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1.
Br J Clin Pharmacol ; 2022 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-35831229

RESUMO

AIMS: Locally advanced rectal cancer (LARC) is an area of unmet medical need with one third of patients dying from their disease. With response to neoadjuvant chemo-radiotherapy being a major prognostic factor, trial SAKK 41/16 assessed potential benefits of adding regorafenib to capecitabine-amplified neoadjuvant radiotherapy in LARC patients. METHODS: Patients received regorafenib at three dose levels (40/80/120 mg once daily) combined with capecitabine 825 mg/m2 bidaily and local radiotherapy. We developed population pharmacokinetic models from plasma concentrations of capecitabine and its metabolites 5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine as well as regorafenib and its metabolites M-2 and M-5 as implemented into SAKK 41/16 to assess potential drug-drug interactions (DDI). After establishing parent-metabolite base models, drug exposure parameters were tested as covariates within the respective models to investigate for potential DDI. Simulation analyses were conducted to quantify their impact. RESULTS: Plasma concentrations of capecitabine, regorafenib and metabolites were characterized by one and two compartment models and absorption was described by parallel first- and zero-order processes and transit compartments, respectively. Apparent capecitabine clearance was 286 L/h (relative standard error [RSE] 14.9%, interindividual variability [IIV] 40.1%) and was reduced by regorafenib cumulative area under the plasma concentration curve (median reduction of 45.6%) as exponential covariate (estimate -4.10 × 10-4 , RSE 17.8%). Apparent regorafenib clearance was 1.94 L/h (RSE 12.1%, IIV 38.1%). Simulation analyses revealed significantly negative associations between capecitabine clearance and regorafenib exposure. CONCLUSIONS: This work informs the clinical development of regorafenib and capecitabine combination treatment and underlines the importance of studying potential DDI with new anticancer drug combinations.

2.
J Clin Med ; 11(15)2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35893345

RESUMO

(1) Adverse drug events (ADEs) are a common cause of emergency department visits and occur frequently during hospitalisation. Instruments that facilitate the detection of the most relevant ADEs could lead to a more targeted and efficient use of limited resources in research and practice. (2) We conducted two consensus processes based on the RAND/UCLA appropriateness method, in order to prioritise ADEs leading to hospital admission (panel 1) and occurring during hospital stay (panel 2) for inclusion in future ADE measurement instruments. In each panel, the experts were asked to assess the "overall importance" of each ADE on a four-point Likert scale (1 = not important to 4 = very important). ADEs with a median rating of ≥3 without disagreement were defined as "prioritised". (3) The 13 experts in panel 1 prioritised 38 out of 65 ADEs, while the 12 experts in panel 2 prioritised 34 out of 63 ADEs. The highest rated events were acute kidney injury and hypoglycaemia (both panels), as well as Stevens-Johnson syndrome in panel 1 and rhabdomyolysis in panel 2. (4) The survey led to a set of ADEs for which there was consensus that they were of particular importance as presentations of acute medication-related harm, thereby providing a focus for further medication safety research and clinical practice.

3.
Cancers (Basel) ; 14(12)2022 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-35740506

RESUMO

Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10-8) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10-10, HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10-8, HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated.

4.
Z Evid Fortbild Qual Gesundhwes ; 168: 27-32, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35148970

RESUMO

BACKGROUND: Ensuring medication accuracy during transitions in care is one of the five highly prevalent patient safety problems focused on within the World Health Organization High 5s Project. Medication reconciliation is a standardized patient care process that can be used to address this problem. The aim of the current study is to implement medication reconciliation in a German university hospital. METHODS: The study was conducted at the Emergency Department of the University Hospital Aachen, Germany. All discrepancies between the Best Possible Medication History and the Admission Medication Order were documented and classified as documentation errors or medication errors. The type of error was also recorded. A negative binomial regression model was used to test several factors influencing the number of discrepancies. RESULTS: The medications of 105 patients were reconciled. The mean number of discrepancies per patient was 4.6± 3.6, with a total of 298 medication errors and 189 documentation errors. The most common type of medication error was the omission of a drug (n=208; 69.8 %). In the negative binomial regression analysis, the care status (p=0.0015) as well as the number of preadmission drugs (p=0.0007) were significantly associated with medication errors. DISCUSSION: A high number of discrepancies was detected and analysed. Patients admitted from nursing homes were less likely to have discrepancies in their medication reconciliation, perhaps because a structured documentation system for medications is already in place at nursing homes including error prone products (special dosage forms or food supplements). CONCLUSIONS: In this study, medication reconciliation was implemented at a German full-care university hospital. The actual number of discrepancies observed strongly indicates the need for medication reconciliation at hospital admission.


