RESUMEN
Preclinical studies have demonstrated that liposomal irinotecan (CPT-11), a topoisomerase I inhibitor, has broad activity against adult cancers, including pancreatic, gastric, colon, lung, glioma, ovarian, and breast cancer. Encapsulation of irinotecan into liposomes can modify its pharmacokinetic properties dramatically. Also, the pharmacokinetic profiles of liposomal drug formulations are not fully understood; thus, bioanalytical methods are needed to separate and quantify nonencapsulated vs. encapsulated concentrations. In this study, two robust, specific, and sensitive LC-MS/MS methods were developed and validated to separate and quantify the nonencapsulated CPT-11 (NE-CPT-11) from the sum-total CPT-11 (T-CPT-11) and its major metabolite, SN-38, in human plasma after intravenous administration of liposomal irinotecan. NE-CPT-11 and SN-38 were separated from plasma samples by using solid-phase extraction, and T-CPT-11 was measured by protein precipitation. The liposomal CPT-11 formulation was unstable during sample storage and handling, resulting in elevated NE-CPT-11 concentration. To improve the stability of liposomal CPT-11, a cryoprotectant solution was added to human plasma samples prior to storage and processing. CPT-11, SN-38, and their respective internal standards, CPT-11-d10 and SN-38-d3, were chromatographically separated on a reversed-phase C18 analytical column. The drugs were detected on a triple quadrupole mass spectrometer in the positive MRM ion mode by monitoring the transitions 587.3 > 124.1 (CPT-11) and 393.0 > 349.1 (SN-38). The calibration curves demonstrated a good fit across the concentration ranges of 10-5000 ng/mL for T-CPT-11, 2.5-250 ng/mL for NE-CPT-11, and 1-500 ng/mL for SN-38. The accuracy and precision were within the acceptable limits, matrix effects were nonsignificant, recoveries were consistent and reproducible, and the analytes were stable under all tested storage conditions. Finally, the LC-MS/MS methods were successfully applied in a phase I clinical pharmacokinetic study of nanoliposomal irinotecan (Onivyde®) in pediatric patients with recurrent solid malignancies or Ewing sarcoma.
Asunto(s)
Camptotecina , Estabilidad de Medicamentos , Irinotecán , Liposomas , Neoplasias , Espectrometría de Masas en Tándem , Humanos , Irinotecán/farmacocinética , Irinotecán/sangre , Liposomas/química , Liposomas/sangre , Espectrometría de Masas en Tándem/métodos , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Camptotecina/sangre , Camptotecina/administración & dosificación , Niño , Neoplasias/tratamiento farmacológico , Neoplasias/sangre , Reproducibilidad de los Resultados , Límite de Detección , Femenino , Modelos Lineales , Cromatografía Liquida/métodos , Masculino , AdolescenteRESUMEN
There have been many attempts in pharmaceutical industries and academia to improve the pharmacokinetic characteristics of anti-tumor small-molecule drugs by conjugating them with large molecules, such as monoclonal antibodies, called ADCs. In this context, albumin, one of the most abundant proteins in the blood, has also been proposed as a large molecule to be conjugated with anti-cancer small-molecule drugs. The half-life of albumin is 3 weeks in humans, and its distribution to tumors is higher than in normal tissues. However, few studies have been conducted for the in vivo prepared albumin-drug conjugates, possibly due to the lack of robust bioanalytical methods, which are critical for evaluating the ADME/PK properties of in vivo prepared albumin-drug conjugates. In this study, we developed a bioanalytical method of the albumin-conjugated MAC glucuronide phenol linked SN-38 ((2S,3S,4S,5R,6S)-6-(4-(((((((S)-4,11-diethyl-4-hydroxy-3,14-dioxo-3,4,12,14-tetrahydro-1H-pyrano [3',4':6,7] indolizino [1,2-b] quinolin-9-yl)oxy)methyl)(2 (methylsulfonyl)ethyl)carbamoyl)oxy)methyl)-2-(2-(3-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-methylpropanamido)acetamido)phenoxy)-3,4,5-trihydroxytetra-hydro-2H-pyran-2-carboxylic acid) as a proof-of-concept. This method is based on immunoprecipitation using magnetic beads and the quantification of albumin-conjugated drug concentration using LC-qTOF/MS in mouse plasma. Finally, the developed method was applied to the in vivo intravenous (IV) mouse pharmacokinetic study of MAC glucuronide phenol-linked SN-38.
