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BACKGROUND: Interindividual pharmacokinetic variability may influence the clinical benefit or toxicity of cabozantinib in metastatic renal cell carcinoma (mRCC). We aimed to investigate the exposure-toxicity and exposure-response relationship of cabozantinib in unselected mRCC patients treated in routine care. METHODS: This ambispective multicenter study enrolled consecutive patients receiving cabozantinib in monotherapy. Steady-state trough concentration (Cmin,ss) within the first 3 months after treatment initiation was used for the PK/PD analysis with dose-limiting toxicity (DLT) and survival outcomes. Logistic regression and Cox proportional-hazards models were used to identify the risk factors of DLT and inefficacy in patients, respectively. RESULTS: Seventy-eight mRCC patients were eligible for the statistical analysis. Fifty-two patients (67%) experienced DLT with a median onset of 2.1 months (95%CI 0.7-8.2). In multivariate analysis, Cmin,ss was identified as an independent risk factor of DLT (OR 1.46, 95%CI [1.04-2.04]; p = 0.029). PFS and OS were not statistically associated with the starting dose (p = 0.81 and p = 0.98, respectively). In the multivariate analysis of PFS, Cmin, ss > 336 ng/mL resulted in a hazard ratio of 0.28 (95%CI, 0.10-0.77, p = 0.014). By contrast, Cmin, ss > 336 ng/mL was not statistically associated with longer OS. CONCLUSION: Early plasma drug monitoring may be useful to optimise cabozantinib treatment in mRCC patients treated in monotherapy, especially in frail patients starting at a lower than standard dose.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Anilidas/efeitos adversos , Piridinas/efeitos adversos , Estudos RetrospectivosRESUMO
We conducted a single-centre retrospective cohort study in a French University Hospital between 2010 and 2018 to describe the risk of severe infectious event (SIE) within 2 years after the date of first rituximab infusion (T0) prescribed after the evidence of acquired hypogammaglobulinemia (gamma globulins [GG] ≤ 6 g/L) in the setting of autoimmune diseases (AID) other than rheumatoid arthritis. SIE occurred in 26 out of 121 included patients. Two years cumulative incidence rates were 12.7 % (95 % CI 5.1-23.9) in the multiple sclerosis/neuromyelitis optica spectrum disorder group (n = 48), 27.6 % (95 % CI 15.7-40.9) in the ANCA-associated vasculitis group (n = 48) and 30.6 % (95 % CI 13.1-50.3) in the 'other AID' group (n = 25). Median GG level at T0 was 5.3 g/l (IQR 4.1-5.6) in the 'SIE' group and 5.6 g/l (IQR 4.7-5.8) in the 'no SIE' group (p = 0.04). In regression analysis, risk of SIE increased with Charlson comorbidity index ≥ 3 (OR 2.77; 95 % CI 1.01-7.57), lung disease (OR 3.20; 95 % CI 1.27-7.99), GG < 4 g/L (OR 3.39; 95 % CI 1.02-11.19), concomitant corticosteroid therapy (OR 4.13; 95 % CI 1.63-10.44), previous cyclophosphamide exposure (OR 2.69; 95 % CI 1.10-6.61), a lymphocyte count < 1000 cells/µL (OR 2.86; 95 % CI 1.12-7.21) and absence of pneumococcal vaccination (OR 3.50; 95 % CI 1.41-8.70). These results may help to inform clinical decision when considering a treatment by rituximab in immunosuppressed AID patients with hypogammaglobulinemia.