Assuntos
Erros de Medicação , Reconciliação de Medicamentos , Alemanha , Hospitais Universitários , Humanos , Erros de Medicação/prevenção & controle , Estudos Prospectivos
5.
Cancers (Basel) ; 13(24)2021 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-34944899

RESUMO

Exposure-efficacy and/or exposure-toxicity relationships have been identified for up to 80% of oral anticancer drugs (OADs). Usually, OADs are administered at fixed doses despite their high interindividual pharmacokinetic variability resulting in large differences in drug exposure. Consequently, a substantial proportion of patients receive a suboptimal dose. Therapeutic Drug Monitoring (TDM), i.e., dosing based on measured drug concentrations, may be used to improve treatment outcomes. The prospective, multicenter, non-interventional ON-TARGET study (DRKS00025325) aims to investigate the potential of routine TDM to reduce adverse drug reactions in renal cell carcinoma patients receiving axitinib or cabozantinib. Furthermore, the feasibility of using volumetric absorptive microsampling (VAMS), a minimally invasive and easy to handle blood sampling technique, for sample collection is examined. During routine visits, blood samples are collected and sent to bioanalytical laboratories. Venous and VAMS blood samples are collected in the first study phase to facilitate home-based capillary blood sampling in the second study phase. Within one week, the drug plasma concentrations are measured, interpreted, and reported back to the physician. Patients report their drug intake and toxicity using PRO-CTCAE-based questionnaires in dedicated diaries. Ultimately, the ON-TARGET study aims to develop a nationwide infrastructure for TDM for oral anticancer drugs.

6.
Res Social Adm Pharm ; 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34838476

RESUMO

BACKGROUND: Medication errors may occur during chemotherapy and can have fatal consequences. Healthcare Failure Mode and Effects Analysis (FMEA) is a method used to detect potential risks and prevent them. OBJECTIVE: Aim of this study was to evaluate the medication process of intravenous tumor therapy in order to guarantee a high standard of patient safety. METHODS: The main part of the study was performed at the University Hospital of Bonn, Germany. After assembling a multidisciplinary team, the individual steps of prescription, compounding, transport, and administration of chemotherapy were mapped in a flow diagram. The possible failures were identified and analyzed by calculating the risk priority numbers (RPNs). Finally, corrective actions were developed and after hypothetical implementation re-analyzed to measure their effects on the process. Subsequently, a shortened FMEA based on the catalogue failure modes developed in Bonn was carried out at the University Hospital of Cologne in order to evaluate its transferability to another hospital. RESULTS: A total of 52 potential failure modes was identified in Bonn. Relating to the RPNs the most critically steps in the process were associated with the prescription, namely, incorrect information about individual parameters of the patient; non-standardized chemotherapy protocols; and problems related to supportive therapy. A significant risk reduction for most of the failure modes was assessed by implementing suitable corrective actions. The shortened FMEA in Cologne led to a different ranking of failure modes. CONCLUSION: The implementation of this analysis has not only identified various safety gaps, but also shows how patient safety during chemotherapy can be enhanced. Moreover, it has sensitized the practitioners to failure modes potentially occurring in their work routine.