Asunto(s)
Albúminas , Inmunoprecipitación , Irinotecán , Cromatografía Líquida con Espectrometría de Masas , Animales , Humanos , Ratones , Albúminas/química , Albúminas/farmacocinética , Glucuronidasa/metabolismo , Glucurónidos/química , Glucurónidos/metabolismo , Inmunoprecipitación/métodos , Irinotecán/sangre , Irinotecán/química , Irinotecán/metabolismo , Irinotecán/farmacocinética , Cromatografía Líquida con Espectrometría de Masas/métodos , Magnetismo , Fenol/químicaRESUMEN
In this work, a surface plasmon resonance (SPR)-based assay for the quantification of antineoplastic drug irinotecan in human plasma samples has been developed for the first time. The selective binding of irinotecan with an aptamer receptor, operating in human plasma, allowed to set-up a novel analytical methodology to detect the drug in the analytical range of interest by using SPR as detection technique. After hybridizing the aptamer to the sensing platform and optimizing the sample preparation procedure, a quantitative assay was validated according to FDA regulatory guidelines. The analytical working range was found between 100 and 7500 ng mL-1 with negligible interferences from plasma components and co-medication associated with the administration of irinotecan. The utility of the new SPR assay was confirmed by analyzing plasma samples in parallel with LC-MS as reference technique, providing a new analytical tool for the therapeutic drug monitoring of irinotecan in patients under chemotherapy regimens.
Asunto(s)
Antineoplásicos/sangre , Aptámeros de Nucleótidos/química , Irinotecán/sangre , Resonancia por Plasmón de Superficie/métodos , Monitoreo de Drogas/métodos , Humanos , Límite de Detección , Hibridación de Ácido Nucleico/métodosRESUMEN
To evaluate pharmacokinetic and safety profile of LifePearl microspheres loaded with irinotecan (LifePearl-IRI) in the treatment of liver-dominant, metastatic colorectal carcinoma (LM-CRC) by transarterial chemoembolization. In a prospective, multicentre pharmacokinetic study, 14 patients with LM-CRC progressing on at least one line of chemotherapy were treated with LifePearl-IRI. Six patients received unilobar treatment, treating one lobe per session with 100 mg of irinotecan every 2 weeks. Eight patients received bilobar treatment, treating two lobes per session with 100 mg of irinotecan each (200 mg in total), every 4 weeks. At 24 h, near complete plasma clearance occurred for both irinotecan and SN-38, regardless of the dose. Mean plasma Cmax(100 mg) was 254.50 ± 104.17 ng/mL for irinotecan and 46.72 ± 13.75 ng/mL for SN-38. Mean Cmax(200 mg) was 970.09 ± 353.75 ng/mL for irinotecan and 118.45 ± 25.11 ng/mL for SN-38. Significantly higher Cmax-iri(200 mg) than Cmax-iri (100 mg) supported rate-limiting irinotecan-to-SN-38 conversion. Adverse events during the first 30 days upon initial treatment were hypertension in 21.4%, abdominal pain in 14.3%, and increased transaminases and fever in 7.1% of patients. Four serious adverse events were noted: respiratory failure, constipation, necrotizing pancreatitis, and ischaemic cholecystitis. Chemoembolization with LifePearl-IRI is technically feasible and relatively well tolerated, with a good pharmacokinetic profile and minimal systemic exposure of both irinotecan and SN-38, after both unilobar and bilobar treatment with 100 or 200 mg, respectively.
