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1.
Br J Cancer ; 127(1): 79-83, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35361918

RESUMO

BACKGROUND: In ovarian carcinomas, the likelihood of disease cure following first-line medical-surgical treatment has been poorly addressed. The objective was to: (a) assess the likelihood of long-term disease-free (LDF) > 5 years; and (b) evaluate the impact of the tumour primary chemosensitivity (assessed with the modelled CA-125 KELIM) with respect to disease stage, and completeness of debulking surgery. METHODS: Three Phase III trial datasets (AGO-OVAR 9; AGO-OVAR 7; ICON-7) were retrospectively investigated in an "adjuvant dataset", whilst the Netherlands Cancer Registry was used in a "neoadjuvant dataset". The prognostic values of KELIM, disease stage and surgery outcomes regarding the likelihood of LDF were assessed using univariate/multivariate analyses. RESULTS: Of 2029 patients in the "adjuvant dataset", 82 (4.0%) experienced LDF (Stage I-II: 25.9%; III: 2.1%; IV: 0.5%). Multivariate analyses identified disease stage and KELIM (OR = 4.24) as independent prognostic factors. Among the 1452 patients from the "neoadjuvant dataset", 36 (2.4%) had LDF (Stage II-III: 3.3%; IV: 1.3%). Using multivariate tests, high-risk diseases (OR = 0.18) and KELIM (OR = 2.96) were significant. CONCLUSION: The probability of LDF > 5 years after first-line treatment in 3486 patients (<4%) was lower than thought. These data could represent a reference for future studies meant to assess progress related to PARP inhibitors.


Assuntos
Antineoplásicos , Neoplasias Ovarianas , Antineoplásicos/uso terapêutico , Carcinoma Epitelial do Ovário/patologia , Quimioterapia Adjuvante , Ensaios Clínicos Fase III como Assunto , Procedimentos Cirúrgicos de Citorredução/métodos , Feminino , Humanos , Terapia Neoadjuvante/métodos , Estadiamento de Neoplasias , Neoplasias Ovarianas/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Probabilidade , Estudos Retrospectivos
2.
Gynecol Oncol ; 166(3): 389-396, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35902297

RESUMO

BACKGROUND: Anti-angiogenic rechallenge with bevacizumab plus chemotherapy is effective in recurrent ovarian cancer (rOC); however, data are limited on tyrosine kinase inhibitors after progression on maintenance bevacizumab. METHODS: In the randomized phase II TAPAZ trial, patients with rOC during the first year of bevacizumab maintenance therapy were assigned 2:1 to either weekly paclitaxel 65 mg/m2 plus pazopanib 600-800 mg daily or standard weekly paclitaxel 80 mg/m2. The primary endpoint was 4-month progression-free survival (PFS) rate. RESULTS: Overall, 116 patients were randomized and treated: 79 with combination therapy and 37 with single-agent paclitaxel. Median follow-up was 13.1 months. There was no difference between treatment arms in 4-month PFS rate (61% [95% CI, 51-73%] with the combination versus 68% [95% CI, 54-85%] with paclitaxel alone), median PFS (4.9 [95% CI, 4.1-6.1] versus 5.8 [95% CI, 4.8-7.4] months, respectively) or median overall survival (13.6 versus 12.9 months, respectively). The combination was associated with more grade 3/4 toxicities (87% versus 70%, respectively) and toxicity-related paclitaxel discontinuations (22% versus 11%). Pazopanib was discontinued for toxicity in 44% of patients, most commonly for gastrointestinal and vascular events. There were two treatment-related deaths, both in the combination arm (pulmonary embolism and gastrointestinal perforation). At month 4, patient-reported outcomes deteriorated from baseline in the combination arm, particularly for abdominal/gastrointestinal symptoms, which showed a clinically important difference versus paclitaxel alone. CONCLUSIONS: In rOC progressing during maintenance bevacizumab, adding pazopanib to paclitaxel did not improve efficacy, increased toxicity, and compromised chemotherapy delivery. CLINICALTRIALS: govregistration:NCT02383251.


Assuntos
Neoplasias Ovarianas , Paclitaxel , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/etiologia , Feminino , Humanos , Indazóis , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/etiologia , Neoplasias Ovarianas/etiologia , Pirimidinas , Sulfonamidas
3.
J Pharmacokinet Pharmacodyn ; 49(3): 381-394, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35166967

