ABSTRACT
Lurbinectedin is a novel and potent selective inhibitor of active transcription of protein-coding genes, triggering apoptosis of cancerous cells. It has been approved for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. Studies exploring the disposition and metabolism of lurbinectedin were performed in vitro and in vivo (by intravenous administration of lurbinectedin). Low blood cell partitioning for lurbinectedin in rats, nonhuman primates (NHP), and humans was determined as 23.4%, 29.8%, and 9.8%, respectively. Protein binding was very high (>95%) in total plasma (rat, NHP, and human), albumin, and α-1-acid glycoprotein (both human). In vitro, lurbinectedin underwent intense liver microsome-mediated metabolism-in 10 minutes, 80% of the compound is metabolized in human-with CYP3A4 being the isoform involved in that metabolism. Results also showed NHPs being the nonclinical species which, metabolically, most closely resembles humans. Mass balance studies performed in rats (both genders), NHPs (male only), and patients (both genders) demonstrated that the principal route of excretion of 14C-lurbinectedin-related radioactivity was through the feces (88.7% ± 10.1% in patients), with only a minor fraction recovered from the urine (5.6% ± 2.0% in patients). In plasma samples, the majority of lurbinectedin-related radioactivity was attributed to unchanged compound (95% ± 3.1% and 70.2% ± 10.9% in NHPs and humans, respectively). Plasma metabolic profiling demonstrated the major (% compared with unchanged compound) circulating metabolites were N-Desmethyl-lurbinectedin (0.4% ± 0.2% and 10.4% ± 2.2% in NHPs and patients, respectively) and 1',3'-Desmethylene-lurbinectedin (0.9% ± 0.7% and 14.3% ± 10.4% in NHP and patients, respectively). SIGNIFICANCE STATEMENT: Lurbinectedin is a novel and potent selective inhibitor of active transcription of protein-coding genes, triggering apoptosis of cancerous cells, and was recently approved for the treatment of patients with metastatic small-cell lung cancer with disease progression on or after platinum-based chemotherapy. The present study provides a complete set of information on the pharmacokinetics, biotransformation, and elimination of 14C-lurbinectedin and its metabolites, following a single intravenous administration to nonclinical species (rats and nonhuman primates) and patients.
Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Animals , Carbolines/pharmacology , Carbolines/therapeutic use , Feces , Female , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Male , Rats , Small Cell Lung Carcinoma/chemically induced , Small Cell Lung Carcinoma/drug therapy , Small Cell Lung Carcinoma/pathologyABSTRACT
BACKGROUND: Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with â¼4 years of additional study follow-up. PATIENTS AND METHODS: ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: At data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib. CONCLUSIONS: These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Thyroid Carcinoma, Anaplastic , Thyroid Neoplasms , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Humans , Imidazoles/therapeutic use , Mutation , Oximes/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Pyridones/therapeutic use , Pyrimidinones/therapeutic use , Thyroid Carcinoma, Anaplastic/drug therapy , Thyroid Carcinoma, Anaplastic/genetics , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/geneticsABSTRACT
PURPOSE: We studied EGFR mutations in circulating tumor DNA (ctDNA) and explored their role in predicting the progression-free survival (PFS) of non-small cell lung cancer (NSCLC) patients treated with erlotinib or gefitinib. METHODS: The L858R, T790M mutations and exon 19 deletions were quantified in plasma using digital droplet polymerase chain reaction (ddPCR). The dynamics of ctDNA mutations over time and relationships with PFS were explored. RESULTS: In total, 249 plasma samples (1-13 per patient) were available from 68 NSCLC patients. The T790M and L858R or exon 19 deletion were found in the ctDNA of 49 and 56% patients, respectively. The median (range) concentration in these samples were 7.3 (5.1-3688.7), 11.7 (5.1-12,393.3) and 27.9 (5.9-2896.7) copies/mL, respectively. Using local polynomial regression, the number of copies of EGFR mutations per mL increased several months prior to progression on standard response evaluation. CONCLUSION: This change was more pronounced for the driver mutations than for the resistance mutations. In conclusion, quantification of EGFR mutations in plasma ctDNA was predictive of treatment outcomes in NSCLC patients. In particular, an increase in driver mutation copy number could predict disease progression.