Asunto(s)
Neoplasias Colorrectales/patología , Sistemas de Liberación de Medicamentos/métodos , Irinotecán/administración & dosificación , Irinotecán/farmacocinética , Neoplasias Hepáticas/tratamiento farmacológico , Anciano , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Neoplasias Colorrectales/tratamiento farmacológico , Embolización Terapéutica/efectos adversos , Embolización Terapéutica/métodos , Estudios de Factibilidad , Femenino , Humanos , Irinotecán/efectos adversos , Irinotecán/sangre , Neoplasias Hepáticas/secundario , Masculino , Microesferas , Persona de Mediana EdadRESUMEN
A simple and rapid bioanalytical method was developed for the simultaneous quantification of irinotecan and SN-38 in mouse plasma and tissue homogenates using High-Performance Liquid Chromatography with Fluorescence detection (HPLC-FL). Camptothecin was used as internal standard and protein precipitation with acetonitrile-methanol (1:1, v/v) followed by acidification with 0.5 M hydrochloric acid was used for sample pre-treatment. The analytes and the internal standard were detected using an excitation and emission wavelength of 368 and 515 nm, respectively. The linearity, selectivity, accuracy and precision, carry-over, limit of detection and lower limit of quantification of the method are described. The method was linear from 7.5 to 1500 ng/mL for irinotecan and from 5 to 1000 ng/mL for SN-38. For all matrices, the accuracy bias and precision variation were within ±15% and ≤15%, respectively. This method was successfully applied to study the pharmacokinetics of irinotecan and SN-38 using in vivo mouse models.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Irinotecán/sangre , Espectrometría de Fluorescencia/métodos , Animales , Camptotecina , Irinotecán/análisis , Irinotecán/química , Irinotecán/farmacocinética , Límite de Detección , Modelos Lineales , Ratones , Reproducibilidad de los Resultados , Distribución TisularRESUMEN
We here explore the soluble Human Leukocyte Antigen-G (sHLA-G) expression level as clinical biomarker in metastatic colorectal cancer (mCRC). To this aim the sHLA-G protein was measured in plasma samples of 40 patients with mCRC treated with the FOLFIRI (irinotecan (CPT-11) plus 5-fluorouracil (5-FU) and leucovorin (LV)) regimen. The results suggest a link between HLA-G levels and irinotecan (CPT-11) pharmacokinetic, leading to hypothesize a molecular interaction between sHLA-G and CPT-11. This interaction was confirmed experimentally by fluorescence spectroscopy. HLA-G is known to exist in a number of polymorphs that affect both the protein expression levels and its peptide-binding cleft. The interaction between HLA-G polymorphs and CPT-11 was explored by means of computational modelling, confirming the hypothesis that CPT-11 could actually target the peptide binding cleft of the most common HLA-G polymorphs.
Asunto(s)
Adenocarcinoma/secundario , Antígenos de Neoplasias/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Antígenos HLA-G/sangre , Irinotecán/sangre , Adenocarcinoma/tratamiento farmacológico , Anciano , Antígenos de Neoplasias/química , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Sitios de Unión , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Femenino , Fluorouracilo/administración & dosificación , Antígenos HLA-G/química , Humanos , Irinotecán/administración & dosificación , Irinotecán/farmacocinética , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Modelos Moleculares , Unión Proteica , Conformación Proteica , Isoformas de Proteínas/sangre , Isoformas de Proteínas/química , Solubilidad , Espectrometría de FluorescenciaRESUMEN
Irinotecan (CPT-11) is an anticancer agent widely used in the treatment of a variety of adult solid tumors. The objective of this study was to develop an optimal sampling strategy model that accurately estimates pharmacokinetic parameters of CPT-11 and its active metabolite, SN-38. This study included 221 patients with advanced solid tumors or lymphoma receiving CPT-11 single or combination therapy with 5-fluorouracil (5-FU)/leucovorin (LV) (FOLFIRI) plus bevacizumab from 4 separate clinical trials. Population pharmacokinetic analysis of CPT-11 and SN-38 was performed by non-linear mixed effects modeling. The optimal sampling strategy model was developed using D-optimality with expected distribution approach. The pharmacokinetic profiles of CPT-11 and SN-38 were best described by a 3- and 2-compartment model, respectively, with first-order elimination. Body surface area and co-administration with 5-FU/LV plus bevacizumab were significant covariates (p < 0.01) for volumes of the central compartment of CPT-11 and SN-38, and clearance of CPT-11. Pre-treatment total bilirubin and co-administration with 5-FU/LV and bevacizumab were significant covariates (p < 0.01) for clearance of SN-38. Accurate and precise predictive performance (r2 > 0.99, -2 < bias (%ME) < 0, precision (% RMSE) < 12) of both CPT-11 and SN-38 was achieved using: (i) 6 fixed sampling times collected at 1.5, 3.5, 4, 5.75, 22, 23.5 hours post-infusion; or (ii) 1 fixed time and 2 sampling windows collected at 1.5, [3-5.75], [22-23.5] hours post-infusion. The present study demonstrates that an optimal sampling design with three blood samples achieves accurate and precise pharmacokinetic parameter estimates for both CPT-11 and SN-38.