7.
Clin Pharmacol Ther ; 110(5): 1240-1249, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34137456

RESUMO

Creatinine clearance is an important tool to describe the renal elimination of drugs in pharmacokinetic (PK) evaluations and clinical practice. In critically ill patients, unstable kidney function invalidates the steady-state assumption underlying equations, such as Cockcroft-Gault. Although measured creatinine clearance (mCrCL) is often used in nonsteady-state situations, it assumes that observed data are error-free, neglecting frequently occurring errors in urine collection. In contrast, compartmental nonlinear mixed effects models of creatinine allow to describe dynamic changes in kidney function while explicitly accounting for a residual error associated with observations. Based on 530 serum and 373 urine creatinine observations from 138 critically ill patients, a one-compartment creatinine model with zero-order creatinine generation rate (CGR) and first-order CrCL was evaluated. An autoregressive approach for interoccasion variability provided a distinct model improvement compared to a classical approach (Δ Akaike information criterion (AIC) -49.0). Fat-free mass, plasma urea concentration, age, and liver transplantation were significantly related to CrCL, whereas weight and sex were linked to CGR. The model-based CrCL estimates were superior to standard approaches to estimate CrCL (or glomerular filtration rate) including Cockcroft-Gault, mCrCL, four-variable modification of diet in renal disease (MDRD), six-variable MDRD, and chronic kidney disease epidemiology collaboration as a covariate to describe cefepime and meropenem PKs in terms of objective function value. In conclusion, a dynamic model of creatinine kinetics provides the means to estimate actual CrCL despite dynamic changes in kidney function, and it can easily be incorporated into population PK evaluations.


Assuntos
Creatinina/metabolismo , Estado Terminal/terapia , Taxa de Filtração Glomerular/fisiologia , Testes de Função Renal/métodos , Modelos Biológicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
8.
BMC Cancer ; 21(1): 719, 2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-34147089

RESUMO

BACKGROUND: The aim of this study was to identify sources of variability including patient gender and body surface area (BSA) in pharmacokinetic (PK) exposure for high-dose methotrexate (MTX) continuous infusion in a large cohort of patients with hematological and solid malignancies. METHODS: We conducted a retrospective PK analysis of MTX plasma concentration data from hematological/oncological patients treated at the University Hospital of Cologne between 2005 and 2018. Nonlinear mixed effects modeling was performed. Covariate data on patient demographics and clinical chemistry parameters was incorporated to assess relationships with PK parameters. Simulations were conducted to compare exposure and probability of target attainment (PTA) under BSA adjusted, flat and stratified dosing regimens. RESULTS: Plasma concentration over time data (2182 measurements) from therapeutic drug monitoring from 229 patients was available. PK of MTX were best described by a three-compartment model. Values for clearance (CL) of 4.33 [2.95-5.92] L h- 1 and central volume of distribution of 4.29 [1.81-7.33] L were estimated. An inter-occasion variability of 23.1% (coefficient of variation) and an inter-individual variability of 29.7% were associated to CL, which was 16 [7-25] % lower in women. Serum creatinine, patient age, sex and BSA were significantly related to CL of MTX. Simulations suggested that differences in PTA between flat and BSA-based dosing were marginal, with stratified dosing performing best overall. CONCLUSION: A dosing scheme with doses stratified across BSA quartiles is suggested to optimize target exposure attainment. Influence of patient sex on CL of MTX is present but small in magnitude.


Assuntos
Monitoramento de Medicamentos/métodos , Metotrexato/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Superfície Corporal , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
10.
J Oncol Pharm Pract ; 27(6): 1439-1446, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33019873

