RESUMEN
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.
Asunto(s)
Decitabina , Espectrometría de Masas en Tándem , Animales , Espectrometría de Masas en Tándem/métodos , Decitabina/farmacocinética , Decitabina/sangre , Decitabina/administración & dosificación , Ratones , Cromatografía Líquida de Alta Presión/métodos , Reproducibilidad de los Resultados , Azacitidina/farmacocinética , Azacitidina/sangre , Azacitidina/análogos & derivados , Azacitidina/administración & dosificación , Azacitidina/química , Modelos Lineales , Uridina/farmacocinética , Uridina/sangre , Uridina/análogos & derivados , Sensibilidad y Especificidad , Límite de DetecciónRESUMEN
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.
Asunto(s)
Azacitidina , Decitabina , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Síndromes Mielodisplásicos/tratamiento farmacológico , Leucemia Mieloide Aguda/tratamiento farmacológico , Administración Oral , Azacitidina/farmacocinética , Azacitidina/administración & dosificación , Azacitidina/análogos & derivados , Azacitidina/uso terapéutico , Decitabina/farmacocinética , Decitabina/administración & dosificación , Antimetabolitos Antineoplásicos/farmacocinética , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/uso terapéutico , Uridina/farmacocinética , Uridina/análogos & derivados , Uridina/administración & dosificación , Uridina/uso terapéutico , Uridina/farmacologíaRESUMEN
BACKGROUND: Standard care for patients with high-risk myelodysplastic syndrome (MDS) is hypomethylating agents such as azacitidine (AZA), which can induce expression of methylated tumor-associated antigens and therefore potentiate immunotherapeutic targeting. METHOD: In this phase 1 trial, we combined AZA with a therapeutic peptide vaccine targeting antigens encoded from NY-ESO-1, MAGE-A3, PRAME, and WT-1, which have previously been demonstrated to be upregulated by AZA treatment. RESULT: Five patients who had responded to AZA monotherapy were included in the study and treated with the vaccine. The combination therapy showed only few adverse events during the study period, whereof none classified as serious. However, no specific immune responses could be detected using intracellular cytokine staining or ELISpot assays. Minor changes in the phenotypic composition of immune cells and their expression of stimulatory and inhibitory markers were detected. All patients progressed to AML with a mean time to progression from inclusion (TTP) of 5.2 months (range 2.8 to 7.6). Mean survival was 18.1 months (range 10.9 to 30.6) from MDS diagnosis and 11.3 months (range 4.3 to 22.2) from inclusion. Sequencing of bone marrow showed clonal expansion of malignant cells, as well as appearance of novel mutations. CONCLUSION: The patients progressed to AML with an average time of only five months after initiating the combination therapy. This may be unrelated to the experimental treatment, but the trial was terminated early as there was no sign of clinical benefit or immunological response. Why the manuscript is especially interesting This study is the first to exploit the potential synergistic effects of combining a multi-peptide cancer vaccine with epigenetic therapy in MDS. Although our results are negative, they emphasize challenges to induce immune reactivity in patients with high-risk MDS.
Asunto(s)
Antígenos de Neoplasias/inmunología , Azacitidina/uso terapéutico , Vacunas contra el Cáncer/uso terapéutico , Epigénesis Genética , Síndromes Mielodisplásicos/tratamiento farmacológico , Anciano , Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/farmacocinética , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/farmacocinética , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Dosis Máxima Tolerada , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/patología , Pronóstico , Distribución TisularRESUMEN
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.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Decitabina/uso terapéutico , Síndromes Mielodisplásicos/tratamiento farmacológico , Uridina/análogos & derivados , Administración Oral , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/farmacocinética , Azacitidina/administración & dosificación , Azacitidina/farmacocinética , Decitabina/administración & dosificación , Decitabina/farmacocinética , Femenino , Humanos , Calidad de Vida , Uridina/administración & dosificación , Uridina/farmacocinética , Uridina/uso terapéuticoRESUMEN
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.