RESUMO

Tusamitamab ravtansine (SAR408701) is an antibody-drug conjugate (ADC), combining a humanized monoclonal antibody (IgG1) targeting carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and a potent cytotoxic maytansinoid derivative, DM4, inhibiting microtubule assembly. SAR408701 is currently in clinical development for the treatment of advanced solid tumors expressing CEACAM5. It is administered intravenously as a conjugated antibody with an average Drug Antibody Ratio (DAR) of 3.8. During SAR408701 clinical development, four entities were measured in plasma: conjugated antibody (SAR408701), naked antibody (NAB), DM4 and its methylated metabolite (MeDM4), both being active. Average DAR and proportions of individual DAR species were also assessed in a subset of patients. An integrated and semi-mechanistic population pharmacokinetic model describing the time-course of all entities in plasma and DAR measurements has been developed. All DAR moieties were assumed to share the same drug disposition parameters, excepted for clearance which differed for DAR0 (i.e. NAB entity). The conversion of higher DAR to lower DAR resulted in a DAR-dependent ADC deconjugation and was represented as an irreversible first-order process. Each conjugated antibody was assumed to contribute to DM4 formation. All data were fitted simultaneously and the model developed was successful in describing the pharmacokinetic profile of each entity. Such a structural model could be translated to other ADCs and gives insight of mechanistic processes governing ADC disposition. This framework will further be expanded to evaluate covariates impact on SAR408701 pharmacokinetics and its derivatives, and thus can help identifying sources of pharmacokinetic variability and potential efficacy and safety pharmacokinetic drivers.


Assuntos
Antineoplásicos , Imunoconjugados , Maitansina , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/farmacocinética , Moléculas de Adesão Celular , Humanos , Imunoconjugados/farmacocinética , Maitansina/química , Maitansina/farmacocinética
4.
Antimicrob Agents Chemother ; 65(9): e0104321, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34228545

RESUMO

Rifamycins are widely used for treating mycobacterial and staphylococcal infections. Drug-drug interactions (DDI) caused by rifampicin (RIF) are a major issue. We used a model-based approach to predict the magnitude of DDI with RIF and rifabutin (RBT) for 217 cytochrome P450 (CYP) substrates. On average, DDI caused by low-dose RIF were twice as potent as those caused by RBT. Contrary to RIF, RBT appears unlikely to cause severe DDI, even with sensitive CYP substrates.


Assuntos
Preparações Farmacêuticas , Rifamicinas , Interações Medicamentosas , Rifabutina/farmacologia , Rifampina/farmacologia
5.
Pharmacogenomics J ; 21(5): 559-565, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33731883

RESUMO

The demonstration of the link between certain genetic variations and drug response has allowed the emergence of pharmacogenetics, which offers many opportunities to improve patient care. Type-2 diabetes mellitus is a disease for which several gene polymorphisms have been reported to be associated with drug response. Sulfonylureas are commonly used for the management of this disease. Genetic polymorphisms of CYP2C9, the main enzyme involved in the metabolism of sulfonylureas, have been associated with the risk of severe hypoglycaemia, particularly in poor metabolizers carrying CYP2C9 *3/*3 genotype, and especially in the case of patients treated with glimepiride. The objectives of the present study were to evaluate the potential clinical and economic outcomes of using CYP2C9 genotype data to guide the management of SU regimen in patients initiating glimepiride therapy, and to identify factors affecting the cost-effectiveness of this treatment scheme. The analysis was conducted using a decision tree, considering a 1-year time horizon, and taking as perspective that of the French national health insurance system. With pharmacogenetic-guided therapy, the cost to avoid an episode of severe hypoglycaemia event per 100 000 patients treated was €421 834. Genotyping cost was the most influential factor on the incremental cost-effectiveness ratio. In conclusion, the potential cost of CYP2C9 genotype-guided dosing for glimepiride therapy is relatively high, and associated with modest improvements with respect to the number of hypoglycaemia avoided, as compared with standard dosing. Additional economic studies are required to better specify the usefulness of CYP2C9 genotyping prior to glimepiride regimen initiation.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Compostos de Sulfonilureia/uso terapêutico , Análise Custo-Benefício , Citocromo P-450 CYP2C9/genética , Diabetes Mellitus Tipo 2/economia , Diabetes Mellitus Tipo 2/genética , Técnicas de Genotipagem/economia , Técnicas de Genotipagem/métodos , Custos de Cuidados de Saúde , Humanos , Hipoglicemiantes/economia , Polimorfismo Genético , Compostos de Sulfonilureia/economia , Resultado do Tratamento
6.
Pharm Res ; 38(3): 415-428, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33686560

RESUMO

PURPOSE: For decades, inflammation has been considered a cause of pharmacokinetic variability, mainly in relation to the inhibitory effect of pro-inflammatory cytokines on the expression level and activity of cytochrome P450 (CYP). In vitro and clinical studies have shown that two major CYPs, CYP2C19 and CYP3A4, are both impaired. The objective of the present study was to quantify the impact of the inflammatory response on the activity of both CYPs in order to predict the pharmacokinetic profile of their substrates according to systemic C-reactive protein (CRP). METHODS: The relationships between CRP concentration and both CYPs activities were estimated and validated using clinical data first on midazolam then on voriconazole. Finally, clinical data on omeprazole were used to validate the findings. For each substrate, a physiologically based pharmacokinetics model was built using a bottom-up approach, and the relationships between CRP level and CYP activities were estimated by a top-down approach. After incorporating the respective relationships, we compared the predictions and observed drug concentrations. RESULTS: Changes in pharmacokinetic profiles and parameters induced by inflammation seem to be captured accurately by the models. CONCLUSIONS: These findings suggest that the pharmacokinetics of CYP2C19 and CYP3A4 substrates can be predicted depending on the CRP concentration.