RESUMO

BACKGROUND: Head and neck cancer (HNC) patients are particularly vulnerable to drug-related problems (DRPs) given the toxicity of concomitant chemoradiotherapy (CCRT). OBJECTIVE: To investigate the number and type of potential DRPs (pDRPs) in HNC outpatients undergoing five consecutive cycles of CCRT. METHODS: A single-centre, non-randomized, non-interventional, observational study was conducted at the Oncological Outpatient Clinic of the Center for Integrated Oncology at the University Hospital Bonn, Germany. Clinical pharmacists took a comprehensive medication history, documented laboratory data, assessed patients' symptom burden, and retrospectively performed medication reviews at study entry and on the first day of each therapy cycle without any clinical intervention. RESULTS: In 26 patients, the mean number of pDRPs continuously increased during therapy course, from 4.8 (SD 2.7, range 2-12) at cycle 1 to 6.9 (SD 2.6, range 2-12) at cycle 5, with drug-drug interactions, adverse drug reactions, inappropriate durations of use, and inappropriate dosage intervals being the most common. Considering only new and recurrent pDRPs, the mean number was 4.3 (SD 2.3, range 2-9) at cycle 1 and lower in the further therapy course with an average of 1.3 (SD 1.7, range 0-7) at cycle 2 and 1.9 (SD 1.5, range 0-5) at cycle 5. The number of pDRPs was found to be associated with medication regimen complexity and health-related quality of life assessed in the first therapy cycle. CONCLUSION: pDRPs frequently occurred in HNC outpatients demonstrating the need for pharmaceutical care. A methodological framework for repeated medication reviews was established, facilitating implementation into routine healthcare practice.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Neoplasias de Cabeça e Pescoço , Preparações Farmacêuticas , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Farmacêuticos , Qualidade de Vida , Estudos Retrospectivos
11.
Eur J Clin Pharmacol ; 77(4): 441-464, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33165648

RESUMO

PURPOSE: This review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug monitoring (TDM). Factors influencing the pharmacokinetic exposure in OAD therapy are depicted together with an overview of different TDM approaches. Finally, current evidence for TDM for all approved OADs is reviewed. METHODS: A comprehensive literature search (covering literature published until April 2020), including primary and secondary scientific literature on pharmacokinetics and dose individualisation strategies for OADs, together with US FDA Clinical Pharmacology and Biopharmaceutics Reviews and the Committee for Medicinal Products for Human Use European Public Assessment Reports was conducted. RESULTS: OADs are highly potent drugs, which have substantially changed treatment options for cancer patients. Nevertheless, high pharmacokinetic variability and low treatment adherence are risk factors for treatment failure. TDM is a powerful tool to individualise drug dosing, ensure drug concentrations within the therapeutic window and increase treatment success rates. After reviewing the literature for 71 approved OADs, we show that exposure-response and/or exposure-toxicity relationships have been established for the majority. Moreover, TDM has been proven to be feasible for individualised dosing of abiraterone, everolimus, imatinib, pazopanib, sunitinib and tamoxifen in prospective studies. There is a lack of experience in how to best implement TDM as part of clinical routine in OAD cancer therapy. CONCLUSION: Sub-therapeutic concentrations and severe adverse events are current challenges in OAD treatment, which can both be addressed by the application of TDM-guided dosing, ensuring concentrations within the therapeutic window.


Assuntos
Antineoplásicos/uso terapêutico , Monitoramento de Medicamentos , Administração Oral , Antineoplásicos/farmacocinética , Humanos
12.
Expert Opin Drug Metab Toxicol ; 17(12): 1407-1422, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35029518

RESUMO

INTRODUCTION: Therapeutic drug monitoring (TDM) of the anticancer drug fluorouracil (5FU) as a method to support dose adjustments has been researched and discussed extensively. Despite manifold evidence of the advantages of 5FU-TDM, traditional body surface area (BSA)-guided dosing is still widely applied. AREAS COVERED: This review covers the latest evidence on 5FU-TDM based on a literature search in PubMed between June and September 2021. It particularly highlights new approaches of implementing 5FU-TDM into precision medicine by combining TDM with pharmacogenetic testing and/or pharmacometric models. This review further discusses remaining obstacles in order to incorporate 5FU-TDM into clinical routine. EXPERT OPINION: New data on 5FU-TDM further strengthen the advantages compared to BSA-guided dosing as it is able to reduce pharmacokinetic variability and thereby improve treatment efficacy and safety. Interprofessional collaboration has the potential to overcome the remaining barriers for its implementation. Preemptive pharmacogenetic testing followed by 5FU-TDM can further improve 5FU exposure in a substantial proportion of patients. Developing a model framework integrating pharmacokinetics and pharmacodynamics of 5FU will be crucial to fully advance into the precision medicine era. Model applications can potentially support clinicians in dose finding before starting chemotherapy. Additionally, TDM provides further assistance in continuously improving model predictions.