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Antimetabolitos Antineoplásicos/administración & dosificación , Decitabina/administración & dosificación , Aprobación de Drogas , Leucemia Mieloide Aguda/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Uridina/análogos & derivados , Antimetabolitos Antineoplásicos/efectos adversos , Antimetabolitos Antineoplásicos/farmacocinética , Azacitidina/administración & dosificación , Azacitidina/efectos adversos , Azacitidina/farmacocinética , Disponibilidad Biológica , Ensayos Clínicos Fase III como Asunto , Metilación de ADN/efectos de los fármacos , Decitabina/efectos adversos , Decitabina/farmacocinética , Combinación de Medicamentos , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de Remisión/métodos , Uridina/administración & dosificación , Uridina/efectos adversos , Uridina/farmacocinéticaRESUMEN
BACKGROUND: Epigenetic therapy through demethylation of 5-methylcytosine has been largely ineffective in treating lung cancer, most likely due to poor tissue distribution with oral or subcutaneous delivery of drugs such as 5-azacytidine (5AZA). An inhalable, stable dry powder formulation of 5AZA was developed. METHODS: Pharmacokinetics of inhaled dry powder and aqueous formulations of 5AZA were compared to an injected formulation. Efficacy studies and effect of therapy on the epigenome were conducted in an orthotopic rat lung cancer model for inhaled formulations. RESULTS: Inhaled dry powder 5AZA showed superior pharmacokinetic properties in lung, liver, brain and blood compared to the injected formulation and for all tissues except lung compared to an inhaled aqueous formulation. Only dry powder 5AZA was detected in brain (~4-h half-life). Inhaled dry powder was superior to inhaled aqueous 5AZA in reducing tumour burden 70-95%. Superiority of inhaled 5AZA dry powder was linked to effectively reprogramming the cancer genome through demethylation and gene expression changes in cancer signalling and immune pathways. CONCLUSIONS: These findings could lead to widespread use of this drug as the first inhaled dry powder therapeutic for treating local and metastatic lung cancer, for adjuvant therapy, and in combination with immunotherapy to improve patient survival.
Asunto(s)
Azacitidina/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Administración por Inhalación , Animales , Antígenos de Neoplasias/análisis , Azacitidina/farmacocinética , Desmetilación , Composición de Medicamentos , Epigenoma , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Polvos , Ratas , Ratas Sprague-Dawley , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Purpose The objective of this mass balance trial was to determine the excretory pathways and metabolic profile of the novel anticancer agent guadecitabine in humans after administration of a 14C-radiolabeled dose of guadecitabine. Experimental design Included patients received at least one cycle of 45 mg/m2 guadecitabine subcutaneously as once-daily doses on Days 1 to 5 of a 28-day cycle, of which the 5th (last) dose in the first cycle was spiked with 14C-radiolabeled guadecitabine. Using different mass spectrometric techniques in combination with off-line liquid scintillation counting, the exposure and excretion of 14C-guadecitabine and metabolites in the systemic circulation, excreta, and intracellular target site were established. Results Five patients were enrolled in the mass balance trial. 14C-guadecitabine radioactivity was rapidly and almost exclusively excreted in urine, with an average amount of radioactivity recovered of 90.2%. After uptake in the systemic circulation, guadecitabine was converted into ß-decitabine (active anomer), and from ß-decitabine into the presumably inactive metabolites M1-M5. All identified metabolites in plasma and urine were ß-decitabine related products, suggesting almost complete conversion via cleavage of the phosphodiester bond between ß-decitabine and deoxyguanosine prior to further elimination. ß-decitabine enters the intracellular activation pathway, leading to detectable ß-decitabine-triphosphate and DNA incorporated ß-decitabine levels in peripheral blood mononuclear cells, providing confirmation that the drug reaches its DNA target site. Conclusion The metabolic and excretory pathways of guadecitabine and its metabolites were successfully characterized after subcutaneous guadecitabine administration in cancer patients. These data support the clinical evaluation of safety and efficacy of the subcutaneous guadecitabine drug product.
Asunto(s)
Antineoplásicos/farmacocinética , Azacitidina/análogos & derivados , Neoplasias/metabolismo , Anciano , Antineoplásicos/sangre , Antineoplásicos/orina , Azacitidina/sangre , Azacitidina/farmacocinética , Azacitidina/orina , Radioisótopos de Carbono , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/orinaRESUMEN
Guadecitabine (SGI-110), a dinucleotide of ßdecitabine and deoxyguanosine, is currently being evaluated in phase II/III clinical trials for the treatment of hematological malignancies and solid tumors. This article describes the development and validation of bioanalytical assays to quantify guadecitabine and its active metabolite ßdecitabine in human plasma, whole blood and urine using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Since ßdecitabine is rapidly metabolized further by cytidine deaminase, plasma and whole blood samples were kept on ice-water after collection and stabilized with tetrahydrouridine (THU) directly upon sample collection. Sample preparation consisted of protein precipitation for plasma and whole blood and dilution for urine samples and was further optimized for each matrix and analyte separately. Final extracts were injected onto a C6-phenyl column for guadecitabine analysis, or a Nova-Pak Silica column for ßdecitabine analysis. Gradient elution was applied for both analytes using the same eluents for each assay and detection was performed on triple quadrupole mass spectrometers operating in the positive ion mode (Sciex QTRAP 5500 and QTRAP 6500). The assay for guadecitabine was linear over a range of 1.0-200â¯ng/mL (plasma, whole blood) and 10-2000â¯ng/mL (urine). For ßdecitabine the assay was linear over a range of 0.5-100â¯ng/mL (plasma, whole blood) and 5-1000â¯ng/mL (urine). The presented methods were successfully validated according to the latest FDA and EMA guidelines for bioanalytical method validation and applied in a guadecitabine clinical mass balance trial in patients with advanced cancer.