Asunto(s)
Irinotecán/sangre , Inhibidores de Topoisomerasa I/sangre , Adulto , Anciano , Ensayos Clínicos como Asunto , Femenino , Humanos , Irinotecán/farmacocinética , Masculino , Persona de Mediana Edad , Modelos Estadísticos , Inhibidores de Topoisomerasa I/farmacocinéticaRESUMEN
In this paper, a fast method for the detection of irinotecan (CPT-11) in plasma samples was investigated. CPT-11 is widely used in a number of chemotherapeutic treatments of several solid tumors. The method is based on the combination of a solid phase extraction and an electrochemical detection step. The extraction of CPT-11 from plasma was performed using solid phase extraction (SPE) columns and acetonitrile as eluent. The procedure included also a cleaning step to eliminate interference due to plasma endogenous compounds and the co-therapeutics 5-fluoroacil (5-FU) and folinic acid (FA). The latter are administered together with CPT-11 in the FOLFIRI regimen. The detection of CPT-11 was performed by differential pulse voltammetry at a glassy carbon electrode (GCE) in basified acetonitrile media. Under these conditions, a well-defined peak due to the oxidation of the tertiary ammine end of CPT-11, also free from interference due to main metabolites, was obtained. Calibration plots showed a good linear response with limit of detection and quantification of 1.10 × 10-7 and 3.74 × 10-7 M, respectively. The suitability of the method proposed here for clinical applications was verified by determining the concentration of CPT-11 in plasma samples of an oncological patient, collected after 30 and 180 min from the infusion of the drug. Graphical abstract.
Asunto(s)
Técnicas Electroquímicas/métodos , Irinotecán/sangre , Extracción en Fase Sólida/métodos , Inhibidores de Topoisomerasa I/sangre , HumanosRESUMEN
Irinotecan is a chemotherapeutic drug used in the treatment of advanced colorectal cancer and elevated blood concentrations of its active metabolite, SN-38 leads to increased gastrointestinal (GI) toxicity and diarrhea in patients. In this study, we investigated the effects of inflammation on the pharmacokinetics (PK) of irinotecan (CPT-11) and its active metabolite, SN-38. Mice were i.p.-injected with either saline or lipopolysaccharide (LPS) to induce inflammation. After 16 h, irinotecan was administered orally. Blood was collected from the tail vein of mice from 0 to 24 h after dosing. Concentrations of irinotecan, SN-38 and SN-38G were analyzed using LC-MS/MS. The AUC, Cmax, and tmax were derived using WinNonlin® 5.2. A PK model was developed using Phoenix NLME® to describe the PK of irinotecan and SN-38 during inflammation. Results indicated a significant increase in the blood concentrations of irinotecan and SN-38 in mice during inflammation. The AUC of irinotecan and SN-38 in LPS group were 2.6 and 2-folds, respectively, of those in control saline-treated mice. The Cmax of irinotecan and SN-38 in LPS treated mice were 2.4 and 2.3-folds of those in saline-treated mice. The PK model was successfully developed and validated. The best-fit plots of individual PK analysis showed a good correlation between observed and predicted concentrations of irinotecan and SN-38. Together, this study reveals that SN-38 concentrations are elevated during inflammation, which may increase the GI toxicity and diarrhea in patients who receive irinotecan; and the developed PK model can quantitatively describe the PK of irinotecan and SN-38 during inflammation.
Asunto(s)
Inflamación/etiología , Irinotecán/farmacocinética , Administración Oral , Animales , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Semivida , Inflamación/metabolismo , Irinotecán/administración & dosificación , Irinotecán/sangre , Lipopolisacáridos/toxicidad , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Teóricos , Curva ROC , Espectrometría de Masas en TándemRESUMEN
Background: SN38 (7-ethyl-10-hydroxy camptothecin), as a potent metabolite of irinotecan, is highly efficacious in cancer treatment. However, the clinical utility of SN38 has been greatly limited due to its undesirable properties, such as poor solubility and low stability. Materials and methods: In order to overcome these weaknesses, moeixitecan, a lipophilic SN38 prodrug containing a SN-38, a trolox, a succinic acid linker, and a hexadecanol chain, was loaded into liposomal nanoparticles by ethanol injection method. Results: Experiments showed that the moeixitecan-loaded liposomal nanoparticles (MLP) with a diameter of 105.10±1.49 nm have a satisfactory drug loading rate (90.54±0.41%), high solubility and stability, and showed sustained release of SN38. Notably, MLP exhibited better antitumor activity against human colon adenocarcinoma cells than irinotecan, a FDA-approved drug for the treatment of advanced colorectal cancer. Furthermore, xenograft model results showed that MLP outperformed irinotecan in terms of pharmacokinetics, in vivo therapeutic efficacy and safety. Finally, we used molecular dynamic simulations to explore the association between the structure of MLP and the physical and functional properties of MLP, moeixitecan molecules in MLP folded themselves inside the hydrocarbon chain of the lipid bilayer, which led an increased acyl chain order of the lipid bilayer, and therefore enhanced the lactone ring stability protecting it from hydrolysis. Conclusion: Our MLP constructing strategy by liposome engineering technology may serve a promising universal approach for the effective and safe delivery of lipophilic prodrug.