Assuntos
Antineoplásicos , Monitoramento de Medicamentos , Antineoplásicos/efeitos adversos , Superfície Corporal , Monitoramento de Medicamentos/métodos , Fluoruracila , Humanos , Medicina de Precisão
13.
Cancer Chemother Pharmacol ; 86(3): 435-444, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32852627

RESUMO

PURPOSE: The inclusion of the patient's perspective has become increasingly important when reporting adverse events and may assist in management of toxicity. The relationship between drug exposure and toxicity can be quantified by combining Markov elements with pharmacometric models. A minimal continuous-time Markov model (mCTMM) was applied to patient-reported outcomes using hand-foot syndrome (HFS) induced by capecitabine anti-cancer therapy as an example. METHODS: Patient-reported HFS grades over time of 150 patients from two observational studies treated with oral capecitabine were analyzed using a mCTMM approach. Grading of HFS severity was based on the Common Terminology Criteria for Adverse Events. The model was evaluated by visual predictive checks (VPC). Furthermore, a simulation study of the probability of HFS severity over time was performed in which the standard dosing regimen and dose adjustments according to HFS severity were investigated. RESULTS: The VPC of the developed dose-toxicity model indicated an accurate description of HFS severity over time. Individual absolute daily dose was found to be a predictor for HFS. The simulation study demonstrated a reduction of severe HFS using the recommended dose adjustment strategy. CONCLUSION: A minimal continuous-time Markov model was developed based on patient-reported severity of hand-foot syndrome under capecitabine. Thus, a modeling framework for patient-reported outcomes was created which may assist in the optimization of dosage regimens and adjustment strategies aiming at minimizing symptom burden during anti-cancer drug therapy.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Capecitabina/efeitos adversos , Síndrome Mão-Pé/patologia , Cadeias de Markov , Neoplasias/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Síndrome Mão-Pé/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Prognóstico , Estudos Prospectivos
14.
Transl Psychiatry ; 10(1): 210, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32612257

RESUMO

Antidepressant therapy is still associated with delays in symptomatic improvement and low response rates. Incomplete understanding of molecular mechanisms underlying antidepressant effects hampered the identification of objective biomarkers for antidepressant response. In this work, we studied transcriptome-wide expression followed by pathway analysis in lymphoblastoid cell lines (LCLs) derived from 17 patients documented for response to SSRI antidepressants from the Munich Antidepressant Response Signatures (MARS) study upon short-term incubation (24 and 48 h) with citalopram. Candidate transcripts were further validated with qPCR in MARS LCLs from responders (n = 33) vs. non-responders (n = 36) and afterward in an independent cohort of treatment-resistant patients (n = 20) vs. first-line responders (n = 24) from the STAR*D study. In MARS cohort we observed significant associations of GAD1 (glutamate decarboxylase 1; p = 0.045), TBC1D9 (TBC1 Domain Family Member 9; p = 0.014-0.021) and NFIB (nuclear factor I B; p = 0.015-0.025) expression with response status, remission status and improvement in depression scale, respectively. Pathway analysis of citalopram-altered gene expression indicated response-status-dependent transcriptional reactions. Whereas in clinical responders neural function pathways were primarily up- or downregulated after incubation with citalopram, deregulated pathways in non-responders LCLs mainly involved cell adhesion and immune response. Results from the STAR*D study showed a marginal association of treatment-resistant depression with NFIB (p = 0.068) but not with GAD1 (p = 0.23) and TBC1D9 (p = 0.27). Our results propose the existence of distinct pathway regulation mechanisms in responders vs. non-responders and suggest GAD1, TBC1D9, and NFIB as tentative predictors for clinical response, full remission, and improvement in depression scale, respectively, with only a weak overlap in predictors of different therapy outcome phenotypes.