Asunto(s)
Antineoplásicos/sangre , Azacitidina/análogos & derivados , Cromatografía Liquida/métodos , Decitabina/sangre , Espectrometría de Masas en Tándem/métodos , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/orina , Azacitidina/sangre , Azacitidina/química , Azacitidina/farmacocinética , Azacitidina/orina , Decitabina/química , Decitabina/farmacocinética , Decitabina/orina , Humanos , Modelos Lineales , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
1. The present study investigated inhibitory effects of enasidenib and its metabolite AGI-16903 on (a) recombinant human nucleoside transporters (hNTs) in hNT-producing Xenopus laevis oocytes, and (b) azacitidine uptake in a normal B-lymphoblast peripheral blood cell line (PBC) and acute myeloid leukemia (AML) cell lines. 2. Enasidenib inhibited hENT1, hENT2, hENT3, and hENT4 in oocytes with IC50 values of 7, 63, 27, and 76 µM, respectively, but exhibited little inhibition of hCNT1-3. AGI-16903 exhibited little inhibition of any hNT produced in oocytes. 3. Azacitidine uptake was more than 2-fold higher in AML cells than in PBC. Enasidenib inhibited azacitidine uptake into OCI-AML2, TF-1 and PBC cells in a concentration-dependent manner with IC50 values of 0.27, 1.7, and 1.0 µM in sodium-containing transport medium, respectively. 4. IC50 values shifted approximately 100-fold higher when human plasma was used as the incubation medium (27 µM in OCI-AML2, 162 µM in TF-1, and 129 µM in PBC), likely due to high human plasma protein binding of enasidenib (98.5% bound). 5. Although enasidenib inhibits hENTs and azacitidine uptake in vitro, plasma proteins attenuate this inhibitory effect, likely resulting in no meaningful in vivo effects in humans.
Asunto(s)
Aminopiridinas , Azacitidina , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Proteínas de Transporte de Nucleósidos/metabolismo , Triazinas , Aminopiridinas/farmacocinética , Aminopiridinas/farmacología , Animales , Azacitidina/farmacocinética , Azacitidina/farmacología , Línea Celular , Humanos , Proteínas de Transporte de Nucleósidos/genética , Triazinas/farmacocinética , Triazinas/farmacología , Xenopus laevisRESUMEN
DNA hypermethylation is an epigenetic event that is commonly found in malignant cells and is used as a therapeutic target for ß-decitabine (ß-DEC) containing hypomethylating agents (eg Dacogen® and guadecitabine). ß-DEC requires cellular uptake and intracellular metabolic activation to ß-DEC triphosphate before it can get incorporated into the DNA. Once incorporated in the DNA, ß-DEC can exert its hypomethylating effect by trapping DNA methyltransferases (DNMTs), resulting in reduced 5-methyl-2'-deoxycytidine (5mdC) DNA content. ß-DEC DNA incorporation and its effect on DNA methylation, however, have not yet been investigated in patients treated with ß-DEC containing therapies. For this reason, we developed and validated a sensitive and selective LC-MS/MS method to determine total intracellular ß-DEC nucleotide (ß-DEC-XP) concentrations, as well as to quantify ß-DEC and 5mdC DNA incorporation relative to 2'-deoxycytidine (2dC) DNA content. The assay was successfully validated according to FDA and EMA guidelines in a linear range from 0.5 to 100 ng/mL (ß-DEC), 50 to 10,000 ng/mL (2dC), and 5 to 1,000 ng/mL (5mdC) in peripheral blood mononuclear cell (PBMC) lysate. An additional calibrator at a concentration of 0.1 ng/mL was added for ß-DEC to serve as a limit of detection (LOD). Clinical applicability of the method was demonstrated in patients treated with guadecitabine. Our data support the use of the validated LC-MS/MS method to further explore the intracellular pharmacokinetics in patients treated with ß-DEC containing hypomethylating agents.