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/administration & dosage , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/genetics , Circulating Tumor DNA/genetics , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Erlotinib Hydrochloride/administration & dosage , Erlotinib Hydrochloride/pharmacology , Female , Gefitinib/administration & dosage , Gefitinib/pharmacology , Humans , Lung Neoplasms/genetics , Male , Middle Aged , Mutation , Progression-Free Survival , Protein Kinase Inhibitors/pharmacology , Treatment OutcomeABSTRACT
In the PERISCOPE I study, gastric cancer patients with limited peritoneal dissemination were treated with systemic chemotherapy followed by (sub)total gastrectomy, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with 460 mg/m2 hyperthermic oxaliplatin followed by normothermic docetaxel in escalating doses (0, 50, 75 mg/m2). In total, 25 patients completed the study protocol. Plasma samples were collected before the start of the HIPEC procedure, after oxaliplatin washing, after docetaxel washing and the following morning. Median peak plasma concentrations were 5.5∗10-3 mg/ml for oxaliplatin, 89∗10-6 mg/ml for docetaxel (dose 50 mg/m2) and 113∗10-6 mg/ml for docetacel (dose 75 mg/m2). The following morning median plasma concentrations were 32% and 4% of the measured peak concentrations for oxaliplatin and docetaxel, respectively. For both cytostatic agents, no correlation was found between intraperitoneal fluid concentration and peak plasma concentration. High doses oxaliplatin and docetaxel can be given intraperitoneally without causing potentially toxic systemic concentrations.
Subject(s)
Docetaxel/administration & dosage , Oxaliplatin/administration & dosage , Peritoneal Neoplasms/therapy , Peritonitis/therapy , Stomach Neoplasms/therapy , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Combined Modality Therapy , Docetaxel/pharmacokinetics , Dose-Response Relationship, Drug , Gastrectomy , Humans , Injections, Intraperitoneal , Oxaliplatin/pharmacokinetics , Peritoneal Neoplasms/complications , Peritoneal Neoplasms/metabolism , Peritonitis/etiology , Stomach Neoplasms/complications , Stomach Neoplasms/metabolismABSTRACT
In the original publication of the article, the second author name has been misspelled.
ABSTRACT
BACKGROUND: The role of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer is unknown. This non-randomized dose-finding phase I-II study was designed to assess the safety and feasibility of HIPEC, following systemic chemotherapy, in patients with gastric cancer and limited peritoneal dissemination. The maximum tolerated dose of normothermic intraperitoneal docetaxel in combination with a fixed dose of intraperitoneal oxaliplatin was also explored. METHODS: Patients with resectable cT3-cT4a gastric adenocarcinoma with limited peritoneal metastases and/or tumour-positive peritoneal cytology were included. An open HIPEC technique was used with 460 mg/m2 hyperthermic oxaliplatin for 30 min followed by normothermic docetaxel for 90 min in escalating doses (0, 50, 75 mg/m2 ). RESULTS: Between 2014 and 2017, 37 patients were included. Of 25 patients who completed the full study protocol, four were treated at dose level 1 (0 mg/m2 docetaxel), six at dose level 2 (50 mg/m2 ) and four at dose level 3 (75 mg/m2 ). At dose level 3, two dose-limiting toxicities occurred, both associated with postoperative ileus. Thereafter, another 11 patients were treated at dose level 2, with no more dose-limiting toxicities. Based on this, the maximum tolerated dose was 50 mg/m2 intraperitoneal docetaxel. Serious adverse events were scored in 17 of 25 patients. The reoperation rate was 16 per cent (4 of 25) and the treatment-related mortality rate was 8 per cent (2 patients, both in dose level 3). CONCLUSION: Gastrectomy combined with cytoreductive surgery and HIPEC was feasible using 460 mg/m2 oxaliplatin and 50 mg/m2 normothermic docetaxel.
