos adversos , Antivirais/farmacocinética , Sofosbuvir/efeitos adversos , Sofosbuvir/farmacocinética , Adulto , Povo Asiático , Feminino , Voluntários Saudáveis , Hepatite C Crônica/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Sofosbuvir/sangue , Uridina/análogos & derivados , Uridina/sangue , Uridina/farmacocinética , Adulto JovemRESUMO
This Phase I, open-label, two-group, fixed-sequence study evaluated the pharmacokinetics and safety of AL-335, odalasvir, and simeprevir in healthy subjects. Group 1 (n = 16) received AL-335 800 mg once daily (QD) (days 1-3, 11-13, and 21-23), simeprevir 150 mg QD (days 4-23), and odalasvir 150 mg (day 14) followed by 50 mg QD (days 15-23). Group 2 (n = 16) received the same AL-335 regimen as in Group 1 plus odalasvir 150 mg (day 4) followed by 50 mg QD (days 5-23) and simeprevir 150 mg QD (days 14-23). Blood samples were collected to determine plasma concentrations of AL-335 (prodrug) and its metabolites, ALS-022399 (monophosphate precursor) and ALS-022227 (parent nucleoside), odalasvir, and simeprevir. Thirty-two subjects were enrolled. Odalasvir and simeprevir given alone, or in combination, increased AL-335 area under plasma concentration-time curve over 24 hours (AUC 0-24 h) 3-, 4-, and 7- to 8-fold, respectively; ALS-022399 AUC 0-24 h increased 2-, 2-, and 3-fold, respectively. Simeprevir had no effect on ALS-022227 AUC 0-24 h, whereas odalasvir with/without simeprevir increased ALS-022227 AUC 0-24 h 1.5-fold. AL-335 had no effect on odalasvir or simeprevir pharmacokinetics. Odalasvir and simeprevir AUC 0-24 h increased 1.5- to 2-fold for both drugs when coadministered irrespective of AL-335 coadministration. Study medications were well tolerated with no serious adverse events. One subject prematurely discontinued study drugs (unrelated event). This study defined the preliminary pharmacokinetic and safety profiles of the combination of AL-335, odalasvir, and simeprevir in healthy subjects. These data support the further evaluation of this combination for the treatment of chronic hepatitis C virus infection.
Assuntos
Alanina/análogos & derivados , Antivirais/farmacocinética , Benzimidazóis/farmacocinética , Carbamatos/farmacocinética , Quimioterapia Combinada/efeitos adversos , Indóis/farmacocinética , Pró-Fármacos/farmacocinética , Simeprevir/farmacocinética , Uridina/análogos & derivados , Administração Oral , Adulto , Alanina/efeitos adversos , Alanina/farmacocinética , Antivirais/efeitos adversos , Área Sob a Curva , Benzimidazóis/efeitos adversos , Carbamatos/efeitos adversos , Esquema de Medicação , Feminino , Voluntários Saudáveis , Humanos , Indóis/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fosforamidas , Pró-Fármacos/efeitos adversos , Simeprevir/efeitos adversos , Uridina/efeitos adversos , Uridina/farmacocinética , Proteínas não Estruturais Virais/antagonistas & inibidores , Adulto JovemRESUMO
BACKGROUND: The pharmacokinetics and safety of velpatasvir, a potent pangenotypic hepatitis C virus NS5A inhibitor, were evaluated in two hepatic impairment studies: a phase I study in hepatitis C virus-uninfected subjects and a phase III study (ASTRAL-4) in hepatitis C virus-infected patients. METHODS: In the phase I study, subjects with moderate or severe hepatic impairment (Child-Pugh-Turcotte Class B or C), and demographically matched subjects with normal hepatic function received a single dose of velpatasvir 100 mg. Pharmacokinetics and safety assessments were performed, and pharmacokinetic parameters were calculated using non-compartmental methods and summarized using descriptive statistics and compared statistically by geometric least-squares mean ratios and 90% confidence intervals. In