Assuntos
Citalopram , Transtorno Depressivo Maior , Biomarcadores , Linhagem Celular , Citalopram/uso terapêutico , Depressão/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Humanos , Inibidores de Captação de Serotonina/uso terapêutico , Resultado do Tratamento
15.
Z Evid Fortbild Qual Gesundhwes ; 153-154: 44-53, 2020 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32482507

RESUMO

BACKGROUND: Medication reviews conducted in community pharmacies are a measure to reduce drug-related problems and to increase medication safety. Since 2014, a guideline for medication reviews has been available in Germany. However, the sole existence of a guideline does not guarantee a high quality of this novel service. Quality indicators can contribute to ensure appropriate quality standards. So far, no such indicators have been available in Germany. This project therefore aims at developing suitable indicators to assess the quality of medication reviews type 2a in community pharmacies. METHODS: Based on a literature review, potential quality indicators were generated. Using a two-step Delphi method applying the RUMBA criteria, a set of structure, process, and outcome indicators was developed. RESULTS: The literature review identified 23 potential indicators. Nine further indicators derived from the guideline for medication reviews and expert opinion were amended. After discussion in a focus group, the 32 indicators were reduced to a preliminary set of twelve indicators used for the Delphi survey. Following two Delphi rounds, a final indicator set consisting of three structure indicators, one process indicator and two outcome indicators, was generated. DISCUSSION: The set of quality indicators is potentially suitable for measuring the quality of medication reviews in German community pharmacies. In the next step, these indicators need to be evaluated with regard to their validity and applicability in daily routine.


Assuntos
Farmácias , Alemanha , Indicadores de Qualidade em Assistência à Saúde , Inquéritos e Questionários
16.
Cells ; 9(6)2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32466394

RESUMO

Cisplatin is a widely used drug in the treatment of various solid tumors, such as ovarian cancer. However, while the acquired resistance significantly limits the success of therapy, some tumors, such as colorectal cancer, are intrinsically insensitive to cisplatin. Only a small amount of intracellular platinum binds to the target-genomic DNA. The fate of the remaining drug is largely obscure. This work aimed to identify the cytosolic protein binding partners of cisplatin in ovarian and colorectal cancer cells and to evaluate their relevance for cell sensitivity to cisplatin and oxaliplatin. Using the fluorescent cisplatin analog BODIPY-cisplatin, two-dimensional gel electrophoresis, and mass spectrometry, we identified the protein binding partners in A2780 and cisplatin-resistant A2780cis ovarian carcinoma, as well as in HCT-8 and oxaliplatin-resistant HCT-8ox colorectal cell lines. Vimentin, only identified in ovarian cancer cells; growth factor receptor-bound protein 2, only identified in colorectal cancer cells; and glutathione-S-transferase π, identified in all four cell lines, were further investigated. The effect of pharmacological inhibition and siRNA-mediated knockdown on cytotoxicity was studied to assess the relevance of these binding partners. The silencing of glutathione-S-transferase π significantly sensitized intrinsically resistant HCT-8 and HCT-8ox cells to cisplatin, suggesting a possible involvement of the protein in the resistance of colorectal cancer cells to the drug. The inhibition of vimentin with FiVe1 resulted in a significant sensitization of A2780 and A2780cis cells to cisplatin, revealing new possibilities for improving the chemosensitivity of ovarian cancer cells.


Assuntos
Cisplatino/farmacologia , Compostos de Boro/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Corantes Fluorescentes/química , Proteína Adaptadora GRB2/metabolismo , Técnicas de Silenciamento de Genes , Glutationa S-Transferase pi/metabolismo , Humanos , Ligação Proteica/efeitos dos fármacos , Vimentina/metabolismo
17.
J Clin Pharmacol ; 60(9): 1237-1253, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32427354