Assuntos
Antifúngicos/farmacocinética , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP3A/metabolismo , Inflamação/tratamento farmacológico , Simulação por Computador , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Interações Medicamentosas , Humanos , Midazolam/farmacocinética , Modelos Biológicos , Omeprazol/farmacocinética , Voriconazol/farmacocinética
7.
Invest New Drugs ; 38(6): 1796-1806, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32451663

RESUMO

The attrition rate of anticancer drugs during the clinical development remains very high. Interspecies extrapolation of anticancer drug pharmacodynamics (PD) could help to bridge the gap between preclinical and clinical settings and to improve drug development. Indeed, when combined with a physiologically-based-pharmacokinetics (PBPK) approach, PD interspecies extrapolation could be a powerful tool for predicting drug behavior in clinical trials. The present study aimed to explore this field for anticipating the clinical efficacy of a new Bcl-2 inhibitor, S 55746, for which dose ranging studies in xenografted mice and clinical data from a phase 1 trial involving cancer patients were available. Different strategies based on empirical or more mechanistic assumptions (based on PBPK-PD modelling) were developped and compared: the Rocchetti approach (ROC); the Orthogonal Rocchetti approach (oROC), a variant of ROC based on an orthogonal regression; the Consistent across species approach, bringing out an efficacy parameter assumed to be consistent across species; and the Scaling species-specific parameters approach, assuming the concentration-efficacy link is the same in mice as in humans, after allometric scaling. Empirical approaches (ROC and oROC) gave similar predictive performances and seemed to overestimate the active S 55746 dose compared to mechanistic approaches, while strategies elaborated from semi-mechanistic concepts and PBPK-PD modelling did not seem to be invalidated by clinical efficacy data. Also, empirical methods only predict a single dose level for the subsequent clinical studies, whereas mechanism-based strategies are more informative about the dose response relationship, highlighting the potential interest of such approaches in drug development.


Assuntos
Antineoplásicos/administração & dosagem , Modelos Biológicos , Neoplasias/tratamento farmacológico , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Administração Oral , Animais , Anti-Infecciosos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Feminino , Humanos , Camundongos SCID , Neoplasias/sangue , Neoplasias/metabolismo , Neoplasias/patologia , Especificidade da Espécie , Pesquisa Translacional Biomédica/métodos
8.
Gynecol Oncol ; 159(1): 256-263, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32712155

RESUMO

OBJECTIVE: MicroRNAs (miRNAs) are promising biomarkers in ovarian cancer. Their kinetics during treatment might be useful for monitoring disease burden, and guiding treatments in patients treated with peri-operative chemotherapy and interval debulking surgery (IDS). METHODS: Serial blood samples of patients enrolled in the randomized phase II CHIVA trial, comparing first line carboplatin-paclitaxel +/- nintedanib (NCT01583322) and IDS, were investigated to assess the kinetics of 11 relevant miRNAs. Their prognostic/predictive values regarding the likelihood of complete IDS, and the patient survival, were assessed and compared to those of CA125 kinetics. The selection of the miRNAs (miR-15b-5p, miR-16-5p, miR-20a-5p, miR-21-5p, miR-93-5p, miR-122-5p, miR-150-5p, miR-195-5p, miR-200b-3p, miR-148b-5p and miR-34a-5p) was based on the expression levels found with a large explorative panel, and on the literature data. RESULTS: 756 serial blood samples from 119 patients were analyzed for a total of 8172 miRNA assays, and 1299 CA125 values. The longitudinal kinetics of the miRNA expressions were highly inconsistent, and were not related to CA125 dynamics. The miRNA changes during neoadjuvant treatment were not found associated with RECIST tumor response or IDS outcomes. Decreases of miR-34a-5p and miR-93-5p were associated with PFS benefit (p = .009) and OS benefits (p < .001), respectively, using univariate tests. CONCLUSIONS: The longitudinal kinetics of miRNA expressions during neoadjuvant treatment in ovarian cancer patients were inconsistent, and were not found to be associated with tumor burden changes. Although some prognostic value could be discussed, no predictive value regarding tumor responses or IDS quality could be identified.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Antígeno Ca-125/sangue , MicroRNA Circulante/sangue , Proteínas de Membrana/sangue , Neoplasias Ovarianas/diagnóstico , Adulto , Idoso , Carboplatina/uso terapêutico , Procedimentos Cirúrgicos de Citorredução , Feminino , Humanos , Indóis/uso terapêutico , Cinética , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/terapia , Paclitaxel/uso terapêutico , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão , Critérios de Avaliação de Resposta em Tumores Sólidos
9.
Drug Metab Dispos ; 47(6): 648-656, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30940629