ASTRAL-4, subjects with decompensated cirrhosis (Child-Pugh-Turcotte Class B) were randomized to receive treatment with either sofosbuvir/velpatasvir ± ribavirin for 12 weeks or sofosbuvir/velpatasvir for 24 weeks. Pharmacokinetic and safety assessments were performed and pharmacokinetic parameters were calculated using a non-compartmental analysis and summarized using descriptive statistics and were compared to pharmacokinetics from ASTRAL-1 [subjects without cirrhosis or with compensated (Child-Pugh-Turcotte Class A) cirrhosis]. RESULTS: In the phase I study, plasma exposures (area under the concentration-time curve) were similar in subjects with Child-Pugh-Turcotte Class B (n = 10) or Child-Pugh-Turcotte Class C hepatic impairment (n = 10) compared with normal hepatic function (n = 13). Percent free velpatasvir was similar in subjects without or with any degree of hepatic impairment. In the phase III study, velpatasvir overall exposure (area under the concentration-time curve over the 24-h dosing interval; AUCtau) was similar and sofosbuvir exposures were higher (~ 100%) for patients with Child-Pugh-Turcotte Class B hepatic impairment compared with the ASTRAL-1 population, which was not considered clinically relevant. CONCLUSIONS: No sofosbuvir/velpatasvir dose modification is warranted for patients with any degree of hepatic impairment.
Assuntos
Carbamatos/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Sofosbuvir/farmacocinética , Adolescente , Adulto , Idoso , Antivirais/efeitos adversos , Antivirais/sangue , Antivirais/farmacocinética , Antivirais/uso terapêutico , Carbamatos/efeitos adversos , Carbamatos/sangue , Combinação de Medicamentos , Quimioterapia Combinada/estatística & dados numéricos , Feminino , Insuficiência Hepática/sangue , Insuficiência Hepática/tratamento farmacológico , Hepatite C/sangue , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Compostos Heterocíclicos de 4 ou mais Anéis/sangue , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/complicações , Masculino , Pessoa de Meia-Idade , Ribavirina/uso terapêutico , Sofosbuvir/efeitos adversos , Uridina/análogos & derivados , Uridina/sangue , Uridina/farmacocinética , Adulto JovemRESUMO
We report on the assembly of multi-layered polyelectrolyte thin films containing an immobilized enzyme to perform conversion of externally administered prodrugs and achieve delivery of the resulting therapeutics to adhering cells. Towards this goal, multi-layered coatings were assembled using poly(sodium styrene sulfonate) and poly(allylamine hydrochloride). Activity of the incorporated enzyme was quantified as a function of the assembly conditions, position of the enzyme within the multi-layered architecture, concentration of the enzyme in the adsorption solution, and concentration of the administered prodrug. Biocatalytic coatings exhibited sustained levels of enzymatic activity over at least one week of incubation in physiological buffers without signs of loss of activity of the enzyme. Developed enzyme-containing polymer films afforded zero-order release of the in situ synthesized cargo with kinetics of synthesis (nM per hour) covering at least 3 orders of magnitude. Internalization of the synthesized product by adhering cells was visualized using a fluorogenic enzyme substrate. Therapeutic utility of biocatalytic coatings was demonstrated using a myoblast cell line and a prodrug for the anti-proliferative agent, 5-fluorouridine. Taken together, this work presents a novel approach to delivery of small molecule drugs using multi-layered polymer thin films with utility in surface-mediated drug delivery, assembly of therapeutic implantable devices, and tissue engineering.