Asunto(s)
Antimetabolitos Antineoplásicos/farmacocinética , Azacitidina/análogos & derivados , ADN/química , Decitabina/análisis , Desoxicitidina/análogos & derivados , Adulto , Antimetabolitos Antineoplásicos/química , Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/química , Azacitidina/farmacocinética , Azacitidina/uso terapéutico , Cromatografía Líquida de Alta Presión/instrumentación , Cromatografía Líquida de Alta Presión/métodos , Ensayos Clínicos Fase II como Asunto , ADN/metabolismo , Metilación de ADN/efectos de los fármacos , Decitabina/química , Desoxicitidina/análisis , Desoxicitidina/química , Humanos , Leucocitos Mononucleares , Límite de Detección , Neoplasias/sangre , Neoplasias/tratamiento farmacológico , Ensayos Clínicos Controlados Aleatorios como Asunto , Espectrometría de Masas en Tándem/instrumentación , Espectrometría de Masas en Tándem/métodosRESUMEN
PURPOSE: Chemotherapeutic resistance eventually develops in all patients with metastatic colorectal cancer (mCRC). Gene silencing through promoter demethylation is one potential reversible mechanism of resistance with administration of hypomethylating agents. We evaluated the safety and tolerability of guadecitabine and irinotecan in patients with mCRC previously treated with irinotecan. PATIENTS AND METHODS: In this 3+3 dose-escalation study, patients with mCRC previously exposed to irinotecan received guadecitabine days 1 to 5 of a 28-day cycle and irinotecan 125 mg/m2 days 8 and 15 [dose level (DL) 1, guadecitabine 45 mg/m2; DL -1: guadecitabine 30 mg/m2; DL -1G: guadecitabine 30 mg/m2 with growth factor support (GFS); DL 1G: guadecitabine 45 mg/m2 with GFS]. RESULTS: Twenty-two patients were treated across four DLs. Dose-limiting toxicities were neutropenic fever (DL 1 and -1G), biliary drain infection (DL -1), colonic obstruction (DL -1), and severe dehydration (DL 1G). Most common toxicities were neutropenia (82% any grade, 77% Grade 3/4), neutropenic fever (23%), leukopenia (73% any grade, 50% Grade 3/4), and injection site reactions (64% total, 0% Grade 3/4). Patients received a median of 4.5 cycles of treatment; 12/17 evaluable patients had stable disease as best response, with one having initial disease progression but subsequently durable partial response. Circulating tumor DNA showed decrease in global demethylation by LINE-1 after treatment. CONCLUSIONS: We report the first study of chemo-priming with epigenetic therapy in gastrointestinal cancers. Guadecitabine 45 mg/m2 and irinotecan 125 mg/m2 with GFS was safe and tolerable in patients with mCRC, with early indication of benefit. These data have provided the basis for an ongoing phase II randomized, multicenter trial.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina/administración & dosificación , Azacitidina/análogos & derivados , Azacitidina/farmacocinética , Neoplasias Colorrectales/genética , Metilación de ADN/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Femenino , Humanos , Irinotecán/administración & dosificación , Irinotecán/farmacocinética , Elementos de Nucleótido Esparcido Largo/genética , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Retratamiento , Resultado del TratamientoRESUMEN
Treatment of acute myeloid leukemia (AML) among the elderly is challenging because of intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMAs followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMAs. Those eligible had Eastern Cooperative Oncology Group status 0 to 1 and previously untreated CD33-positive AML, and declined intensive therapy. Vadastuximab talirine was administered intravenously at 10 µg/kg on last day of HMA (azacitidine or decitabine) infusion in 4-week cycles. Among 53 patients treated, the median age was 75 years. Patients had adverse (38%) or intermediate (62%) cytogenetic risk. Median treatment duration was 19.3 weeks. No dose-limiting toxicities were reported. The majority of adverse events were a result of myelosuppression, with some causing therapy delays. Thirty- and 60-day mortality rates were 2% and 8%, respectively. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery) was 70%. Fifty-one percent of remissions were minimal residual disease-negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged at least 75 years, and with adverse cytogenetic risk. Median relapse-free survival and overall survival were 7.7 and 11.3 months, respectively. Compared with historical data for HMA monotherapy, the combination of vadastuximab talirine with HMAs produced a high remission rate, but was accompanied by increased hematologic toxicity.