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Agamaglobulinemia , Artrite Reumatoide , Doenças Autoimunes , Infecções , Humanos , Rituximab/efeitos adversos , Estudos Retrospectivos , Agamaglobulinemia/tratamento farmacológico , Agamaglobulinemia/epidemiologia , Agamaglobulinemia/induzido quimicamente , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/induzido quimicamente , Artrite Reumatoide/tratamento farmacológico , Infecções/induzido quimicamenteRESUMO
AIMS: Dose-banding (DB) consists in approximating the theoretical dose of anticancer drugs calculated according to the body surface area (Dose-BSA) of patients. This concept is supported by pharmacokinetic but not by clinical data. The aim of this study was to assess the clinical outcome of DB defined as dose-fitting up to ±10%. METHODS: This was a retrospective study conducted in patients receiving weekly paclitaxel in neoadjuvant (NAT) and metastatic (M+) settings. Three groups of patients were considered according to type of paclitaxel dosing: Dose-BSA, DB approximated down (DB-Low) and DB approximated up (DB-High). Efficacy was evaluated by the rate of pathological complete response for patients in NAT setting and by the median of progression-free survival plus overall survival for those in M+ setting. Toxicity and efficacy were compared in the 3 groups. RESULTS: A total of 224 and 209 patients were assessable in the M+ and NAT settings, respectively. A toxic event was observed for 31.7 and 27.3% in M+ and NAT, respectively. The rate of pathological complete response was 41.6% in NAT. The median progression-free survival was 5.2 (4.1-5.8) months and overall survival was 16.3 (14.6-18.4) months for patients in M+. Efficacy and toxicity were not different in DB-Low and DB-High groups compared to Dose-BSA group. CONCLUSION: DB with approximated doses up to ±10% does not seem to influence clinical outcome of patients treated with weekly paclitaxel. This is the first study to include clinical observations, which lends support to DB as a safe and effective dosing method.
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Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Paclitaxel/efeitos adversos , Estudos Retrospectivos , Antineoplásicos/uso terapêutico , Intervalo Livre de Progressão , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Seven tyrosine kinase inhibitor compounds with anti-angiogenic properties remain key drugs to treat advanced renal cell carcinoma. There is a strong rationale to develop therapeutic drug monitoring for these drugs. General considerations of such monitoring of the several groups of anticancer drugs are given, with a focus on oral therapy. Pharmacokinetics and the factors of inter- and intraindividual variabilities of these tyrosine kinase inhibitors are described together with an exhaustive presentation of their pharmacokinetic/pharmacodynamic relationships. The latter was observed in studies where every patient was treated with the same dose, and the results of several prospective studies based on dose individualization support the practice of increasing individual dosage in case of low observed plasma drug concentrations. Finally, the benefits and limits of therapeutic drug monitoring as a routine practice are discussed.
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Protein kinase inhibitors share pharmacokinetic (PK) pathways among themselves. They are all metabolized by several cytochromes P450 (CYP). For most of them, CYP3A4 is the predominant metabolic pathway. However, their oral bioavailability differs. For example, the oral bioavailability of imatinib has been estimated at nearly 100%, but that of ibrutinib averages 3% due to its high hepatic first-pass effect. Overall, the smaller the oral bioavailability, the larger its interindividual PK variability. Indeed, for drugs with low oral bioavailability, the extent of their absorption is an additional cause (along with elimination variability) of differences in drug exposure among patients. The impact of drug-drug interaction (DDI) also differs between drugs with low or high oral bioavailability. We describe and explain why the impact of CYP3A4 inhibitors and inducers is much greater for protein kinase inhibitors with low oral bioavailability. The effect of food on protein kinase inhibitors and DDIs corresponding to plasma protein binding will also be considered. Finally, the benefits of these concepts in clinical practice (including therapeutic drug monitoring) will be discussed. Overall, our main objective was to apply fundamental PK concepts to understanding the main clinical issues of these oral anticancer drugs.