Assuntos
Enzimas Imobilizadas/química , Poliaminas/química , Poliestirenos/química , Uridina/análogos & derivados , beta-Galactosidase/química , Animais , Catálise , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Membranas Artificiais , Camundongos , Próteses e Implantes , Engenharia Tecidual , Uridina/química , Uridina/farmacocinética , Uridina/farmacologiaRESUMO
Doxifluridine (5'-deoxy-5-fluorouridine, 5'-dFUR) is a fluoropyrimidine derivative that is activated preferentially in malignant cells by thymidine phosphorylase to form 5-fluorouracil (5-FU). The purpose of this study was to investigate the pharmacokinetic properties of doxifluridine and its two major metabolites, 5-FU, and 5-fluorouridine (5-FUrd), in beagle dogs following a single oral administration of 200 mg doxifluridine capsule (Furtulon(®)). After the administration of 200 mg of Furtulon to 23 beagle dogs, the plasma concentrations of doxifluridine, 5-FU, and 5-FUrd were measured simultaneously, using LC-MS/MS. The parent-metabolite compartment model with first-order absorption and Michaelis-Menten kinetics described the pharmacokinetics of doxifluridine, 5-FU, and 5-FUrd. Michaelis-Menten kinetics sufficiently explained the generation and elimination processes of 5-FU and 5-FUrd. The studies described here are the first to evaluate the relationship between pharmacokinetics of doxifluridine and its metabolites in dogs, and these findings will help in understanding the toxicity mechanism of doxifluridine.
Assuntos
Antimetabólitos Antineoplásicos/farmacocinética , Floxuridina/farmacocinética , Fluoruracila/farmacocinética , Uridina/análogos & derivados , Administração Oral , Algoritmos , Animais , Área Sob a Curva , Cápsulas , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Cães , Indicadores e Reagentes , Espectrometria de Massas , Espectrometria de Massas em Tandem , Uridina/farmacocinéticaAssuntos
Fibrose Cística/tratamento farmacológico , Nucleotídeos de Desoxicitosina/uso terapêutico , Uridina/análogos & derivados , Adolescente , Alelos , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Nucleotídeos de Desoxicitosina/farmacocinética , Progressão da Doença , Desenho de Fármacos , Indústria Farmacêutica , Feminino , Humanos , Inflamação , Masculino , Projetos de Pesquisa , Escarro/metabolismo , Fatores de Tempo , Resultado do Tratamento , Uridina/farmacocinética , Uridina/uso terapêuticoRESUMO
RATIONALE: Denufosol stimulates chloride secretion independent of the chloride channel which is dysfunctional in cystic fibrosis (CF) and therefore has the potential to benefit CF patients regardless of genotype. OBJECTIVES: To assess the efficacy of denufosol in CF patients with mild lung function impairment age 5 years and older. METHODS: This multicenter, randomized, parallel group double-blind placebo-controlled trial was conducted at 102 CF care centers in Australia, Canada and the United States (NCT00625612) The active group (n=233) received 60 mg denufosol via inhalation three times daily The primary efficacy endpoint was change in FEV(1) in liters from Day 0 to week 48. MEASUREMENTS AND MAIN RESULTS: 685 patients were screened for the study and 466 patients (233 in each group) were randomized to study treatment. The adjusted mean change in FEV(1)was 40 mL for denufosol and 32 mL for placebo with a resulting treatment effect of 8 mL (95% CI -0.040, 0.056). The average rate of change in FEV(1) percent of predicted over 0 to 48 weeks was -3.04% for placebo vs. -2.30 for denufosol (a difference of 24% relative to placebo) among all patients. The incidence of pulmonary exacerbation was 26% vs. 21% for the placebo and denufosol groups with no differences in the time to first event. The study treatments were well tolerated and there was no evidence of systemic effects in any safety parameter assessed. CONCLUSIONS: In patients with CF treatment with denufosol for 48 weeks did not improve pulmonary function or reduce the incidence of pulmonary exacerbations.