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Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda/tratamiento farmacológico , Lectina 3 Similar a Ig de Unión al Ácido Siálico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Azacitidina/administración & dosificación , Azacitidina/efectos adversos , Azacitidina/farmacocinética , Benzodiazepinas/administración & dosificación , Benzodiazepinas/efectos adversos , Benzodiazepinas/farmacocinética , Decitabina/administración & dosificación , Decitabina/efectos adversos , Decitabina/farmacocinética , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Neoplasia Residual , Pirroles/administración & dosificación , Pirroles/efectos adversos , Pirroles/farmacocinética , Tasa de SupervivenciaRESUMEN
CC-486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC-486 dosing included patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n = 18, CMML n = 4, and AML n = 9) entered a clinical phase in which they received CC-486 300 mg once-daily for 21 days of repeated 28-day cycles. Median age was 71 years (range: 53-93); 42% of patients were aged ≥75 years. A total of 5 patients with AML (63%) had prior MDS. Median number of CC-486 treatment cycles was 4 (range: 1-32). The most common treatment-emergent adverse events (TEAEs) were gastrointestinal (84% of patients) and hematologic (81%). Most common grade 3-4 TEAEs were neutropenia (n = 13, 42%) and anemia (n = 9, 29%). Ten patients experienced grade 4 neutropenia. Infrequently, CC-486 dose was interrupted or reduced due to gastrointestinal (n = 5, 16%) or hematologic (n = 6, 19%) TEAEs. Overall response rate (complete remission [CR], CR with incomplete hematological recovery [CRi], partial remission [PR], marrow CR) in the MDS/CMML subgroups was 32% and in the AML subgroup (CR/CRi/PR) was 22%. Red blood cell transfusion independence rates in the MDS/CMML and AML subgroups were 33% and 25%, respectively, and 2 MDS/CMML patients attained hematologic improvement as a best response on-study. No baseline gene mutation was predictive of response/nonresponse. CC-486 allows flexible dosing and schedules to improve tolerability or response. Neutropenia in early treatment cycles deserves scrutiny and may warrant initiation of prophylactic antibiotics. KEY POINTS: The safety profile of oral CC-486 was comparable to that of injectable azacitidine; most adverse events were hematological and gastrointestinal. Extended (21-day/cycle) CC-486 dosing induced responses in patients with hematological malignancies, many of whom had prior DNMTi failure.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Azacitidina/administración & dosificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Administración Oral , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/farmacocinética , Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/efectos adversos , Azacitidina/farmacocinética , Azacitidina/uso terapéutico , Metilación de ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Fatiga/inducido químicamente , Femenino , Alimentos , Interacciones Alimento-Droga , Determinación de la Acidez Gástrica , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Hematológicas/inducido químicamente , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de la Bomba de Protones/farmacologíaRESUMEN
Purpose: Epigenetic changes are implicated in acquired resistance to platinum. Guadecitabine is a next-generation hypomethylating agent (HMA). Here, we report the clinical results, along with pharmacokinetic (PK) and pharmacodynamic analyses of the phase I study of guadecitabine and carboplatin in patients with recurrent, platinum-resistant high-grade serous ovarian cancer, primary peritoneal carcinoma (PPC), or fallopian tube cancer (FTC).Experimental Design: Guadecitabine was administered once daily on days 1 to 5 followed by carboplatin i.v. on day 8 of a 28-day cycle. Patients had either measurable or detectable disease. Safety assessments used CTCAE v4.Results: Twenty patients were enrolled and treated. Median age was 56 years (38-72 years). The median number of prior regimens was 7 (1-14). In the first cohort (N = 6), the starting doses were guadecitabine 45 mg/m2 and carboplatin AUC5. Four patients experienced dose-limiting toxicity (DLT; neutropenia and thrombocytopenia), leading to dose deescalation of guadecitabine to 30 mg/m2 and of carboplatin to AUC4. No DLTs were observed in the subsequent 14 patients. Grade ≥3 adverse events ≥10% were neutropenia, leukopenia, anemia, nausea, vomiting, ascites, constipation, hypokalemia, pulmonary embolism, small-intestinal obstruction, and thrombocytopenia. Three patients had a partial response (PR), and 6 patients had stable disease (SD) >3 months, for an overall response rate (ORR) and clinical benefit rate of 15% and 45%, respectively. LINE-1 demethylation in PBMCs and promoter demethylation/gene reexpression in paired tumor biopsies/ascites were recorded.Conclusions: Guadecitabine and carboplatin were tolerated and induced clinical responses in a heavily pretreated platinum-resistant ovarian cancer population, supporting a subsequent randomized phase II trial. Clin Cancer Res; 24(10); 2285-93. ©2018 AACR.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Azacitidina/administración & dosificación , Azacitidina/análogos & derivados , Azacitidina/farmacocinética , Carboplatino/administración & dosificación , Carboplatino/farmacocinética , Monitoreo de Drogas , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/mortalidad , Compuestos de Platino/farmacología , Compuestos de Platino/uso terapéutico , Recurrencia , RetratamientoRESUMEN