Assuntos
Inibidores do Citocromo P-450 CYP3A , Inibidores de Proteínas Quinases , Humanos , Inibidores de Proteínas Quinases/farmacocinética , Disponibilidade Biológica , Interações Medicamentosas , Mesilato de Imatinib , Inibidores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/metabolismoRESUMO
BACKGROUND: Recently, the combination of venetoclax plus a hypomethylating agent (HMA; azacitidine ordecitabine) or low-dose cytarabine (LDAC) showed promise in Phase III trials in previously untreated AML. In France at the time of this study, venetoclax was not yet approved for AML and there were therefore no formal usage recommendations. Here we report the first study in a French cohort that assessed venetoclax in combination with existing treatments for AML under real-life conditions. METHOD: This retrospective, real-life study collected data on venetoclax use and management in a French cohort with acute myeloid leukemia (AML) ineligible for intensive chemotherapy. RESULT: Of 118 patients, 81 were in second line/beyond (71.6% also hypomethylating agent [HMA]; 23.5% lowdose cytarabine [LDAC]) and 37 in first line. For venetoclax initiation, 57.3% underwent ramp up and 74.6% were hospitalized. Median venetoclax duration was 2.5 months (range 0.03-16.2). With all treatment lines and regimens, most common grade 3/4 adverse events were hematologic (overall 96.4% of patients) and infections (57.1%). Dosage adjustments for drug interactions and safety varied between centers. In second-line/beyond, median progression-free survival was 4.0 months (95% confidence interval [CI] 2.7-12.8) with venetoclax-HMA and 3.4 months (1.3-8.9) with venetoclax-LDAC; overall response rate was 51.9% and 41.2%, respectively. Thus, we showed that venetoclax-based treatment yields promising findings in patients with AML, but to address treatment complexity, practice harmonization is needed.
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Citarabina , Leucemia Mieloide Aguda , Humanos , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/efeitos adversosAssuntos
COVID-19 , Assistência Farmacêutica , COVID-19/epidemiologia , Humanos , Pandemias , Farmacêuticos , SARS-CoV-2RESUMO
Pharmacokinetic (PK) parameter estimation is a critical and complex step in the model-informed precision dosing (MIPD) approach. The mapbayr package was developed to perform maximum a posteriori Bayesian estimation (MAP-BE) in R from any population PK model coded in mrgsolve. The performances of mapbayr were assessed using two approaches. First, "test" models with different features were coded, for example, first-order and zero-order absorption, lag time, time-varying covariates, Michaelis-Menten elimination, combined and exponential residual error, parent drug and metabolite, and small or large inter-individual variability (IIV). A total of 4000 PK profiles (combining single/multiple dosing and rich/sparse sampling) were simulated from each test model, and MAP-BE of parameters was performed in both mapbayr and NONMEM. Second, a similar procedure was conducted with seven "real" previously published models to compare mapbayr and NONMEM on a PK outcome used in MIPD. For the test models, 98% of mapbayr estimations were identical to those given by NONMEM. Some discordances could be observed when dose-related parameters were estimated or when models with large IIV were used. The exploration of objective function values suggested that mapbayr might outdo NONMEM in specific cases. For the real models, a concordance close to 100% on PK outcomes was observed. The mapbayr package provides a reliable solution to perform MAP-BE of PK parameters in R. It also includes functions dedicated to data formatting and reporting and enables the creation of standalone Shiny web applications dedicated to MIPD, whatever the model or the clinical protocol and without additional software other than R.
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Teorema de Bayes , Farmacocinética , Software , Estatística como Assunto , Humanos , Modelos BiológicosRESUMO
Therapeutic drug monitoring of ibrutinib is based on the area under the curve of concentration vs. time (AUCIBRU) instead of trough concentration (Cmin,ss) because of a limited accumulation in plasma. Our objective was to identify a limited sampling strategy (LSS) to estimate AUCIBRU associated with Bayesian estimation. The actual AUCIBRU of 85 patients was determined by the Bayesian analysis of the full pharmacokinetic profile of ibrutinib concentrations (pre-dose T0 and 0.5, 1, 2, 4 and 6 h post-dose) and experimental AUCIBRU were derived considering combinations of one to four sampling times. The T0-1-2-4 design was the most accurate LSS (root-mean-square error RMSE = 11.0%), and three-point strategies removing the 1 h or 2 h points (RMSE = 22.7% and 14.5%, respectively) also showed good accuracy. The correlation between the actual AUCIBRU and Cmin,ss was poor (r2 = 0.25). The joint analysis of dihydrodiol-ibrutinib metabolite concentrations did not improve the predictive performance of AUCIBRU. These results were confirmed in a prospective validation cohort (n = 27 patients). At least three samples, within the pre-dose and 4 h post-dose period, are necessary to estimate ibrutinib exposure accurately.