Asunto(s)
Neoplasias del Colon/tratamiento farmacológico , Irinotecán/uso terapéutico , Lípidos/química , Profármacos/uso terapéutico , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Apoptosis/efectos de los fármacos , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Camptotecina/farmacología , Camptotecina/uso terapéutico , Liberación de Fármacos , Femenino , Células HT29 , Humanos , Irinotecán/sangre , Irinotecán/farmacocinética , Liposomas , Ratones Desnudos , Simulación de Dinámica Molecular , Nanopartículas/química , Profármacos/química , Profármacos/farmacología , Ratas Sprague-Dawley , Solubilidad , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Irinotecan hydrochloride liposome injection (IHLI) is a formulation of anticancer drug irinotecan hydrochloride (CPT-11) entrapped in the aqueous core of liposomes. To understand the pharmacokinetic property and evaluate the relationship between pharmacokinetics and pharmacodynamics/toxicity of IHLI, it is of prime importance to determine the concentrations of free CPT-11, total CPT-11 and its main metabolites (SN-38 and SN-38 G) in human plasma. In this paper, we developed and validated a sensitive and reliable ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to quantify the concentrations of these related substances in human plasma. Free CPT-11, SN-38 and SN-38 G in human plasma were simultaneously separated and extracted by 96-well solid phase extraction (SPE) plate, while total CPT-11 was extracted by protein precipitation (PP) method. The analytes were chromatographed on an Acquity UPLC BEH C18 column and then detected on a Xevo TQ-S tandem mass spectrometer in multiple reactions monitoring (MRM) mode using positive electrospray ionization (ESI). The UPLC-MS/MS method combined with SPE and PP techniques were fully validated in line with existing guidelines issued by regulatory agencies. In brief, all the analytes achieved a satisfactory selectivity and sensitivity in this method. The calibration curves were proved to be linear over the concentration range of 10-10000 ng/mL for total CPT-11, 0.5-1000 ng/mL for free CPT-11, 0.5-200 ng/mL for SN-38 and SN-38 G, respectively. For all the analytes, the intra- and inter-run precisions were less than 11.4% and the accuracies (in terms of RE%) were within -7.7-7.3% except for accuracies of LLOQs were within -15.8 to 7.2%. Besides, carry-over, extraction recovery, matrix effect, dilution integrity, stability and special matrices were also assessed. Finally, the method was successfully applied to a phase I clinical pharmacokinetic study of IHLI in Chinese subjects with advanced solid tumors.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Irinotecán/sangre , Plasma/química , Espectrometría de Masas en Tándem/métodos , Administración Intravenosa/métodos , Humanos , Inyecciones/métodos , Liposomas/química , Reproducibilidad de los Resultados , Extracción en Fase Sólida/métodosRESUMEN
PURPOSE: Irinotecan (CPT-11) is a drug used against a wide range of tumor types. The individualized dosing of CPT-11 is essential to ensure optimal pharmacotherapy in cancer patients, given the wide interindividual pharmacokinetic variability of this drug and its active metabolite SN-38. Moreover, the reabsorption from SN-38-G to SN-38, by enterohepatic recirculation, is critical due to its influence in the treatment tolerance. The aim of this research was to build a joint population pharmacokinetic model for CPT-11 and its metabolites (SN-38, and its glucuronide, SN-38-G) that enabled an individualized posology adjustment. METHODS: We used data of 53 treatment cycles of FOLFIRINOX scheme corresponding to 20 patients with metastatic colorectal cancer. In order to build the population pharmacokinetic model, we implemented parametric and non-parametric methods using the Pmetrics library package for R. We also built multivariate regression models to predict the area under the curve and the maximum concentration using basal covariates. RESULTS: The final model was a multicompartmental model which represented the transformations from CPT-11 to its active metabolite SN-38 and from SN-38 to inactive SN-38-G. Besides, the model also represented the extensive elimination of SN-38-G and the reconversion of the remaining SN-38-G to SN-38 by enterohepatic recirculation. We carried out internal validation with 1000 simulations. The regression models predicted the PK parameters with R squared adjusted up to 0.9499. CONCLUSION: CPT-11, SN-38, and SN-38-G can be correctly described by the multicompartmental model presented in this work. As far as we know, it is the first time that a joint model for CPT-11, SN-38, and SN-38-G that includes the process of reconversion from SN-38-G to SN-38 is characterized.