ANTECEDENTES: El papel de la cirugía citorreductora (cytoreductive surgery, CRS) combinado con la quimioterapia intraperitoneal hipertérmica (hyperthermic intraperitoneal chemotherapy, HIPEC) en el cáncer gástrico no está definido. Este estudio fase I-II no aleatorizado de escalado de dosis fue diseñado para evaluar la seguridad y la viabilidad de HIPEC, después de la quimioterapia sistémica, en pacientes con cáncer gástrico con diseminación peritoneal limitada. Además, se exploró la máxima dosis tolerada (maximum tolerated dose, MTD) de docetaxel intraperitoneal normotérmico en combinación con una dosis fija de oxaliplatino intraperitoneal. MÉTODOS: Se incluyeron pacientes con adenocarcinoma gástrico cT3-cT4a resecable con metástasis peritoneales limitadas y/o citología peritoneal positiva. Se utilizó una técnica HIPEC abierta con 460 mg/m2 de oxaliplatino hipertérmico (30 minutos) seguido de docetaxel normotérmico (90 minutos) en dosis crecientes (0, 50, 75 mg/m2 ). RESULTADOS: Entre 2014 y 2017, se incluyeron 37 pacientes. De los 25 pacientes que completaron la totalidad del protocolo del estudio, 4 pacientes fueron tratados en el nivel de dosis 1 (0 mg/m2 de docetaxel), 6 pacientes en el nivel de dosis 2 (50 mg/m2 ) y 4 pacientes en el nivel de dosis 3 (75 mg/m2 ). En el nivel de dosis 3, se produjeron dos casos de toxicidad limitante de dosis (dose-limiting toxicities, DLTs), ambas asociadas con un íleo postoperatorio. Posteriormente, otros 11 pacientes fueron tratados con el nivel de dosis 2, y no se produjeron más DLTs. La MTD de docetaxel intraperitoneal fue de 50 mg/m2 . Se registraron efectos adversos graves en 17 de 25 pacientes. La tasa de reoperación fue del 16% (n = 4) y la mortalidad relacionada con el tratamiento fue del 8% (n = 2; ambos en el nivel de dosis 3).
Subject(s)
Adenocarcinoma/secondary , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemotherapy, Cancer, Regional Perfusion/methods , Cytoreduction Surgical Procedures/methods , Hyperthermia, Induced/methods , Peritoneal Neoplasms/secondary , Stomach Neoplasms/pathology , Adenocarcinoma/mortality , Adenocarcinoma/therapy , Aged , Antineoplastic Agents/therapeutic use , Combined Modality Therapy , Docetaxel/therapeutic use , Dose-Response Relationship, Drug , Drug Administration Schedule , Feasibility Studies , Female , Gastrectomy , Humans , Male , Middle Aged , Oxaliplatin/therapeutic use , Peritoneal Neoplasms/mortality , Peritoneal Neoplasms/therapy , Stomach Neoplasms/mortality , Treatment OutcomeABSTRACT
Microdose studies are exploratory trials to determine early drug pharmacokinetics in humans. In this trial we examined whether the pharmacokinetics of gemcitabine at a therapeutic dose could be predicted from the pharmacokinetics of a microdose. In this prospective, open-label microdosing study, a gemcitabine microdose (100 µg) was given intravenously to participants on day 1, followed by a therapeutic dose (1250 mg/m2 ) on day 2. Gemcitabine and its metabolite 2',2'-difluorodeoxyuracil (dFdU) were quantified in plasma and intracellularly by using liquid chromatography-mass spectrometry). Noncompartmental pharmacokinetic analysis was performed. Ten patients participated in this study. The mean area under the plasma concentration-time curve (AUC0-8 ) of gemcitabine after microdosing was 0.00074 h·mg/L and after therapeutic dosing was 16 h·mg/L. The mean AUC0-8 of dFdU following the microdose and therapeutic dose were 0.022 h·mg/L and 169 h·mg/L, respectively. Exposure to gemcitabine after the therapeutic dose was within 2-fold of the exposure following a microdose, when linearly extrapolated to 1250 mg/m2 . However, the shape of the concentration-time curve was different, as reflected by poor scalability in volume of distribution (939 L versus 222 L). Furthermore, intracellularly phosphorylated gemcitabine and phosphorylated dFdU levels could not be predicted from the microdose. The AUC0-8 of gemcitabine at therapeutic dose was accurately predicted by the pharmacokinetics of a microdose, when linearly extrapolated to 1250 mg/m2 . Volume of distribution, elimination rate constant, and intracellular pharmacokinetics of the therapeutic dose could not be predicted from the microdose, which demonstrates limitations of the microdose approach in this case.