RESUMO
We report the case of a 44-year-old patient who experienced severe toxicity while being treated with capecitabine at standard dose for metastatic breast cancer. As the patient had already received 5-FU within the FEC protocol (5-FU 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2) 10 years ago without experiencing any severe adverse event, no DPD deficiency testing was performed before capecitabine treatment. Nevertheless, she experienced severe diarrhea and grade 2 hand-foot syndrome from the first cycle, forcing her to stop the treatment. Phenotypic and genotypic investigation of DPD activity revealed that the patient had a partial deficiency and had therefore been exposed to a higher risk of developing severe toxicities on fluoropyrimidines. This case proves that tolerance to low-dose fluoropyrimidines does not preclude DPD deficiency and the occurrence of severe toxicities if higher doses of fluoropyrimidines are used as a second-line treatment. It emphasizes the role of DPD phenotyping testing based on uracilemia in patients scheduled for fluoropyrimidine drugs, even if previous courses with low-dose 5-FU were safely administered.
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Neoplasias da Mama/tratamento farmacológico , Capecitabina/efeitos adversos , Deficiência da Di-Hidropirimidina Desidrogenase/complicações , Fluoruracila/efeitos adversos , Adulto , Feminino , HumanosRESUMO
INTRODUCTION: Brentuximab vedotin (Bv) has been approved for the treatment of Refractory/Relapsed (R/R) Anaplastic Large Cell Lymphomas (ALCL) and cutaneous T-Cell Lymphomas, but is also effective in other CD30+ malignancies. We report here the outcomes of patients with various R/R Peripheral T Cell Lymphoma (PTCL) treated with Bv in real life practice. METHOD: This was a retrospective, single-center study based on medical records of patients with R/R PTCL treated either with Bv alone or in combination with chemotherapy. RESULTS: Among 27 patients treated with Bv, neutropenia was the main serious adverse event observed in particular when Bv was used as combination treatment. The complete Response Rates (CRR) was 40.7%; it was significantly improved when Bv was used as combination treatment. The majority of eligible patients (7/10) underwent Stem Cell Transplantation. Median Progression Free Survival (PFS) and Overall Survival (OS) were 5.2 months and 12.5 months respectively. CONCLUSION: Our current study shows that Bv used in combination with chemotherapy provides a high CRR and thereby allows SCT in R/R PTCL. The use of Bv treatments in this setting warrants further investigation.
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Imunoconjugados , Linfoma de Células T Periférico , Brentuximab Vedotin , Humanos , Imunoconjugados/uso terapêutico , Antígeno Ki-1 , Linfoma de Células T Periférico/tratamento farmacológico , Recidiva Local de Neoplasia , Estudos RetrospectivosRESUMO
The aims of this study were to characterize the incidence and outcomes of severe toxicities following the administration of high-dose methotrexate (HD-MTX; ≥1 g/m2). Among the 468 patients included in the study, 69 (14.9%) developed at least one episode of acute kidney injury (AKI; 138/1264 HD-MTX administrations), including 34 (7.2%) who developed KDIGO stage 2-3 AKI. The three baseline factors independently associated with the risk of developing AKI were age, body mass index and a diagnosis of acute lymphoblastic leukemia. Higher plasma MTX concentration was associated with AKI and extra-renal toxicities. Notwithstanding potentially confounding factors, most patients with AKI who received glucarpidase (n = 41) developed extra-renal toxicity (leading to the death of two patients) despite early administration. Thus, severe toxicity and death can occur whether or not glucarpidase is administered, which confirms the need for further interventional studies to provide greater precision on its role in the management of HD-MTX toxicity.