RESUMO

The extent of a drug-drug interaction (DDI) mediated by cytochrome P450 (CYP) 3A inhibitors is highly variable during a dosing interval, as it depends on the temporal course of victim and perpetrator drug concentrations at intestinal and hepatic CYP3A expression sites. Capturing the time course of inhibition is therefore difficult using standard DDI studies assessing changes in area under the curve; thus, a novel design was developed. In a 4-period changeover pilot study, 6 healthy men received intraduodenal or intravenous infusions of the CYP3A substrate midazolam (MDZ) at a rate of 0.26 mg/h for 24 hours. This was combined with intraduodenal or intravenous infusion of the CYP3A inhibitor voriconazole (VRZ), administered at rates of 7.5 mg/h from 8 to 16 hours and of 15 mg/h from 16 to 24 hours, after starting midazolam administration. Plasma and urine concentrations of VRZ, MDZ, and its major metabolites were quantified by liquid chromatography-tandem mass spectrometry and analyzed by semiphysiological population pharmacokinetic nonlinear mixed-effects modeling. A model including mechanism-based inactivation of the metabolizing enzymes (maximum inactivation rate constant kinact , 2.83 h-1 ; dissociation rate constant K I , 9.33 µM) described the pharmacokinetics of VRZ well. By introducing competitive inhibition by VRZ on primary and secondary MDZ metabolism, concentration-time profiles, MDZ and its metabolites were captured appropriately. The model provides estimates of local concentrations of substrate and inhibitor at the major CYP3A expression sites and thus of the respective dynamic extent of inhibition. A combination of intravenous and intraduodenal infusions of inhibitors and substrates has the potential to provide a more accurate assessment of DDIs occurring in both gut wall and liver.


Assuntos
Ansiolíticos/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/efeitos dos fármacos , Intestinos/enzimologia , Fígado/enzimologia , Midazolam/farmacocinética , Voriconazol/farmacocinética , Adulto , Ansiolíticos/administração & dosagem , Ansiolíticos/metabolismo , Biotransformação/efeitos dos fármacos , Simulação por Computador , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/metabolismo , Interações Medicamentosas , Duodeno , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Infusões Parenterais , Intestinos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Midazolam/administração & dosagem , Midazolam/metabolismo , Modelos Biológicos , Projetos Piloto , Voriconazol/administração & dosagem , Voriconazol/metabolismo
18.
Cancer Chemother Pharmacol ; 85(4): 711-722, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32152679

RESUMO

PURPOSE: To describe 5-fluorouracil (5FU) pharmacokinetics, myelotoxicity and respective covariates using a simultaneous nonlinear mixed effect modelling approach. METHODS: Thirty patients with gastrointestinal cancer received 5FU 650 or 1000 mg/m2/day as 5-day continuous venous infusion (14 of whom also received cisplatin 20 mg/m2/day). 5FU and 5-fluoro-5,6-dihydrouracil (5FUH2) plasma concentrations were described by a pharmacokinetic model using NONMEM. Absolute leukocyte counts were described by a semi-mechanistic myelosuppression model. Covariate relationships were evaluated to explain the possible sources of variability in 5FU pharmacokinetics and pharmacodynamics. RESULTS: Total clearance of 5FU correlated with body surface area (BSA). Population estimate for total clearance was 249 L/h. Clearances of 5FU and 5FUH2 fractionally changed by 77%/m2 difference from the median BSA. 5FU central and peripheral volumes of distribution were 5.56 L and 28.5 L, respectively. Estimated 5FUH2 clearance and volume of distribution were 121 L/h and 96.7 L, respectively. Baseline leukocyte count of 6.86 × 109/L, as well as mean leukocyte transit time of 281 h accounting for time delay between proliferating and circulating cells, was estimated. The relationship between 5FU plasma concentrations and absolute leukocyte count was found to be linear. A higher degree of myelosuppression was attributed to combination therapy (slope = 2.82 L/mg) with cisplatin as compared to 5FU monotherapy (slope = 1.17 L/mg). CONCLUSIONS: BSA should be taken into account for predicting 5FU exposure. Myelosuppression was influenced by 5FU exposure and concomitant administration of cisplatin.