Subject(s)
Antimetabolites, Antineoplastic/pharmacokinetics , Chromatography, Liquid/methods , Deoxycytidine/analogs & derivatives , Dose-Response Relationship, Drug , Mass Spectrometry/instrumentation , Administration, Intravenous , Aged , Antimetabolites, Antineoplastic/administration & dosage , Antimetabolites, Antineoplastic/blood , Antimetabolites, Antineoplastic/therapeutic use , Area Under Curve , Carcinoma, Non-Small-Cell Lung/drug therapy , Deoxycytidine/administration & dosage , Deoxycytidine/blood , Deoxycytidine/pharmacokinetics , Deoxycytidine/therapeutic use , Female , Humans , Male , Mesothelioma/drug therapy , Middle Aged , Pilot Projects , Predictive Value of Tests , Prospective Studies , Thymoma/drug therapy , GemcitabineABSTRACT
BACKGROUND: Poly (ADP-ribose) Polymerase (PARP) inhibitors are promising novel radiosensitisers. Pre-clinical models have demonstrated potent and tumour-specific radiosensitisation by PARP inhibitors. Olaparib is a PARP inhibitor with a favourable safety profile in comparison to clinically used radiosensitisers including cisplatin when used as single agent. However, data on safety, tolerability and efficacy of olaparib in combination with radiotherapy are limited. METHODS: Olaparib is dose escalated in combination with radical (chemo-)radiotherapy regimens for non-small cell lung cancer (NSCLC), breast cancer and head and neck squamous cell carcinoma (HNSCC) in three parallel single institution phase 1 trials. All trials investigate a combination treatment of olaparib and radiotherapy, the NSCLC trial also investigates a triple combination of olaparib, radiotherapy and concurrent low dose cisplatin. The primary objective is to identify the maximum tolerated dose of olaparib in these combination treatments, defined as the dose closest to but not exceeding a 15% probability of dose limiting toxicity. Each trial has a separate dose limiting toxicity definition, taking into account incidence, duration and severity of expected toxicities without olaparib. Dose escalation is performed using a time-to-event continual reassessment method (TITE-CRM). TITE-CRM enables the incorporation of late onset toxicity until one year after treatment in the dose limiting toxicity definition while maintaining an acceptable trial duration. Olaparib treatment starts two days before radiotherapy and continues during weekends until two days after radiotherapy. Olaparib will also be given two weeks and one week before radiotherapy in the breast cancer trial and HNSCC trial respectively to allow for translational research. Toxicity is scored using common terminology criteria for adverse events (CTCAE) version 4.03. Blood samples, and tumour biopsies in the breast cancer trial, are collected for pharmacokinetic and pharmacodynamic analyses. DISCUSSION: We designed three parallel phase 1 trials to assess the safety and tolerability of the PARP inhibitor olaparib in combination with radical (chemo-)radiotherapy treatment regimens. PARP inhibitors have the potential to improve outcomes in patients treated with radical (chemo-)radiotherapy, by achieving higher locoregional control rates and/or less treatment associated toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT01562210 (registered March 23, 2012), NCT02227082 (retrospectively registered August 27, 2014), NCT02229656 (registered September 1, 2014).
Subject(s)
Antineoplastic Agents/therapeutic use , Neoplasms/drug therapy , Neoplasms/radiotherapy , Phthalazines/therapeutic use , Piperazines/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/radiotherapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/radiotherapy , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/radiotherapy , Head and Neck Neoplasms/drug therapy , Head and Neck Neoplasms/radiotherapy , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/radiotherapy , Maximum Tolerated Dose , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Radiotherapy, AdjuvantABSTRACT
BACKGROUND: Cancer immunotherapy has changed the standard of care for a subgroup of patients with advanced disease. Immune checkpoint blockade (ICB) in particular has shown improved survival compared with previous standards of care for several tumor types. Although proven to be successful in more immunogenic tumors, ICB is still largely ineffective in patients with tumors that are not infiltrated by immune cells, the so-called cold tumors. PATIENTS AND METHODS: This review describes the effects of different chemotherapeutic agents on the immune system and the potential value of these different types of chemotherapy as combination partners with ICB in patients with solid tumors. Both preclinical data and currently ongoing clinical trials were evaluated. In addition, we reviewed findings regarding different dosing schedules, including the effects of an induction phase and applying metronomic doses of chemotherapy. RESULTS: Combining ICB with other treatment modalities may lead to improved immunological conditions in the tumor microenvironment and could thereby enhance the antitumor immune response, even in tumor types that are so far unresponsive to ICB