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Irinotecán/farmacocinética , Modelos Biológicos , Anciano , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/sangre , Antineoplásicos Fitogénicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/farmacocinética , Glucuronatos/farmacocinética , Humanos , Irinotecán/administración & dosificación , Irinotecán/sangre , Leucovorina/administración & dosificación , Leucovorina/farmacocinética , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/farmacocinéticaRESUMEN
PURPOSE: Irinotecan is effective for metastatic colorectal cancer (mCRC). SN-38 is an active metabolite of irinotecan, which is formed by carboxylesterase and inactivated by UDP-glucuronyltransferase (UGT) 1A1. The UGT enzyme activity is reduced in patients with homozygous mutation in UGT1A1 genes (*6/*6, *28/*28 and *6/*28); thus dose reduction is required for prevention of severe adverse events associated with irinotecan. The present study was designed to investigate the relationship between UGT1A1 polymorphisms and the incidence of adverse events or the therapeutic effect in mCRC patients who received irinotecan. METHODS: Sixty-three mCRC patients who received irinotecan during January 2014 and May 2018 were the subjects of this study. The incidence of adverse events, including diarrhea and neutropenia, and the therapeutic effect of irinotecan were compared among homozygous group, heterozygous group and wild-type group. The initial dose of irinotecan was 150 mg/m2 in the heterozygous group and wild-type group, while the dose was reduced by 20% (120 mg/m2) in the homozygous group. RESULTS: The UGT1A1 polymorphisms occurred in 15.9%, 33.3%, and 50.8% for homozygous group, heterozygous group, and wild-type group, respectively. The average dose of irinotecan during overall cycles was not significantly different among three groups, despite the reduction of initial dose in homozygous group. There were no significant differences in the incidence rates of adverse events, tumor response, or time to treatment failure among three groups. CONCLUSION: The present study demonstrated that dose reduction by 20% ensured safety and efficacy of irinotecan in mCRC patients with homozygous mutation in UGT1A1 genes.
Asunto(s)
Neoplasias Colorrectales/tratamiento farmacológico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucuronosiltransferasa/genética , Irinotecán/administración & dosificación , Polimorfismo Genético , Inhibidores de Topoisomerasa I/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Genotipo , Homocigoto , Humanos , Irinotecán/sangre , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de Supervivencia , Inhibidores de Topoisomerasa I/sangreRESUMEN
BACKGROUND: Many novel drug delivery systems have been extensively studied to exploit the full therapeutic potential of SN38, which is one of the most potent antitumor analogs of camptothecins (CPTs), whose clinical application is seriously hindered by poor water solubility, low plasmatic stability, and severe toxicity, but results are always unsatisfactory. METHODS: In this study, combining the advantages of prodrug and nanotechnology, a lipophilic prodrug of SN38, SN38-PA, was developed by conjugating palmitic acid to SN38 via ester bond at C10 position, and then the lipophilic prodrug was encapsulated into a long-circulating liposomal carrier by film dispersion method. RESULTS: The SN38-PA liposomes were characterized as follows: an average particle size of 80.13 nm, an average zeta potential of -33.53 mv, and the entrapment efficiency of 99%. Compared with CPT-11, SN38-PA liposome was more stable in close lactone form, more efficient in conversion rate to SN38, and more potent in cytotoxicity against tumor cells. Pharmacokinetic study showed that SN38-PA liposome had significantly enhanced plasma half-life (t1/2) value of SN38 and increased area under the curve (AUC) of SN38, which was 7.5-fold higher than that of CPT-11. Biodistribution study showed that SN38-PA liposome had more active metabolite SN38 in each tissue. Finally, the pharmacodynamic study showed that SN38-PA liposome had higher antitumor effect with the antitumor inhibition rate of 1.61 times than that of CPT-11. CONCLUSION: These encouraging data merit further investigation on this novel SN38-PA liposome.