Assuntos
Antimetabólitos Antineoplásicos/efeitos adversos , Fluoruracila/efeitos adversos , Neoplasias Gastrointestinais/tratamento farmacológico , Modelos Biológicos , Células Mieloides/patologia , Adulto , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Seguimentos , Neoplasias Gastrointestinais/patologia , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Células Mieloides/efeitos dos fármacos , Dinâmica não Linear , Prognóstico , Distribuição Tecidual
19.
J Geriatr Oncol ; 11(6): 997-1005, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31928942

RESUMO

OBJECTIVES: To compare the CARG (Cancer and Aging Research Group) and CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) score regarding the predictive performance for severe toxicity in older patients with cancer. METHODS: We recruited patients ≥70 years and applied the CARG and CRASH score before the start of systemic cancer treatment. The CARG predicts severe overall toxicity; the CRASH additionally predicts hematologic and nonhematologic toxicity. We captured ≥ grade 3 toxicity according to Common Terminology Criteria for Adverse Events (CTCAE) from medical records. Predictive performance was assessed using logistic regression and the area under the receiver operating characteristic curve (ROC-AUC). RESULTS: The study cohort comprised 120 patients (50% female, mean age 77.2 years, 57% solid tumors). The median of the CARG (range 0-23) and the combined CRASH (range 0-12) were 9 and 8, respectively. 81% of patients experienced toxicity; 67% showed hematologic toxicity. The predictive performance of the CARG and the combined CRASH was similar for overall toxicity (CARG: Odds ratio per unit increase (OR) 1.266, P = .015; ROC-AUC 0.681, P = .010; combined CRASH: OR 1.337, P = .029; ROC-AUC 0.650, P = .032). For hematologic toxicity, the hematologic CRASH was a significant predictor and showed numerically a higher ROC-AUC than the CARG which was not statistically different (CARG: OR 1.048, P = .462; ROC-AUC 0.564, P = .271; hematologic CRASH: OR 1.602, P = .007; ROC-AUC 0.665, P = .005). CONCLUSION: Both scores exhibited similar predictive performance for toxicity in older patients with cancer.


Assuntos
Antineoplásicos , Neoplasias , Medição de Risco , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Feminino , Humanos , Modelos Logísticos , Masculino , Neoplasias/tratamento farmacológico , Curva ROC
20.
BMC Geriatr ; 19(1): 39, 2019 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-30744564

RESUMO

BACKGROUND: The benefit of medication reviews for long-term care (LTC) residents has been generally recognized throughout health care systems. Whereas many studies showed the impact of comprehensive medication reviews performed by specialized clinical pharmacists, little is known about the impact of medication reviews performed by community pharmacists. Involving them in the provision of medication reviews may help satisfy the increasing demand for ensuring medication safety. METHODS: Community pharmacists supplying drugs to the LTC facilities performed a medication review for German LTC residents aged at least 65 years and taking five or more drugs per day based on the patients' medication only. Documented potential drug-related problems (DRPs) and the implementation rate of pharmaceutical interventions were evaluated descriptively. To assess the quality of the medication reviews, we developed a corresponding reference system based on the analysis of two experienced clinical pharmacists. RESULTS: Twelve pharmacies performed medication reviews for 94 LTC residents. Overall, the pharmacists documented 154 potential DRPs (mean 1.6 per patient, SD 1.5) of which the most common were drug-drug interactions (40%) followed by potentially inappropriate medication (PIM) (16%) and inappropriate dosages (14%). 33% of the pharmacists' interventions to solve DRPs were successfully implemented, mostly dosage adjustments. The identification of potentially severe drug-drug interactions and PIM showed the highest agreement (88 and 73%) with the reference system. CONCLUSIONS: The medication review program of community pharmacists for LTC residents led to the identification of relevant DRPs. The reference system assessing the quality of the service can contribute to its transparency and reveals the potential for its improvement. The community pharmacists' knowledge of the LTC residents and their relation to the prescribers is crucial for providing successful medication reviews.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Assistência de Longa Duração/tendências , Reconciliação de Medicamentos/métodos , Farmacêuticos , Papel Profissional , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Interações Medicamentosas/fisiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Farmacêuticos/tendências , Instituições de Cuidados Especializados de Enfermagem/tendências
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