monotherapy. Chemotherapy, that was originally thought to be solely immunosuppressive, can exert immunomodulatory effects which may be beneficial in combination with immunotherapy. Each chemotherapeutic drug impacts the tumor microenvironment differently, and in order to determine the most suitable combination partners for ICB it is crucial to understand these mechanisms. CONCLUSION: Preclinical studies demonstrate that the majority of chemotherapeutic drugs has been shown to exert immunostimulatory effects, either by inhibiting immunosuppressive cells and/or activating effector cells, or by increasing immunogenicity and increasing T-cell infiltration. However, for certain chemotherapeutic agents timing, dose and sequence of administration of chemotherapeutic agents and ICB is important. Further studies should focus on determining the optimal drug combinations, sequence effects and optimal concentration-time profiles in representative preclinical models.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Immunotherapy/methods , Neoplasms/drug therapy , Tumor Microenvironment/immunology , Cell Cycle Checkpoints/drug effects , Drug Therapy, Combination , Humans , Neoplasms/immunology , Neoplasms/pathology , Prognosis , Tumor Microenvironment/drug effectsABSTRACT
Everolimus is a mammalian target of rapamycin inhibitor approved for the treatment of various tumor types. Less invasive measurement of everolimus concentrations could facilitate pharmacokinetic studies and personalized dosing based on whole blood concentrations, known as therapeutic drug monitoring. Volumetric Absorptive Microsampling (VAMS) has been introduced as a patient friendly, less invasive sampling technique to obtain an accurate volume of whole blood regardless of hematocrit value. We describe the bioanalytical validation and clinical application of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method to quantify everolimus using VAMS. For the quantification, 13C2D4-Everolimus was used as internal standard (IS). Everolimus and the IS were extracted with methanol from the VAMS device, which was evaporated after ultrasonification and shaking. The residue was reconstituted in 20â¯mM ammonium formate buffer and methanol (50%, v/v) of which 5⯵L was injected into the LC-MS/MS system. Quantification was performed for the ammonium adduct of everolimus in positive electrospray ion mode. The VAMS method met all pre-defined validation criteria. Accuracy and precision were within 11.1% and ≤14.6%, respectively. Samples were shown to be stable on the VAMS device for at least 362â¯days at ambient temperatures. Considerable biases from -20 to 31% were observed over a 30-50% hematocrit range. Although the method fulfilled all validation criteria, the perceived advantage of VAMS over dried blood spot sampling could not be demonstrated. Despite the effect of hematocrit, using an empirically derived formula the whole blood everolimus concentration could be back calculated with reasonable accuracy in the clinical application study.
Subject(s)
Chromatography, Liquid/methods , Everolimus/blood , Tandem Mass Spectrometry/methods , Drug Monitoring , Drug Stability , Humans , Linear Models , Reproducibility of Results , Sensitivity and SpecificitySubject(s)
Dihydropyrimidine Dehydrogenase Deficiency/diagnosis , Drug-Related Side Effects and Adverse Reactions/prevention & control , Fluorouracil/adverse effects , Neoplasms/drug therapy , Pharmacology, Clinical/standards , Consensus , Dihydropyrimidine Dehydrogenase Deficiency/genetics , Dihydropyrimidine Dehydrogenase Deficiency/metabolism , Dihydrouracil Dehydrogenase (NADP)/genetics , Dihydrouracil Dehydrogenase (NADP)/metabolism , Dose-Response Relationship, Drug , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/metabolism , Europe , Fluorouracil/administration & dosage , Fluorouracil/metabolism , Genetic Testing/standards , Humans , Mass Screening/standards , Medical Oncology/standards , Societies, Medical/standardsABSTRACT
PURPOSE: Plitidepsin absorption, distribution, metabolism and excretion characteristics were investigated in a mass balance study, in which six patients received a 3-h intravenous infusion containing 7 mg 14C-plitidepsin with a maximum radioactivity of 100 µCi. METHODS: Blood samples were drawn and excreta were collected until less than 1% of the administered radioactivity was excreted per matrix for two consecutive days. Samples were pooled within-patients and between-patients and samples were screened for metabolites. Afterwards, metabolites were identified and quantified. Analysis was done using Liquid Chromatography linked to an Ion Trap Mass Spectrometer and offline Liquid Scintillation Counting (LC-Ion Trap MS-LSC). RESULTS: On average 4.5 and 62.4% of the administered dose was excreted via urine over the first 24 h and in faeces over 240 h, respectively. Most metabolites were found in faeces. CONCLUSION: Plitidepsin is extensively metabolised and it undergoes dealkylation (demethylation), oxidation, carbonyl reduction, and (internal) hydrolysis. The chemical formula of several metabolites was confirmed using high resolution mass data.