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Metotrexato , Terapia de Salvação , Antimetabólitos Antineoplásicos/efeitos adversos , Estudos de Coortes , Humanos , Metotrexato/efeitos adversos , Proteínas Recombinantes , gama-Glutamil HidrolaseRESUMO
BACKGROUND: High-dose methotrexate is used for treating several types of cancer. However, it is associated with a high risk of acute kidney injury (AKI), especially in patients with high MTX concentrations. Although therapeutic drug monitoring is performed to monitor MTX concentrations, it is unclear what concentration should be considered critical, thus requiring rescue protocols to prevent nephrotoxicity. METHODS: Patients treated with high-dose methotrexate for lymphoma or acute lymphoblastic leukemia and those benefited from therapeutic drug monitoring were included. The relationship between MTX concentrations and the presence or absence of AKI was assessed. MTX concentrations were analyzed using a population pharmacokinetic approach. Specific attention was given to morphological covariates because MTX doses are individualized according to body surface area (BSA). RESULTS: In total, 328 patients and 657 cycles of treatment were analyzed. Higher MTX concentrations were observed in the AKI+ group. For cycle 1, all patients showing an MTX concentration >6 µM at 36 hours or >2 µM at 48 hours after infusion developed nephrotoxicity. The final pharmacokinetic model had 2 compartments and included the effect of age on clearance (CL) and of body weight on peripheral distribution volume. None of the morphological covariates tested on CL led to significant improvement in the model. Higher MTX concentrations were observed in patients with extreme BSA values (≥2 m2) or body mass index (≥25 kg/m2). Patients with AKI who received at least 1 cycle had higher BSA and BMI. CONCLUSIONS: The results from this study provide additional information on the relationship between MTX concentration and nephrotoxicity. Patients with a plasma MTX concentration >6 µM at 36 hours were more likely to manifest AKI. In addition, the results suggest that overweight patients have a high AKI risk and that BSA-based adjustment of MTX dose is not appropriate.
Assuntos
Antimetabólitos Antineoplásicos , Superfície Corporal , Metotrexato , Leucemia-Linfoma Linfoblástico de Células Precursoras , Injúria Renal Aguda/induzido quimicamente , Adulto , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Humanos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Sobrepeso , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológicoRESUMO
PURPOSE: Infusion of cytotoxic drugs carries the risk of occupational exposure of healthcare workers. Since disconnecting an infusion line is a source of contamination, flushing of tubing after infusion of cytotoxic agents is recommended, but the optimal volume of rinsing solution is unknown. The objective of this study was to assess whether postinfusion line flushing completely eliminates cytotoxics. METHODS: Infusions were simulated with 3 cytotoxics (gemcitabine, cytarabine, and paclitaxel) diluted in 5% dextrose injection or 0.9% sodium chloride injection in 250-mL infusion bags. Infusion lines were flushed using 5% dextrose injection or 0.9% sodium chloride solution at 2 different flow rates. The remaining concentration of cytotoxics in the infusion line was measured by a validated high-performance liquid chromatography (HPLC) method after passage of every 10 mL of flushing volume until a total of 100 mL had been flushed through. RESULTS: All cytotoxics remained detectable even after line flushing with 80 mL of flushing solution (a volume 3-fold greater than the dead space volume within the infusion set). Gemcitabine and cytarabine were still quantifiable via HPLC even after flushing with 100 mL of solution. Efficacy of flushing was influenced by the lipophilicity of drugs but not by either the flushing solvent used or the flushing flow rate. After 2-fold dead space volume flushing, the estimated amount of drug remaining in the infusion set was within 0.19% to 0.56% of the prescribed dose for all 3 cytotoxics evaluated. CONCLUSION: Complete elimination of cytotoxics from an infusion line is an unrealistic objective. Two-fold dead space volume flushing could be considered optimal in terms of administered dose but not from an environmental contamination point of view. Even when flushed, the infusion set should still be considered a source of cytotoxic contamination.