Decitabine (DAC), a potent DNA methyltransferase (DNMT) inhibitor, has a limited oral bioavailability. Its 5'-amino acid ester prodrugs could improve its oral delivery but the specific absorption mechanism is not yet fully understood. The aim of this present study was to investigate the in vivo absorption and activation mechanism of these prodrugs using in situ intestinal perfusion and pharmacokinetics studies in rats. Although PEPT1 transporter is pH dependent, there appeared to be no proton cotransport in the perfusion experiment with a preferable transport at pH 7.4 rather than pH 6.5. This suggested that the transport was mostly dependent on the dissociated state of the prodrugs and the proton gradient might play only a limited role. In pH 7.4 HEPES buffer, an increase in Peff was observed for L-val-DAC, D-val-DAC, L-phe-DAC and L-trp-DAC (2.89-fold, 1.2-fold, 2.73-fold, and 1.90-fold, respectively), compared with the parent drug. When co-perfusing the prodrug with Glysar, a known substrate of PEPT1, the permeabilities of the prodrugs were significantly inhibited compared with the control. To further investigate the absorption of the prodrugs, L-val-DAC was selected and found to be concentration-dependent and saturable, suggesting a carrier-mediated process (intrinsic Km: 7.80⯱â¯2.61â¯mM) along with passive transport. Determination of drug in intestinal homogenate after perfusion further confirmed that the metabolic activation mainly involved an intestinal first-pass effect. In a pharmacokinetic evaluation, the oral bioavailability of L-val-DAC, L-phe-DAC and L-trp-DAC were nearly 1.74-fold, 1.69-fold and 1.49-fold greater than that of DAC. The differences in membrane permeability and oral bioavailability might be due to the different stability in the intestinal lumen and the distinct PEPT1 affinity which is mainly caused by the stereochemistry, hydrophobicity and steric hindrance of the side chains. In summary, the detailed investigation of the absorption mechanism by in vivo intestinal perfusion and pharmacokinetic studies showed that the prodrugs of DAC exhibited excellent permeability and oral bioavailability, which might be attributed to a hybrid (partly PEPT1-mediated and partly passive) transport mode and a rapid activation process in enterocytes.
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Azacitidina/análogos & derivados , Enterocitos/enzimología , Inhibidores Enzimáticos/farmacocinética , Absorción Intestinal , Transportador de Péptidos 1/metabolismo , Profármacos/farmacocinética , Administración Oral , Aminoácidos/química , Animales , Azacitidina/administración & dosificación , Azacitidina/química , Azacitidina/farmacocinética , Disponibilidad Biológica , Permeabilidad de la Membrana Celular , Metilasas de Modificación del ADN/antagonistas & inhibidores , Decitabina , Ésteres/química , Mucosa Intestinal/metabolismo , Intestinos/citología , Masculino , Modelos Animales , Profármacos/administración & dosificación , Profármacos/química , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Azacitidine safety and efficacy were established in studies of mainly Caucasian patients. Differences in drug metabolism enzymes between Caucasian and East Asian populations prevent extrapolation of drug effects between these groups. This phase 2 study evaluated azacitidine safety, efficacy and pharmacokinetics in patients with higher-risk myelodysplastic syndromes (HR-MDS) in mainland China. METHODS: Patients aged ≥18 years with HR-MDS were to receive subcutaneous azacitidine 75 mg/m2 /day for 7 days per 28-day cycle, for ≥6 cycles. Pharmacokinetic blood samples were collected in cycle 1 predose on days 5-7, and postdose on day 7. Pharmacokinetic outcomes are descriptively compared with those of a historical North American cohort. RESULTS: Of 72 participants, 46 (64%) completed ≥6 cycles. Response rate was 96%, driven primarily by stable disease (94%); one patient achieved complete remission. Hematologic improvement was attained by 53% of patients. Azacitidine mean plasma concentration versus time profiles were similar in shape for Chinese (n = 12) and North American (n = 45) patients. Maximum plasma concentration (Cmax ) was higher in Chinese patients; however, mean azacitidine exposure (1190 ng·h/mL) was similar to the North American cohort (1021 ng·h/mL). Most common grade 3-4 treatment-emergent adverse events (TEAEs) were thrombocytopenia (69%) and neutropenia (67%). CONCLUSIONS: Azacitidine was safe and effective in Chinese patients with HR-MDS. Clinical outcomes were comparable to those for primarily Caucasian patients in the phase 3 AZA-001 study. Cmax differences between Chinese and North American patients were not associated with differences in TEAE frequency or severity. No initial azacitidine dose adjustment is required for Chinese patients with HR-MDS.