Subject(s)
Depsipeptides/metabolism , Neoplasms/metabolism , Carbon Radioisotopes , Chromatography, Liquid , Clinical Trials, Phase I as Topic , Depsipeptides/administration & dosage , Depsipeptides/blood , Depsipeptides/urine , Feces , Humans , Neoplasms/blood , Neoplasms/drug therapy , Neoplasms/urine , Peptides, Cyclic , Tandem Mass SpectrometryABSTRACT
PURPOSE: Breast cancer is the most common malignancy in women worldwide. Recurrence rates in breast cancer are considered to be dependent on the serum concentration of endoxifen, the active metabolite of tamoxifen. The goal of this study is to investigate the cost-effectiveness of periodically monitoring serum concentrations of endoxifen in adjuvant estrogen receptor alfa (ERα) positive breast cancer patients treated with tamoxifen in the Netherlands. METHODS: A Markov model with disease-free survival (DFS), recurrent disease (RD), and death states was constructed. The benefit of drug monitoring was modeled via a difference in the fraction of patients achieving adequate serum concentrations. Robustness of results to changes in model assumptions were tested through deterministic and probabilistic sensitivity analyses. RESULTS: Monitoring of endoxifen added 0.0115 quality-adjusted life-years (QALYs) and saved 1564 per patient in the base case scenario. Deterministic sensitivity analysis demonstrated a large effect on the incremental cost-effectiveness ratio (ICER) of the differences in costs and utilities between the DFS and RD states. Probabilistic sensitivity analysis showed that the probability of cost-effectiveness at a willingness to pay of 0 per quality-adjusted life-year (QALY) was 89.8%. CONCLUSIONS: Based on this model, monitoring of endoxifen in adjuvant ERα + breast cancer patients treated with tamoxifen is likely to add QALYs and save costs from a healthcare payer perspective. We advise clinicians to consider integrating serum endoxifen concentration monitoring into standard adjuvant tamoxifen treatment of ERα + breast cancer patients.
Subject(s)
Antineoplastic Agents, Hormonal/pharmacokinetics , Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Cost-Benefit Analysis , Tamoxifen/pharmacokinetics , Tamoxifen/therapeutic use , Aged , Antineoplastic Agents, Hormonal/economics , Chemotherapy, Adjuvant , Disease-Free Survival , Drug Monitoring , Female , Humans , Markov Chains , Middle Aged , Quality-Adjusted Life Years , Reproducibility of Results , Tamoxifen/economics , Treatment OutcomeABSTRACT
Lurbinectedin is a novel highly selective inhibitor of RNA polymerase II triggering caspase-dependent apoptosis of cancerous cells. This article describes the development and validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay to quantify lurbinectedin in human plasma and urine. Plasma samples were pre-treated with 1â¯M aqueous ammonia after which they were brought onto supported liquid extraction (SLE) columns. Lurbinectedin was eluted from the columns using tert-butyl methyl ether (TBME). Urine was first diluted in plasma and lurbinectedin was extracted from this matrix by liquid-liquid extraction using TBME. Samples were measured by LC-MS/MS in the positive electron ion spray mode. The method was linear over 0.1-100â¯ng/mL and 1-1000â¯ng/mL in plasma and urine, respectively, with accuracies and precisions within ±15% (20% for LLOQ) and below 15% (20% for LLOQ), respectively. The method was developed to support a mass balance study in which patients received a dose of 5â¯mg lurbinectedin.