Assuntos
Antineoplásicos/isolamento & purificação , Descontaminação/métodos , Infusões Parenterais/instrumentação , Exposição Ocupacional/prevenção & controle , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Cromatografia Líquida de Alta Pressão , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Citarabina/isolamento & purificação , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/isolamento & purificação , Pessoal de Saúde , Humanos , Exposição Ocupacional/efeitos adversos , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Paclitaxel/isolamento & purificação , GencitabinaRESUMO
PURPOSE: Sunitinib and pazopanib, two tyrosine kinase inhibitors (TKI), may be targets of potential pharmacokinetic drug-drug interactions (P-PK-DDIs). While strong cytochrome P4503A (CYP3A4) inhibitors or inducers should cause a clinically relevant modification in plasma TKI concentrations, the effect of weak inhibitors is unknown. The objective of this study was to evaluate the association between weak P-PK-DDI and clinically relevant toxicity in real life. PATIENTS AND METHODS: This was a single-center retrospective study including patients treated with sunitinib or pazopanib for any malignancies, for whom a PK-DDI analysis was performed before starting TKI. The primary endpoint was the correlation between P-PK-DDIs and a dose decrease after 1 month of treatment. The secondary endpoint was the correlation between PK-DDIs and drug withdrawal due to toxicity. RESULTS: Seventy-six patients were assessed. A P-PK-DDI with weak CYP3A4 or P-gp inhibition was found in 14 patients. In patients with P-PK-DDI or without, the dose was reduced during the first month in 57.1% and 17.7% (p = 0.003) and the drug withdrawn in 42.8% and 11.3% (p = 0.011), respectively. In multivariate analysis, a significant correlation was found between P-PK-DDI (CYP3A4 and P-gp inhibitors) and dose reduction, and between drug withdrawal and PK-DDI (CYP3A4 inhibitors). CONCLUSION: P-PK-DDI was correlated with dose reduction and drug withdrawal due to toxicity. The causality of this relationship warrants to be assessed; therefore, therapeutic drug monitoring is necessary in patients treated with TKI.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Inibidores do Citocromo P-450 CYP3A/toxicidade , Pirimidinas/toxicidade , Sulfonamidas/toxicidade , Sunitinibe/toxicidade , Idoso , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Humanos , Indazóis , Masculino , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Estudos Retrospectivos , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Sunitinibe/administração & dosagem , Sunitinibe/farmacocinéticaRESUMO
PURPOSE: While doses of carboplatin are mostly individualized according to the Calvert equation based on estimated Glomerular Filtration Rate (eGFR), there is still uncertainty regarding the best formula to predict GFR. Since Janowitz et al. recently proposed a new equation predicting GFR in cancer patients, we aimed to compare this equation to other carboplatin clearance (carboCL) predicting formulae. METHODS: The actual carboCL of 491 patients was compared to predicted carboCL according to the Calvert formula using several equations to predict GFR (Janowitz, Cockcroft-Gault, MDRD, CKD-EPI, CKD-EPI with cystatin C (CKD-EPI-cysC)); and according to two others that directly predict carboCL (Chatelut and Thomas). The formulae were compared on Mean Percentage Error (MPE), Mean Absolute Percentage Error (MAPE) and percentage of patients with a prediction error above 20% (P20). RESULTS: The MPE, MAPE and P20 were, respectively, within the ranges - 5.2 to + 5.9%; 14.0-21.2% and 23-46%. The MAPE and P20 of Calvert-CKD-EPI-cysC were the lowest. The performance of Calvert-CKD-EPI was better than that of other creatinine-based formulae although not significantly different from the Calvert-Janowitz formula. Among formulae based on creatinine only, Calvert-CKD-EPI and Calvert-Janowitz are the least influenced by patient characteristics. CONCLUSION: Whereas CysC improves carboplatin CL prediction, the Calvert-CKD-EPI equation seems the most suitable creatinine-based formula to predict carboCL homogeneously in all subgroups of patients.