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Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Infusiones Subcutáneas/métodos , Síndromes Mielodisplásicos/tratamiento farmacológico , Adulto , Anciano , Antimetabolitos Antineoplásicos/farmacocinética , Pueblo Asiatico , Azacitidina/farmacocinética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
Decitabine is a hydrophilic drug that acts by hypomethylating DNA. Decitabine is used in Europe for the treatment of acute myeloid leukemia (AML) in patients aged ≥65 years. However, it can only be administered intravenously due to very low oral bioavailability and a large distribution volume. Oral administration would allow outpatient treatment, improving quality of life and reducing treatment costs. The present study proposes to develop lipid nanocapsules (LNCs), originally designed for lipophilic drugs, to encapsulate decitabine. Two different formulations of LNCs were designed: LNCs based on a high proportion of Transcutol® HP (THP-LNCs) and LNCs associated with a mixture of Transcutol® HP and Tween® 80 (THP-T80-LNCs). The second formulation had a diameter of 26.5±0.5 nm, high encapsulation efficiency (>85%), and a drug payload of 472±64 µg/mL. Decitabine-loaded THP-T80-LNC cytotoxicity was evaluated on two AML cell lines depending on their decitabine resistance: HEL (not resistant) and HL-60 (resistant). The permeability of decitabine-loaded THP-T80-LNCs was also evaluated on Caco-2 cell monolayers. Decitabine cytotoxicity against HEL and HL-60 was higher when decitabine was loaded in THP-T80-LNCs than when free. Apparent permeability on Caco-2 cell monolayers was also increased, suggesting a potentially useful formulation to increase the oral bioavailability of decitabine.
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Azacitidina/análogos & derivados , Portadores de Fármacos/química , Leucemia Mieloide Aguda/tratamiento farmacológico , Nanocápsulas/administración & dosificación , Administración Oral , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/farmacocinética , Azacitidina/administración & dosificación , Azacitidina/farmacocinética , Disponibilidad Biológica , Células CACO-2 , Línea Celular Tumoral , Decitabina , Portadores de Fármacos/administración & dosificación , Liberación de Fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Estabilidad de Medicamentos , Glicoles de Etileno/química , Humanos , Lípidos/química , Nanocápsulas/química , Polisorbatos/químicaRESUMEN
Decitabine (DAC), a nucleoside-related DNA methylation inhibitor, is taken up into cancer cells via equilibrative nucleoside transporter 1 (ENT1), and is then monophosphorylated by deoxycytidine kinase (dCK). In the present study, we examined the contribution of dCK to the uptake of DAC in HCT116 colon cancer cells. Irinotecan and etoposide inhibited the uptake of [3H]-uridine and [3H]-DAC at 10 s and 5 min, while cytarabine and gemcitabine only inhibited that of [3H]-DAC at 5 min. Irinotecan and etoposide inhibited [3H]-DAC uptake in negative control small interfering RNA (siRNA)- or dCK siRNA-transfected cells at 10 s, whereas cytarabine and gemcitabine did not. Cytarabine and gemcitabine inhibited DAC monophosphate generation by the cytosolic proteins of HCT116 cells and recombinant human dCK protein, assessed using polyethylenimine cellulose thin-layered chromatography. Simulations using simple kinetic models showed that apparent DAC uptake in dCK and ENT1 siRNA-treated cells was attributed to its conversion to monophosphates or a decrease in the cellular flux, respectively, and that the apparent uptake of DAC in dCK-knockdown and ENT1-knockdown cells was similar at longer times, but differed at a very short time. These results suggest that the apparent uptake of DAC is affected by ENT1 and dCK in HCT116 cells.