RESUMO

S 55746 ((S)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide) is a new selective Bcl-2 (B-cell lymphoma 2) inhibitor developed by Servier Laboratories and used to restore apoptosis functions in cancer patients. The aim of this work was to develop a translational approach using physiologically based (PB) pharmacokinetic (PK) modeling for interspecies extrapolation to anticipate the nonlinear PK behavior of this new compound in patients. A PBPK mouse model was first built using a hybrid approach, defining scaling factors (determined from in vitro data) to correct in vitro clearance parameters and predicted Kp (partition coefficient) values. The qualification of the hybrid model using these empirically determined scaling factors was satisfactorily completed with rat and dog data, allowing extrapolation of the PBPK model to humans. Human PBPK simulations were then compared with clinical trial data from a phase 1 trial in which the drug was given orally and daily to cancer patients. Human PBPK predictions were within the 95% prediction interval for the eight dose levels, taking into account both the nonlinear dose and time dependencies occurring in S 55746 kinetics. Thus, the proposed PK interspecies extrapolation strategy, based on preclinical and in vitro information and physiologic assumptions, could be a useful tool for predicting human plasma concentrations at the early stage of drug development.


Assuntos
Antineoplásicos/farmacocinética , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Animais , Células CACO-2 , Linhagem Celular Tumoral , Modelos Animais de Doenças , Cães , Feminino , Humanos , Masculino , Camundongos , Camundongos SCID , Modelos Biológicos , Ratos , Ratos Wistar
10.
Artigo em Inglês | MEDLINE | ID: mdl-30038037

RESUMO

The empirical use of vancomycin in combination with a broad-spectrum beta-lactam is currently recommended after the initial surgery of prosthetic joint infection (PJI). However, the tolerability of such high-dose intravenous regimens is poorly known. Adult patients receiving an empirical antimicrobial therapy (EAT) for a PJI were enrolled in a prospective cohort study (2011 to 2016). EAT-related adverse events (AE) were described according to the common terminology criteria for AE (CTCAE), and their determinants were assessed by logistic regression and Kaplan-Meier curve analysis. The EAT of the 333 included patients (median age, 69.8 years; interquartile range [IQR], 59.3 to 79.1 years) mostly relies on vancomycin (n = 229, 68.8%), piperacillin-tazobactam (n = 131, 39.3%), and/or third-generation cephalosporins (n = 50, 15%). Forty-two patients (12.6%) experienced an EAT-related AE. Ten (20.4%) AE were severe (CTCAE grade ≥ 3). The use of vancomycin (odds ratio [OR], 6.9; 95% confidence interval [95%CI], 2.1 to 22.9), piperacillin-tazobactam (OR, 3.7; 95%CI, 1.8 to 7.2), or the combination of both (OR, 4.1; 95%CI, 2.1 to 8.2) were the only AE predictors. Acute kidney injury (AKI) was the most common AE (n = 25; 51.0% of AE) and was also associated with the use of the vancomycin and piperacillin-tazobactam combination (OR, 6.7; 95%CI, 2.6 to 17.3). A vancomycin plasma overexposure was noted in nine (37.5%) of the vancomycin-related AKIs only. Other vancomycin-based therapies were significantly less at risk for AE and AKI. The EAT of PJI is associated with an important rate of AE, linked with the use of the vancomycin and the piperacillin-tazobactam combination. These results corroborate recent findings suggesting a synergic toxicity of these drugs in comparison to vancomycin-cefepime, which remains to be evaluated in PJI. (This study has been registered at ClinicalTrials.gov under identifier NCT03010293.).


Assuntos
Anti-Infecciosos/efeitos adversos , Prótese de Quadril/efeitos adversos , Injúria Renal Aguda/induzido quimicamente , Idoso , Anti-Infecciosos/uso terapêutico , Cefepima/efeitos adversos , Cefepima/uso terapêutico , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Ácido Penicilânico/efeitos adversos , Ácido Penicilânico/uso terapêutico , Combinação Piperacilina e Tazobactam/efeitos adversos , Combinação Piperacilina e Tazobactam/uso terapêutico , Estudos Prospectivos , Vancomicina/efeitos adversos , Vancomicina/uso terapêutico
11.
J Pharmacol Exp Ther ; 367(3): 414-424, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30228112