Asunto(s)
Irinotecán/uso terapéutico , Neoplasias/tratamiento farmacológico , Profármacos/uso terapéutico , 1-Octanol/química , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Muerte Celular , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Humanos , Irinotecán/sangre , Irinotecán/farmacocinética , Liposomas , Ratones , Neoplasias/sangre , Neoplasias/patología , Tamaño de la Partícula , Profármacos/química , Solubilidad , Electricidad Estática , Distribución Tisular , Agua/químicaRESUMEN
Differences in drug metabolism associated with UGT1A1 polymorphism could result in individualized local response to hepatic chemoembolization with irinotecan-eluting beads (DEBIRI) or predictable toxicities. Five patients with inoperable hepatic metastases from colorectal or anal malignancies treated with DEBIRI were assessed for UGT1A1 mutations. No difference in area under the curve (AUC) for SN38 in normal liver and tumor tissue samples was noted with variant or wild-type UBT1A1 (P = .16 and P = .05, respectively). Plasma SN-38 AUC was significantly lower in wild-type compared to variant patients (P < .0001). UGT1A1 genotype may not be predictive of hematologic toxicity after DEBIRI.
Asunto(s)
Quimioembolización Terapéutica/métodos , Irinotecán/farmacocinética , Neoplasias Hepáticas/terapia , Inhibidores de Topoisomerasa I/farmacocinética , Adulto , Anciano , Quimioembolización Terapéutica/efectos adversos , Monitoreo de Drogas , Femenino , Genotipo , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Humanos , Irinotecán/administración & dosificación , Irinotecán/efectos adversos , Irinotecán/sangre , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Modelos Biológicos , Mutación , Pruebas de Farmacogenómica , Variantes Farmacogenómicas , Fenotipo , Proyectos Piloto , Estudios Prospectivos , Inhibidores de Topoisomerasa I/administración & dosificación , Inhibidores de Topoisomerasa I/efectos adversos , Inhibidores de Topoisomerasa I/sangre , Resultado del TratamientoRESUMEN
The purpose of this study was to identify early circulating metabolite changes implicated in the mechanism of action of irinotecan, a DNA topoisomerase I inhibitor, in cancer patients. A liquid chromatography-tandem mass spectrometry-based targeted metabolomic platform capable of measuring 254 endogenous metabolites was applied to profile circulating metabolites in plasma samples collected pre- and post-irinotecan treatment from 13 cancer patients. To gain further mechanistic insights, metabolic profiling was also performed for the culture medium of human primary hepatocytes (HepatoCells) and 2 cancer cell lines on exposure to SN-38 (an active metabolite of irinotecan). Intracellular reactive oxygen species (ROS) was detected by dihydroethidium assay. Irinotecan induced a global metabolic change in patient plasma, as represented by elevations of circulating purine/pyrimidine nucleobases, acylcarnitines, and specific amino acid metabolites. The plasma metabolic signature was well replicated in HepatoCells medium on SN-38 exposure, whereas in cancer cell medium SN-38 induced accumulation of pyrimidine/purine nucleosides and nucleobases while having no impact on acylcarnitines and amino acid metabolites. SN-38 induced ROS in HepatoCells, but not in cancer cells. Distinct metabolite signatures of SN-38 exposure in HepatoCells medium and cancer cell medium revealed different mechanisms of drug action on hepatocytes and cancer cells. Elevations in circulating purine/pyrimidine nucleobases may stem from nucleotide degradation following irinotecan-induced DNA double-strand breaks. Accumulations of circulating acylcarnitines and specific amino acid metabolites may reflect, at least in part, irinotecan-induced mitochondrial dysfunction and oxidative stress in the liver. The plasma metabolic signature of irinotecan exposure provides early insights into irinotecan mechanism of action in patients.