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Antimetabolitos Antineoplásicos/farmacocinética , Azacitidina/análogos & derivados , Neoplasias del Colon/tratamiento farmacológico , Desoxicitidina Quinasa/metabolismo , Antimetabolitos Antineoplásicos/metabolismo , Azacitidina/antagonistas & inhibidores , Azacitidina/metabolismo , Azacitidina/farmacocinética , Camptotecina/análogos & derivados , Camptotecina/farmacología , Neoplasias del Colon/patología , Citarabina/farmacología , Decitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacología , Tranportador Equilibrativo 1 de Nucleósido/metabolismo , Etopósido/farmacología , Células HCT116 , Humanos , Irinotecán , Fosforilación , GemcitabinaRESUMEN
Myelodysplastic syndromes (MDS) are a diverse group of bone marrow disorders and clonal hematopoietic stem cell disorders characterized by abnormal blood cells, or reduced peripheral blood cell count. Recent clinical studies on combination therapy of decitabine (DAC) and arsenic trioxide (ATO) have demonstrated synergy on MDS treatment, but the treatment can cause significant side effects to patients. In addition, both drugs have to be administered on a daily basis due to their short half-lives. In addressing key issues of reducing toxic side effects and improving pharmacokinetic profiles of the therapeutic agents, we have developed a new formulation by co-packaging DAC and ATO into alendronate-conjugated bone-targeting nanoparticles (BTNPs). Our pharmacokinetic studies revealed that intravenously administered BTNPs increased circulation time up to 3days. Biodistribution analysis showed that the BTNP facilitated DAC and ATO accumulation in the bone, which is 6.7 and 7.9 times more than untargeted NP. Finally, MDS mouse model treated with BTNPs showed better restoration of complete blood count to normal level, and significantly longer median survival as compared to free drugs or untargeted NPs treatment. Our results support bone-targeted co-delivery of DAC and ATO for effective treatment of MDS.
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Antineoplásicos/administración & dosificación , Arsenicales/administración & dosificación , Azacitidina/análogos & derivados , Síndromes Mielodisplásicos/tratamiento farmacológico , Nanopartículas/administración & dosificación , Óxidos/administración & dosificación , Alendronato/administración & dosificación , Alendronato/química , Alendronato/farmacocinética , Alendronato/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Trióxido de Arsénico , Arsenicales/química , Arsenicales/farmacocinética , Arsenicales/uso terapéutico , Azacitidina/administración & dosificación , Azacitidina/química , Azacitidina/farmacocinética , Azacitidina/uso terapéutico , Células de la Médula Ósea/efectos de los fármacos , Huesos/metabolismo , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Decitabina , Ratones Transgénicos , Síndromes Mielodisplásicos/metabolismo , Nanopartículas/química , Nanopartículas/uso terapéutico , Óxidos/química , Óxidos/farmacocinética , Óxidos/uso terapéutico , Fosfatidiletanolaminas/administración & dosificación , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/farmacocinética , Fosfatidiletanolaminas/uso terapéutico , Polietilenglicoles/administración & dosificación , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Polietilenglicoles/uso terapéutico , Distribución TisularRESUMEN
AIM: Clinical and pharmacokinetic effects of azacitidine in higher-risk myelodysplastic syndromes were established in mainly Caucasian populations. Because of inter-ethnic genotype variability of drug-metabolizing enzymes, it is important to evaluate azacitidine in populations expected to use the drug. METHODS: In this single-arm study, Taiwanese patients with higher-risk myelodysplastic syndromes received azacitidine 75 mg/m2 /day for 7 days/28-day cycle for up to six cycles. Response-evaluable patients had baseline and cycle 6 marrow assessments. Clinical outcomes are compared descriptively with those from a phase 3 study comprising mainly Caucasian patients (N = 179). Pharmacokinetics in a subgroup of Taiwanese patients are descriptively compared with a historical control of North American patients (N = 45). RESULTS: Median age of Taiwanese patients (N = 44) was 64 years (range 36-90), and 46% had poor cytogenetics. Median number of azacitidine cycles was six (1-6). No response-evaluable patient (n = 33) achieved complete or partial remission; however, 22 patients (50%) achieved hematologic improvement, 12 of 32 patients attained RBC transfusion independence and 7 of 18 attained platelet transfusion independence. Most common grade 3-4 treatment-emergent adverse events were neutropenia (52%) and leukopenia (39%). Pharmacokinetic profiles were similar for Taiwanese (N = 12) and North American (N = 45) patients. Maximum plasma concentration was higher in Taiwanese patients; however, mean azacitidine exposure was within the range for North American patients. CONCLUSION: These data confirm the safety and efficacy of azacitidine in Taiwanese patients with higher-risk myelodysplastic syndromes. Clinical outcomes were generally comparable with those for Caucasian patients. No meaningful differences in azacitidine pharmacokinetics were observed for Taiwanese patients, and no initial dose adjustment is necessary.