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Carboplatina/metabolismo , Taxa de Filtração Glomerular/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Creatinina/metabolismo , Feminino , Humanos , Rim/metabolismo , Rim/fisiologia , Cinética , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/metabolismo , Adulto JovemRESUMO
Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy.
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Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Melanoma/tratamento farmacológico , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Animais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Linfócitos T CD8-Positivos/patologia , Feminino , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Nivolumabe/uso terapêutico , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/patologia , Taxa de Sobrevida , Linfócitos T Reguladores/patologia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/fisiologiaRESUMO
Tyrosine kinase inhibitors (TKI) are targeted anticancer drugs that have been successfully developed over the past 2 decades. To date, many of them (around 70%) require warnings for liver injury and five of them, including pazopanib and sunitinib, have Black Box Warning (BBW) labels. Although TKI-induced hepatotoxicity is the first cause of drug failures in clinical trials, BBW labels, and market withdrawals, the underlying mechanisms remain unclear. However, the recent discovery of new reactive metabolites (RM) with aldehyde structures during pazopanib and sunitinib metabolism offers new perspectives for investigating their involvement in the toxicity of these two TKI. These hard electrophiles have a high reactivity potential toward proteins and are thought to be responsible for cytochrome P450 inactivation, drug-drug interactions (DDI), and liver toxicity. We report here, for the first time, the presence of these aldehyde RM in human plasma samples obtained during drug monitoring. Docking experiments in the CYP3A4 active site were performed and showed that pazopanib and sunitinib fitting in the catalytic site are in accordance with their regioselective oxidation to aldehydes. They also suggested that aldehyde RM may react with lysine and arginine residues. Based on these results, we studied the reactivity of the aldehyde RM toward lysine and arginine residues as potential targets on the protein framework to better understand how these RM could be involved in liver toxicity and drug-drug interactions. Adduct formation with different hepatic and plasma proteins was investigated by LC-MS/MS, and adducts between pazopanib or sunitinib aldehyde derivatives and lysine residues on both CYP3A4 and plasma proteins were indeed shown for the first time.
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Aldeídos/metabolismo , Inibidores da Angiogênese/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Sulfonamidas/farmacocinética , Sunitinibe/farmacocinética , Aldeídos/sangue , Inibidores da Angiogênese/efeitos adversos , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Humanos , Indazóis , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Proteínas Recombinantes/metabolismo , Albumina Sérica Humana/metabolismo , Sulfonamidas/efeitos adversos , Sunitinibe/efeitos adversosRESUMO
Tyrosine kinase inhibitors (TKI) are small heterocyclic molecules targeting transmembrane and cytoplasmic tyrosine kinases that have met with considerable success in clinical oncology. TKI are associated with toxicities including liver injury that may be serious and even life-threatening. Many of them require warnings in drug labeling against liver injury, and five of them have Black Box Warning (BBW) labels. Although drug-induced liver injury is a matter of clinical and industrial concern, little is known about the underlying mechanisms that likely involve reactive metabolites (RM). RM are electrophiles or radicals originating from the metabolic activation of particular functional groups, known as structural alerts or toxicophores. RM are able to covalently bind to proteins and macromolecules, causing cellular damage and even cell death. If the adducted protein is the enzyme involved in RM formation, time-dependent inhibition of the enzyme-also called mechanism-based inhibition (MBI) or inactivation-can occur and lead to pharmacokinetic drug-drug interactions. To mitigate RM liabilities, common practice in drug development includes avoiding structural alerts and assessing RM formation via RM trapping screens with soft and hard nucleophiles (glutathione, potassium cyanide, and methoxylamine) in liver microsomes. RM-positive derivatives are further optimized to afford drug candidates with blocked or minimized bioactivation potential. However, different structural alerts are still commonly used scaffolds in drug design, including in TKI structures. This review focuses on the current state of knowledge of the relations among TKI structures, bioactivation pathways, RM characterization, and hepatotoxicity and cytochrome P450 MBI in vitro.