Assuntos
Cloretos/metabolismo , Fibrose Cística/tratamento farmacológico , Nucleotídeos de Desoxicitosina/administração & dosagem , Pneumopatias/tratamento farmacológico , Pulmão/efeitos dos fármacos , Uridina/análogos & derivados , Administração por Inalação , Adolescente , Adulto , Criança , Pré-Escolar , Fibrose Cística/epidemiologia , Nucleotídeos de Desoxicitosina/efeitos adversos , Nucleotídeos de Desoxicitosina/farmacocinética , Método Duplo-Cego , Feminino , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Incidência , Estimativa de Kaplan-Meier , Pulmão/fisiologia , Pneumopatias/epidemiologia , Masculino , Resultado do Tratamento , Uridina/administração & dosagem , Uridina/efeitos adversos , Uridina/farmacocinética , Adulto JovemRESUMO
As one of the most intensively studied probes for imaging of the cellular proliferation, [(18)F]FLT was investigated whether the targeting specificity of thymidine kinase 1 (TK1) dependency could be enhanced through a synergistic effect mediated by herpes simplex type 1 virus (HSV1) tk gene in terms of the TK1 or TK2 expression. 5-[(123)I]Iodo arabinosyl uridine ([(123)I]IaraU) was prepared in a radiochemical yield of 8% and specific activity of 21 GBq/µmol, respectively. Inhibition of the cellular uptake of these two tracers was compared by using the arabinosyl uridine analogs such as 5-iodo, 5-fluoro and 5-(E)-iodovinyl arabinosyl uridine along with 2'-fluoro-5-iodo arabinosyl uridine (FIAU). Due to potential instability of the iodo group, accumulation index of 1.6 for [(123)I]IaraU by HSV1-TK vs. control cells could virtually be achieved at 1.5 h, but dropped to 0.2 compared to 2.0 for [(18)F]FLT at 5 h. The results from competitive inhibition by these nucleosides against the accumulation of [(18)F]FLT implied that FLT exerted a mixed TK1- and TK2-dependent inhibition with HSV1-tk gene transfection because of the shifting of thymidine kinase status. Taken together, the combination of [(18)F]FLT and HSV1-TK provides a synergistic imaging potency.
Assuntos
Didesoxinucleosídeos/farmacocinética , Fibrossarcoma/diagnóstico por imagem , Herpesvirus Humano 1/enzimologia , Timidina Quinase/metabolismo , Uridina/análogos & derivados , Animais , Processos de Crescimento Celular , Linhagem Celular Tumoral , Didesoxinucleosídeos/química , Fibrossarcoma/enzimologia , Fibrossarcoma/genética , Herpesvirus Humano 1/genética , Humanos , Radioisótopos do Iodo/química , Radioisótopos do Iodo/metabolismo , Camundongos , Cintilografia , Compostos Radiofarmacêuticos/farmacocinética , Timidina Quinase/antagonistas & inibidores , Timidina Quinase/genética , Transfecção , Uridina/química , Uridina/farmacocinéticaRESUMO
BACKGROUND: Uridine is a therapy for hereditary orotic aciduria and is being investigated in other disorders caused by mitochondrial dysfunction, including toxicities resulting from treatment with nucleoside reverse transcriptase inhibitors in HIV. Historically, the use of uridine as a therapeutic agent has been limited by poor bioavailability. A food supplement containing nucleosides, NucleomaxX®, has been reported to raise plasma uridine to supraphysiologic levels. METHODOLOGY/PRINCIPAL FINDINGS: Single- and multi-dose PK studies following NucleomaxX® were compared to single-dose PK studies of equimolar doses of pure uridine in healthy human volunteers. Product analysis documented that more than 90% of the nucleoside component of NucleomaxX® is in the form of triacetyluridine (TAU). Single and repeated dosing with NucleomaxX® resulted in peak plasma uridine concentrations 1-2 hours later of 150.9 ± 39.3 µM and 161.4 ± 31.5 µM, respectively, levels known to ameliorate mitochondrial toxicity in vitro. C(max) and AUC were four-fold higher after a single dose of NucleomaxX® than after uridine. No adverse effects of either treatment were observed. CONCLUSIONS/SIGNIFICANCE: NucleomaxX®, containing predominantly TAU, has significantly greater bioavailability than pure uridine in human subjects and may be useful in the management of mitochondrial toxicity.