RESUMO

The Bcl-2 inhibitor S 55746 ((S)-N-(4-hydroxyphenyl)-3-(6-(3-(morpholinomethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzo[d][1,3]dioxol-5-yl)-N-phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide) is able to restore apoptosis functions impaired by tumorigenesis in mice. Data from pharmacokinetic (PK), biomarker, and tumor growth studies in a xenograft mouse model were considered for population modeling. The aim of the modeling exercise was to link the kinetics of the drug to the biomarker and tumor-size time profiles to better understand its dose-effect relationship. The PK, caspase kinetics, and tumor dynamics were successfully characterized by the proposed pharmacokinetic-pharmacodynamic model. The nonlinear plasma PK was best described by a two-compartment disposition model with both saturable absorption and elimination. Caspase was activated above the effective drug-concentration threshold (CTHRE ), at which near-maximal activity was reached. Increasing the dose did not increase the activation but better sustained it. Tumor growth followed a biphasic pattern, with caspase having an all-or-none inhibiting effect, consistent with the bistability property of the caspase pathway. For tumor eradication, the CTHRE in plasma was 2876 ng ml-1, and the relative caspase activity threshold (CaspTHRE) was 46.5. There was a strong relationship between the time spent above these thresholds and tumor growth inhibition. Tumor growth was inhibited by 50% when CaspTHRE was exceeded 13.8% of the time and when CTHRE was exceeded 8.1% of the time per dosing. This semimechanistic approach, based on experimental mice data and in vitro parameters, provides an interesting tool to quantify or simulate antitumor effects and, eventually, to plan phase 1 studies.


Assuntos
Antineoplásicos/farmacologia , Biomarcadores Tumorais/metabolismo , Proliferação de Células/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Animais , Caspases/metabolismo , Modelos Animais de Doenças , Camundongos , Modelos Biológicos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
12.
Toxicol Appl Pharmacol ; 355: 103-111, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-29959026

RESUMO

The high-energy compound 3,4,5-trinitropyrazole (TNP) was developed as an alternative to other less energetic and more sensitive explosive materials, in particular 1-methyl-2,4,6-trinitrobenzene (TNT). However, the level of toxicity of TNP remains understudied. Here using an in vivo CD1 mouse model, we mimicked an acute exposure (24 h) to TNP, given either orally or intravenously, and determined the maximum administrable doses (190 mg/kg and 11 mg/kg, respectively), as well as the lethal dose for 50% (LD50) of female or male mice (390 mg/kg for both) treated intravenously with TNP alone. Several metabolites including nitroso-dinitro-pyrazole, hydroxylamino-dinitro-pyrazole, hydroxyl-dinitro-pyrazole and amino-dinitro-pyrazole were identified in urine. TNP is quickly metabolized and eliminated via urine as two main amino-dinitro-pyrazole metabolites. A comparison of the transcriptomic effects of TNP and TNT after 10 days exposure enabled us to demonstrate no major induction of transcripts involved both in cell death mechanisms (apoptosis, necrosis, autophagy) and physiological pathways (glycolysis, ATP production). Finally, subchronic exposure to TNP was replicated in female mice, fed 16.8-52.8 mg/kg/day of TNP for one month, to study the impact on cellular functions. Although blood TNP levels remained high, a lower rate of TNP accumulation in the liver and lungs were observed than during an acute exposure. Conversely, cellular stress functions explored using the RT2 Profiler™ PCR Array Mouse Molecular Toxicology PathwayFinder remained unaltered after this chronic exposure. These findings demonstrate that TNP can be rapidly eliminated in vivo without accumulating in vital organs.


Assuntos
Substâncias Explosivas/toxicidade , Trifosfato de Adenosina/biossíntese , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biotransformação , Substâncias Explosivas/farmacocinética , Feminino , Glicólise/efeitos dos fármacos , Dose Letal Mediana , Masculino , Camundongos , Necrose , Pirazóis/toxicidade , Distribuição Tecidual , Transcriptoma/efeitos dos fármacos
13.
Future Oncol ; 13(8): 679-693, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28076966

RESUMO

AIM: This novel multiparameter Phase I study aimed to optimize doses/dosing schedules of everolimus and sorafenib drug combination, based on modeling/simulation (NCT01932177). PATIENTS & METHODS: About 26 patients with solid tumors were treated in four different dosing schedules. Everolimus once daily + sorafenib twice daily were given continuously in arms A and B, and intermittently in arms C (alternating every other week) and D (everolimus continuous and sorafenib 3 days on/4 days off). RESULTS: Continuous schedules exhibited higher toxicity risks than intermittent schedules (64.1 vs 35.9%; p < 0.0001), and trends for lower disease control rates (80 vs 100%). No significant pharmacokinetic interaction was identified. CONCLUSION: Feasibility of EVESOR trial is demonstrated. Intermittent schedules might provide better tolerance and efficacy than continuous schedules.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Everolimo/administração & dosagem , Everolimo/farmacocinética , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Niacinamida/farmacocinética , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Sorafenibe , Tomografia Computadorizada por Raios X , Resultado do Tratamento
14.
Biopharm Drug Dispos ; 38(5): 351-362, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28207160