Subject(s)
Antineoplastic Agents/analysis , Carbolines/analysis , Heterocyclic Compounds, 4 or More Rings/analysis , Lung Neoplasms/drug therapy , Small Cell Lung Carcinoma/drug therapy , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Carbolines/pharmacokinetics , Carbolines/therapeutic use , Chromatography, High Pressure Liquid/instrumentation , Chromatography, High Pressure Liquid/methods , Clinical Trials, Phase III as Topic , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Humans , Limit of Detection , Liquid-Liquid Extraction , Lung Neoplasms/blood , Lung Neoplasms/urine , RNA Polymerase II/antagonists & inhibitors , Reproducibility of Results , Sensitivity and Specificity , Small Cell Lung Carcinoma/blood , Small Cell Lung Carcinoma/urine , Tandem Mass Spectrometry/instrumentation , Tandem Mass Spectrometry/methods , Time FactorsABSTRACT
Ibrutinib is a targeted covalent inhibitor frequently used for the treatment of various lymphomas. In addition to oxidative metabolism, it is metabolized through glutathione coupling. The quantitative insight into this kind of metabolism is scarce, and tools for quantitation are lacking. The non-oxidative metabolism could prove a more prominent role when oxidative metabolism is impaired. Also, in-vitro studies could over-estimate the effect of CYP450-inhibition. To gain quantitative insight into this relatively unknown biotransformation pathway of the drug we have developed a validated simple, fast and sensitive bio-analytical assay for ibrutinib, dihydrodiol-ibrutinib, and the glutathione, cysteinylglycine and cysteine conjugates of ibrutinib in human plasma. The method emphasizes on simplicity, the thiol-conjugates were synthesized by a simple one step synthesis, followed by LC-purification. Sample preparation was done by a simple protein crash with acetonitrile containing labeled internal standards, evaporation of solvents, and reconstitution in eluent. Finally, the compounds were quantified using UHPLC-MS/MS. The assay was successfully validated in a 0.5-500nM calibration range for all compounds, and also a lower range of 0.05-50â¯nM was demonstrated for ibrutinib to accommodate for even the lowest trough levels. This assay has a considerably higher sensitivity than previous published assays, with the previous lowest LLOQ being 1.14â¯nM. Both, ibrutinib, dihydrodiol-ibrutinib and the cysteine conjugate were deemed stable under refrigerated or frozen storage conditions. At room temperature, the glutathione conjugate showed rapid degradation into the cysteinylglycine conjugate in plasma. Finally, the applicability of the assay was demonstrated in patient samples.
Subject(s)
Chromatography, Liquid/methods , Glutathione/blood , Naphthalenes/blood , Pyrazoles/blood , Pyrazoles/metabolism , Pyrimidines/blood , Pyrimidines/metabolism , Tandem Mass Spectrometry/methods , Adenine/analogs & derivatives , Aged , Drug Stability , Glutathione/metabolism , Humans , Linear Models , Male , Naphthalenes/metabolism , Piperidines , Pyrazoles/pharmacokinetics , Pyrimidines/pharmacokinetics , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
In microdose clinical trials a maximum of 100⯵g of drug substance is administered to participants, in order to determine the pharmacokinetic properties of the agents. Measuring low plasma concentrations after administration of a microdose is challenging and requires the use of ulta-sensitive equipment. Novel liquid chromatography-mass spectrometry (LC-MS/MS) platforms can be used for quantification of low drug plasma levels. Here we describe the development and validation of an LC-MS/MS method for quantification of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) in the low picogram per milliliter range to support a microdose trial. The validated assay ranges from 2.5-500â¯pg/mL for gemcitabine and 250-50,000â¯pg/mL for dFdU were linear, with a correlation coefficient (r2) of 0.996 or better. Sample preparation with solid phase extraction provided a good and reproducible recovery. All results were within the acceptance criteria of the latest US FDA guidance and EMA guidelines. In addition, the method was successfully applied to measure plasma concentrations of gemcitabine in a patient after administration of a microdose of gemcitabine.