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Irinotecán/sangre , Neoplasias/sangre , Inhibidores de Topoisomerasa I/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Bencimidazoles/farmacología , Línea Celular , Humanos , Irinotecán/farmacocinética , Irinotecán/farmacología , Metabolómica , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Inhibidores de Topoisomerasa I/farmacocinética , Inhibidores de Topoisomerasa I/farmacologíaRESUMEN
PURPOSE: The primary end point of this trial was to determine the feasibility and safety of transarterial chemoembolization with the use of 75-150-µm drug-eluting embolics loaded with irinotecan (DEE-IRI) for the treatment of metastatic colorectal cancer (CRC) refractory to systemic chemotherapy. MATERIALS AND METHODS: Fourteen patients (mean age 57.9 years) with liver-dominant metastatic disease (14.3% unilobar, 85.7% bilobar), who had failed at least 1 line of chemotherapy, were enrolled and received up to 4 (mean 2.3) cycles of DEE-IRI lobar transarterial chemoembolization. Technical complications and adverse events were recorded, and response was assessed by means of imaging-based criteria. Levels of irinotecan and angiogenesis biomarkers in the serum were measured at multiple time points. RESULTS: Thirty-two DEE-IRI transarterial chemoembolizations were successfully performed, and the full dose (100 mg) was delivered in all cases. The only grade 3-4 toxicity was abdominal pain (29%). One patient had objective response according to the Response Evaluation Criteria in Solid Tumors and World Health Organization, and 3 patients had objective response according to the European Association for the Study of the Liver. The median overall survival was 18.14 months, and the 1-year survival was 65%. The average plasma Cmax of the active metabolite was 41.5 ± 26.1 ng/mL, with average Tmax of 1.3 ± 0.5 hours. The treatment significantly reduced levels of vascular endothelial growth factor receptor 1 (VEGFR1) at 24 hours. CONCLUSIONS: Lobar transarterial chemoembolization with the use of DEE-IRI is a technically feasible and well tolerated palliative treatment for patients with refractory liver-predominant CRC metastatic disease and has acceptable pharmacokinetics. VEGFR1 is a potential biomarker for predicting treatment efficacy and risk of adverse events.
Asunto(s)
Antineoplásicos/administración & dosificación , Quimioembolización Terapéutica/métodos , Neoplasias Colorrectales/patología , Portadores de Fármacos , Irinotecán/administración & dosificación , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/sangre , Antineoplásicos/farmacocinética , Biomarcadores de Tumor/sangre , Quimioembolización Terapéutica/efectos adversos , Quimioembolización Terapéutica/mortalidad , Neoplasias Colorrectales/mortalidad , Connecticut , Estudios de Factibilidad , Femenino , Humanos , Irinotecán/efectos adversos , Irinotecán/sangre , Irinotecán/farmacocinética , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/mortalidad , Masculino , Microesferas , Persona de Mediana Edad , Cuidados Paliativos , Estudios Prospectivos , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/sangre , Receptor 1 de Factores de Crecimiento Endotelial Vascular/sangre , Receptor 2 de Factores de Crecimiento Endotelial Vascular/sangreRESUMEN
Irinotecan (CPT-11) is used to treat various cancers but side effects such as delayed diarrhea restrict its use. Darunavir (DRV) is an antiretroviral drug used to treat and prevent human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), but whether DRV is protective against CPT-11-induced intestinal toxicity is unclear. An CPT-11-induced intestinal toxicity model was produced using uninterrupted CPT-11 (ip) for 4 d in mice. Enzyme-linked immuno sorbent assay (ELISA), fecal occult blood test (FOBT), Western blot, histopathological evaluation, and immunohistochemistry staining assays were used to document toxicity. DRV treatment attenuated CPT-11-induced intestinal toxicity via decreasing fecal occult blood and mitigating delayed-onset diarrhea, as well as reducing weight loss, reduced food intake, and pathomorphologic changes without inhibiting ß-glucuronidase (ß-GLU) activity. The high mobility group box-1 protein (HMGB1)-toll-like receptor 4 (TLR4) pathway induced inflammation and tight junction protein (occludin and zonular occluden-1) reduction in the colon was inhibited by DRV. Hepatotoxicity induced by CPT-11 was diminished after treatment with DRV, and activation of the NOD-like receptor 3 inflammasome (NLRP3) was prevented in colon tissue. In addition, DRV didn't reduce the concentration of CPT-11 and 7-ethyl-10-hydroxycamptothecin (SN-38) in plasma at the same dose of irinotecan with DRV. DRV has anti-inflammatory and intestinal-protective properties and may be used to manage CPT-11-induced intestinal toxicity.