RESUMO

PURPOSE: The chromone derivative MBL-II-141, specifically designed to inhibit ABCG2, was previously demonstrated to combine strong inhibition potency, low toxicity and good efficiency in reversing resistance to irinotecan in a xenografted mouse model. Here, the pharmacokinetic interactions in mice between irinotecan, its active metabolite SN-38 and MBL-II-141 were characterized quantitatively in the blood and in the brain. METHODS: Compartmental models were used to fit the data. Goodness-of-fit was assessed by simulation-based diagnostic tools. RESULTS: Irinotecan increased the MBL-II-141 apparent clearance and Vss 1.5-fold, probably by increasing the MBL-II-141 unbound fraction. MBL-II-141 decreased the total apparent clearance of irinotecan by 23%, by decreasing its biliary clearance. MBL-II-141 increased 3-fold the brain accumulation of irinotecan, as a result of the rise of systemic exposure combined with the inhibition of ABCG2-mediated efflux at the blood-brain barrier. Finally, SN-38 exposure was increased by 1.16-fold under treatment with MBL-II-141, owing to the higher irinotecan exposure with increased metabolism towards the formation of SN-38. CONCLUSIONS: These results may help to anticipate the pharmacokinetic interactions between MBL-II-141 and other ABCG2 substrates. The irinotecan-MBL-II-141 interaction is also expected to occur in humans. Copyright © 2017 John Wiley & Sons, Ltd.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/análogos & derivados , Cromonas/farmacocinética , Indóis/farmacocinética , Animais , Antineoplásicos Fitogênicos/sangue , Encéfalo/metabolismo , Camptotecina/sangue , Camptotecina/farmacocinética , Cromonas/sangue , Interações Medicamentosas , Feminino , Indóis/sangue , Irinotecano , Camundongos SCID , Modelos Biológicos
15.
J Antimicrob Chemother ; 71(3): 783-93, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26679250

RESUMO

BACKGROUND: HIV-infected patients with TB need simplified, effective and well-tolerated antiretroviral regimens. METHODS: The French ANRS 129 BKVIR open trial evaluated the once-daily tenofovir DF/emtricitabine and efavirenz combination, started within 12 weeks after TB treatment initiation, in antiretroviral-naive HIV-1-infected patients. Success was defined as an HIV-1 RNA <50 copies/mL and TB cure at 48 weeks. RESULTS: TB was confirmed microbiologically (90%) or histologically (10%) in 69 patients (71% male; median age 43 years; 54% born in Africa). The median time between TB treatment initiation and antiretroviral therapy was 8 weeks (range 1-22 weeks). At baseline, median HIV-1 RNA was 5.4 log10 copies/mL and median CD4 cell count 74 cells/mm(3). In the ITT analysis, combined success at week 48 was achieved in 57/69 patients (83%, 95% CI 74-92). Twelve patients did not achieve virological success, and TB was not cured in one of them. Among the 47 patients who fully adhered to the strategy, the success rate was 96% (95% CI 90-100) and was not affected by low rifampicin and isoniazid serum concentrations. Forty-nine serious adverse events were reported in 31 patients (45%), and 11 led to antiretroviral drug interruption. All adverse events resolved. The immune reconstitution inflammatory syndrome occurred in 23 patients (33%, 95% CI 22-44), and was associated with a low baseline BMI (P = 0.03) and a low haemoglobin level (P = 0.02). CONCLUSION: These results support the use of tenofovir DF/emtricitabine and efavirenz combination therapy for HIV infection in patients with TB.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Benzoxazinas/administração & dosagem , Emtricitabina/administração & dosagem , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Tenofovir/administração & dosagem , Tuberculose/tratamento farmacológico , Adulto , Alcinos , Antituberculosos/administração & dosagem , Ciclopropanos , Quimioterapia Combinada/métodos , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Carga Viral
16.
Future Oncol ; 11(10): 1511-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25963428