Subject(s)
Clinical Trials, Phase I as Topic/standards , Deoxycytidine/analogs & derivatives , Floxuridine/analogs & derivatives , Tandem Mass Spectrometry/standards , Chromatography, Liquid/methods , Chromatography, Liquid/standards , Clinical Trials, Phase I as Topic/methods , Deoxycytidine/blood , Floxuridine/blood , Humans , Reproducibility of Results , Tandem Mass Spectrometry/methods , GemcitabineABSTRACT
To support therapeutic drug monitoring of patients with cancer, a fast and accurate method for simultaneous quantification of the registered anticancer drugs afatinib, axitinib, ceritinib, crizotinib, dabrafenib, enzalutamide, regorafenib and trametinib in human plasma using liquid chromatography tandem mass spectrometry was developed and validated. Human plasma samples were collected from treated patients and stored at -20°C. Analytes and internal standards (stable isotopically labeled analytes) were extracted with acetonitrile. An equal amount of 10 mm NH4 CO3 was added to the supernatant to yield the final extract. A 2 µL aliquot of this extract was injected onto a C18 -column, gradient elution was applied and triple-quadrupole mass spectrometry in positive-ion mode was used for detection. All results were within the acceptance criteria of the latest US Food and Drug Administration guidance and European Medicines Agency guidelines on method validation, except for the carry-over of ceritinib and crizotinib. These were corrected for by the injection order of samples. Additional stability tests were carried out for axitinib and dabrafenib in relation to their reported photostability. In conclusion, the described method to simultaneously quantify the eight selected anticancer drugs in human plasma was successfully validated and applied for therapeutic drug monitoring in cancer patients treated with these drugs.
Subject(s)
Antineoplastic Agents/blood , Chromatography, Liquid/methods , Drug Monitoring/methods , Tandem Mass Spectrometry/methods , Humans , Limit of Detection , Linear Models , Reproducibility of ResultsABSTRACT
The article ''Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14C-microtracer and therapeutic dose in cancer patients'', written by L. van Andel, H. Rosing, Z. Zhang, L. Hughes, V. Kansra, M. Sanghvi, M. M. Tibben, A. Gebretensae, J. H. M. Schellens and J. H. Beijnen, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 17th October 2017 without open access.
ABSTRACT
Dexamphetamine is registered for the treatment of attention deficit hyperactivity disorder and narcolepsy. Current research has highlighted the possible application of dexamphetamine in the treatment of cocaine addiction. To support clinical pharmacologic trials a new simple, fast, and sensitive assay for the quantification of dexamphetamine in human plasma using liquid chromatography tandem mass spectrometry (LC-MS/MS) was developed. Additionally, it is the first reported LC-MS assay with these advantages to be fully validated according to current US FDA and EMA guidelines. Human plasma samples were collected on an outpatient basis and stored at nominally -20°C. The analyte and the internal standard (stable isotopically labeled dexamphetamine) were extracted using double liquid-liquid extraction (plasma-organic and organic-water) combined with snap-freezing. The aqueous extract was filtered and 2µL was injected on a C18-column with isocratic elution and analyzed with triple quadrupole mass spectrometry in positive ion mode. The validated concentration range was from 2.5-250ng/mL and the calibration model was linear. A weighting factor of 1 over the squared concentration was applied and correlation coefficients of 0.997 or better were obtained. At all concentrations the bias was within ±15% of the nominal concentrations and imprecision was ≤15%. All results were within the acceptance criteria of the latest US FDA guidance and EMA guidelines on method validation. In conclusion, the developed method to quantify dexamphetamine in human plasma was fit to support a clinical study with slow-release dexamphetamine.
Subject(s)
Chromatography, High Pressure Liquid/methods , Dextroamphetamine/blood , Dextroamphetamine/chemistry , Plasma/chemistry , Tandem Mass Spectrometry/methods , Calibration , Humans , Limit of Detection , Liquid-Liquid Extraction/methods , Reproducibility of ResultsABSTRACT
INTRODUCTION: Niraparib (Zejula™) is a poly(ADP-ribose) polymerase inhibitor recently approved by the US Food and Drug Administration for the maintenance treatment of patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. The pivotal phase III clinical trial has shown improved progression-free survival in patients receiving niraparib compared with those receiving placebo. PURPOSE: Since niraparib is administered orally, it is of interest to investigate the oral bioavailability (F po) of this novel compound, which is the aim of this study. METHODS: Six patients received an oral therapeutic dose of 300 mg niraparib, followed by a 15-min intravenous infusion of 100 µg 14C-niraparib with a radioactivity of approximately 100 nCi. The niraparib therapeutic dose was measured in plasma using a validated liquid chromatography-tandem mass spectrometry method, whereas the total 14C-radioactivity and 14C-niraparib plasma levels were measured by accelerator mass spectrometry and a validated high performance liquid chromatography assay with AMS. RESULTS: The F po of niraparib was determined to be 72.7% in humans.