RESUMO

Optimal development of targeted drug combinations is one of the future challenges to be addressed. Computerization and mathematical models able to describe biological phenomena and to simulate the effects of changes in experimental conditions may help find solutions to this issue. We propose the concept of 'multiparameter trials', where biological, radiological and clinical data required for modeling purpose are collected and illustrated by the ongoing academic EVESOR trial. The objective of the model-based work would be the determination of the optimized doses and dosing schedules of everolimus and sorafenib, offering the maximization of the predicted modeled benefit/toxicity ratio in patients with solid tumors. It may embody the 'proof of concept' of model-based drug development of anticancer agent combinations.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biópsia , Everolimo/administração & dosagem , Everolimo/farmacocinética , Humanos , Modelos Teóricos , Terapia de Alvo Molecular , Neoplasias/diagnóstico , Niacinamida/administração & dosagem , Niacinamida/análogos & derivados , Niacinamida/farmacocinética , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Sorafenibe , Tomografia Computadorizada por Raios X , Resultado do Tratamento
17.
Antimicrob Agents Chemother ; 58(2): 746-55, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24247130

RESUMO

Prolonged antimicrobial therapy is recommended for methicillin-susceptible Staphylococcus aureus (MSSA) bone and joint infections (BJI), but its safety profile and risk factors for severe adverse events (SAE) in clinical practice are unknown. We addressed these issues in a retrospective cohort study (2001 to 2011) analyzing antimicrobial-related SAE (defined according to the Common Terminology Criteria for Adverse Events) in 200 patients (male, 62%; median age, 60.8 years [interquartile range {IQR}, 45.5 to 74.2 years]) with MSSA BJI admitted to a reference regional center with acute (66%) or chronic arthritis (7.5%), osteomyelitis (9.5%), spondylodiscitis (16%), or orthopedic device-related infections (67%). These patients received antistaphylococcal therapy for a median of 26.6 weeks (IQR, 16.8 to 37.8 weeks). Thirty-eight SAE occurred in 30 patients (15%), with a median time delay of 34 days (IQR, 14.75 to 60.5 days), including 10 patients with hematologic reactions, 9 with cutaneomucosal reactions, 6 with acute renal injuries, 4 with hypokalemia, and 4 with cholestatic hepatitis. The most frequently implicated antimicrobials were antistaphylococcal penicillins (ASP) (13 SAE/145 patients), fluoroquinolones (12 SAE/187 patients), glycopeptides (9 SAE/101 patients), and rifampin (7 SAE/107 patients). Kaplan-Meier curves and stepwise binary logistic regression analyses were used to determine the risk factors for the occurrence of antimicrobial-related SAE. Age (odds ratio [OR], 1.479 for 10-year increase; 95% confidence interval [CI], 1.116 to 1.960; P = 0.006) appeared to be the only independent risk factor for SAE. In patients receiving ASP or rifampin, daily dose (OR, 1.028; 95% CI, 1.006 to 1.051; P = 0.014) and obesity (OR, 8.991; 95% CI, 1.453 to 55.627; P = 0.018) were associated with the occurrence of SAE. The high rate of SAE and their determinants highlighted the importance of the management and follow-up of BJI, with particular attention to be paid to older persons, especially for ASP dosage, and to rifampin dose adjustment in obese patients.


Assuntos
Antibacterianos/efeitos adversos , Osso e Ossos/efeitos dos fármacos , Fluoroquinolonas/efeitos adversos , Articulações/efeitos dos fármacos , Penicilinas/efeitos adversos , Rifampina/efeitos adversos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/microbiologia , Idoso , Artrite Infecciosa/tratamento farmacológico , Artrite Infecciosa/microbiologia , Osso e Ossos/microbiologia , Discite/tratamento farmacológico , Discite/microbiologia , Feminino , Humanos , Hipopotassemia/induzido quimicamente , Hipopotassemia/microbiologia , Inflamação/induzido quimicamente , Inflamação/microbiologia , Icterícia Obstrutiva/induzido quimicamente , Icterícia Obstrutiva/microbiologia , Articulações/microbiologia , Masculino , Pessoa de Meia-Idade , Osteomielite/tratamento farmacológico , Osteomielite/microbiologia , Infecções Relacionadas à Prótese/tratamento farmacológico , Infecções Relacionadas à Prótese/microbiologia , Estudos Retrospectivos , Fatores de Risco , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento
18.
Gynecol Oncol ; 133(3): 460-6, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24726614

RESUMO

OBJECTIVE: Early prediction of the expected benefit of treatment in recurrent ovarian cancer (ROC) patients may help in drug development decisions. The actual value of 50% CA-125 decrease is being reconsidered. The main objective of the present study was to quantify the links between longitudinal assessments of CA-125 kinetics and progression-free survival (PFS) in treated recurrent ovarian cancer (ROC) patients. METHODS: The CALYPSO randomized phase III trial database comparing two platinum-based regimens in ROC patients was randomly split into a "learning dataset" and a "validation dataset". A parametric survival model was developed to associate longitudinal modeled CA-125 changes (ΔCA125), predictive factors, and PFS. The predictive performance of the model was evaluated with simulations. RESULTS: The PFS of 534 ROC patients were properly characterized by a parametric mathematical model. The modeled ΔCA125 from baseline to week 6 was a better predictor of PFS than the modeled fractional change in tumor size. Simulations confirmed the model's predictive performance. CONCLUSIONS: We present the first parametric survival model quantifying the relationship between PFS and longitudinal CA-125 kinetics in treated ROC patients. The model enabled calculation of the increase in ΔCA125 required to observe a predetermined benefit in PFS to compare therapeutic strategies in populations. Therefore, ΔCA125 may be a predictive marker of the expected gain in PFS and an early predictive tool in drug development decisions.


Assuntos
Biomarcadores Tumorais/metabolismo , Antígeno Ca-125/metabolismo , Recidiva Local de Neoplasia/metabolismo , Neoplasias Ovarianas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Descoberta de Drogas , Feminino , Humanos , Cinética , Pessoa de Meia-Idade , Modelos Estatísticos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Paclitaxel/administração & dosagem , Polietilenoglicóis/administração & dosagem , Resultado do Tratamento
19.
Eur J Hosp Pharm ; 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-39137973

RESUMO

OBJECTIVES: Several drug-drug interaction (DDI) checkers such as DDI-Predictor have been developed to detect and grade DDIs. DDI-Predictor gives an estimate of the magnitude of an interaction based on the ratio of areas under the curve. The objective of the present study was to analyse the frequencies of DDIs involving well-known strong interactors such as rifampicin and selective serotonin reuptake inhibitors (SSRIs), as reported by a clinical pharmacy team using DDI-Predictor, and the pharmacist intervention acceptance rate. METHODS: The pharmacist intervention rate and the physician acceptance rate were calculated for DDIs involving rifampicin or the SSRIs fluoxetine, paroxetine, duloxetine and sertraline. The rates were compared with a bilateral χ2 test or Fisher's exact test. RESULTS: Of the 284 DDIs recorded, 38 (13.4%) involved rifampicin and 78 (27.5%) involved SSRIs. The pharmacist intervention rate differed significantly (68.4% for rifampicin vs 48.8% for SSRIs; p=0.045) but the physician acceptance rate did not (84.6% for rifampicin vs 81.6% for SSRIs; p=1). Pharmaceutical interventions for SSRIs were more frequent when the ratio of the area under the drug concentration versus time curve in DDI-Predictor was >2. Pharmacists were more likely to issue a pharmacist intervention for DDIs involving rifampicin because of a high perceived risk of treatment failure and were less likely to issue a pharmacist intervention for DDIs involving an SSRI, except when the suspected interaction was strong. CONCLUSIONS: DDI checkers can help pharmacists to manage DDIs involving strong interactors. DDIs involving strong inhibitors versus a strong inducer differ with regard to their intervention and acceptance rates, notably due to the estimation of the magnitude of the DDI.

20.
Antimicrob Agents Chemother ; 57(1): 517-23, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23147727

RESUMO

Limited data on the pharmacokinetics and pharmacodynamics (PK/PD) of unboosted atazanavir (uATV) in treatment-experienced patients are available. The aim of this work was to study the PK/PD of unboosted atazanavir in a cohort of HIV-infected patients. Data were available for 58 HIV-infected patients (69 uATV-based regimens). Atazanavir concentrations were analyzed by using a population approach, and the relationship between atazanavir PK and clinical outcome was examined using logistic regression. The final PK model was a linear one-compartment model with a mixture absorption model to account for two subgroups of absorbers. The mean (interindividual variability) of population PK parameters were as follows: clearance, 13.4 liters/h (40.7%), volume of distribution, 71.1 liters (29.7%), and fraction of regular absorbers, 0.49. Seven subjects experienced virological failure after switch to uATV. All of them were identified as low absorbers in the PK modeling. The absorption rate constant (0.38 ± 0.20 versus 0.75 ± 0.28 h(-1); P = 0.002) and ATV exposure (area under the concentration-time curve from 0 to 24 h [AUC(0-24)], 10.3 ± 2.1 versus 22.4 ± 11.2 mg · h · liter(-1); P = 0.001) were significantly lower in patients with virological failure than in patients without failure. In the logistic regression analysis, both the absorption rate constant and ATV trough concentration significantly influenced the probability of virological failure. A significant relationship between ATV pharmacokinetics and virological response was observed in a cohort of HIV patients who were administered unboosted atazanavir. This study also suggests that twice-daily administration of uATV may optimize drug therapy.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , HIV/efeitos dos fármacos , Oligopeptídeos/farmacocinética , Piridinas/farmacocinética , Adulto , Área Sob a Curva , Sulfato de Atazanavir , Disponibilidade Biológica , Esquema de Medicação , Feminino , HIV/crescimento & desenvolvimento , Infecções por HIV/virologia , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Oligopeptídeos/sangue , Oligopeptídeos/farmacologia , Piridinas/sangue , Piridinas/farmacologia , Falha de Tratamento
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