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2.
Breast ; 51: 21-28, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32193049

RESUMO

PURPOSE: Discrepancies between clinicians' assessment of chemotherapy-induced peripheral neuropathy (CIPN) and patient-reported outcomes (PRO) have been described, though the underlying reasons are unknown. Our objective was to identify potential patient-specific factors associated with under-describing of CIPN to clinicians in women with non-metastatic breast cancer treated with paclitaxel. METHODS: Patients enrolled in an observational study (n = 60) completed weekly CIPN PRO using the EORTC CIPN20. Clinician-documented CIPN using the NCI CTCAE were abstracted from the electronic medical record and paired with CIPN20 data at weeks 7 and 10. Patients were classified as under-describers if their CIPN20 was above the 80th percentile of the CIPN20 distribution for that CTCAE grade from an independent clinical trial (N08CA). Demographics, Assessment of Survivor Concerns (ASC), Trust in Oncologist Scale (TiOS), and health literacy assessment were collected post-treatment via survey. Repeated measures cumulative logistic regression models were used to identify factors associated with under-describing CIPN. RESULTS: Forty-two women completed the survey (response rate 70%). Three and 9 patients were categorized as under-describers at weeks 7 and 10, respectively. Women who were not working (OR = 9.00, 95%CI 1.06-76.15), had lower income (OR = 7.04, 95%CI 1.5-32.99), and displayed higher trust in their oncologist's competence (OR = 1.29, 95%CI 1.03-1.62 for a 0.1-unit increase in score) were more likely to under-describe CIPN symptoms. CONCLUSIONS: This preliminary study identified non-working status, low income and trust in oncologist's competence as potential factors influencing under-description of CIPN to the clinical team. Further work is needed to clarify these relationships and test additional factors.

3.
Breast Cancer Res Treat ; 180(3): 707-714, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32166478

RESUMO

PURPOSE: Approximately 25% of patients receiving weekly paclitaxel for breast cancer require treatment disruptions to avoid severe, irreversible peripheral neuropathy (PN). Vitamin insufficiencies are PN risk factors in many diseases, but their relevance to chemotherapy-induced PN is unknown. METHODS: We investigated whether baseline insufficiency of vitamin D, vitamin B12, folate, or homocysteine increased PN in patients with breast cancer receiving weekly paclitaxel in a retrospective analysis of a prospective observational study. Patient-reported PN was collected at baseline and during treatment on the Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy (CIPN20). The primary analysis tested associations between vitamin deficiency and the maximum increase from baseline in the CIPN20 sensory subscale (ΔCIPN8). Secondary analyses tested for association with PN-induced treatment disruptions and adjusted associations for treatment and clinical variables. RESULTS: 25-hydroxy-vitamin D was the only nutrient with sufficient deficiency (< 20 ng/mL) for analysis (15/37 = 41%). Vitamin D-deficient patients had a greater mean PN increase than non-deficient patients (ΔCIPN8 ± SD, 36 ± 23 vs. 16 ± 16, p = 0.003) and a non-significant, approximately threefold increase in risk of treatment disruption (OR 2.98, 95% CI [0.72, 12.34], p = 0.16). In multivariable models adjusted for clinical and treatment variables, baseline vitamin D level was inversely associated with PN (ß = - 0.04, p = 0.02). CONCLUSION: Pre-treatment vitamin D deficiency was associated with PN in women receiving weekly paclitaxel for breast cancer. Vitamin D deficiency may be an easily detected PN risk factor that could be resolved prior to treatment to prevent PN, avoid treatment disruptions, and improve treatment outcomes.

5.
Support Care Cancer ; 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31897779

RESUMO

PURPOSE: Cases of chemotherapy-induced peripheral neuropathy (CIPN) under-reporting have been sporadically described in the literature, but no studies have focused on actively examining this behavior. Our primary aim was to identify women who purposefully under-reported CIPN, along with reasons for doing so. A secondary aim was to explore factors enabling or hindering communication of CIPN to clinicians. METHODS: Semi-structured interviews were conducted with women with breast cancer who had received paclitaxel in a prospective observational study. The interview guide was developed based on factors hypothesized to influence side effect disclosure to clinicians. Interviews were recorded, transcribed verbatim, and thematically content analyzed. RESULTS: Thirty-four women were interviewed. Three main themes emerged from the analysis: (1) enablers of CIPN reporting (e.g., positive relationship with the oncology team, sufficient appointment time, existence of alternative communication channels to office visits, expectation of CIPN as a side effect); (2) deterrents to CIPN reporting (e.g., perception of need to complete the full course of therapy, fear of treatment discontinuation, lack of knowledge of long-term consequences of CIPN); and (3) balancing survival versus functional impairment due to CIPN. Women prioritized efficacy over CIPN until physical functioning was meaningfully affected. No patients reported purposeful CIPN under-reporting, but three women admitted having considered doing so. CONCLUSIONS: Despite the lack of evidence of CIPN withholding, women considered both the effectiveness and the toxicity of paclitaxel treatment, as well as beliefs about treatment and long-term consequences of CIPN and relationship with the oncology team, when deciding whether to report CIPN symptoms.

6.
Clin Transl Sci ; 13(1): 116-124, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31647186

RESUMO

Translating CYP2D6 genotype to metabolizer phenotype is not standardized across clinical laboratories offering pharmacogenetic (PGx) testing and PGx clinical practice guidelines, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the Dutch Pharmacogenetics Working Group (DPWG). The genotype to phenotype translation discordance between laboratories and guidelines can cause discordant cytochrome P450 2D6 (CYP2D6) phenotype assignments and, thus lead to inconsistent therapeutic recommendations and confusion among patients and clinicians. A modified-Delphi method was used to obtain consensus for a uniform system for translating CYP2D6 genotype to phenotype among a panel of international CYP2D6 experts. Experts with diverse involvement in CYP2D6 interpretation (clinicians, researchers, genetic testing laboratorians, and PGx implementers; n = 37) participated in conference calls and surveys. After completion of 7 surveys, a consensus (> 70%) was reached with 82% of the CYP2D6 experts agreeing to the final CYP2D6 genotype to phenotype translation method. Broad adoption of the proposed CYP2D6 genotype to phenotype translation method by guideline developers, such as CPIC and DPWG, and clinical laboratories as well as researchers will result in more consistent interpretation of CYP2D6 genotype.

7.
Br J Clin Pharmacol ; 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823378

RESUMO

AIMS: Chemotherapy-induced peripheral neuropathy (PN) is a treatment limiting toxicity of paclitaxel. We evaluated if EPHA genetic variation (EPHA4, EPHA5, EPHA6, and EPHA8) is associated with PN sensitivity by accounting for variability in systemic paclitaxel exposure (time above threshold). METHODS: Germline DNA from 60 patients with breast cancer was sequenced. PN was measured using the 8-item sensory subscale (CIPN8) of the patient-reported CIPN20. Associations for 3 genetic models were tested by incorporating genetics into previously published PN prediction models integrating measured paclitaxel exposure and cumulative treatment. Significant associations were then tested for association with PN-related treatment disruption. RESULTS: EPHA5 rs7349683 (minor allele frequency = 0.32) was associated with increased PN sensitivity (ß-coefficient = 0.39, 95% confidence interval 0.11-0.67, p = 0.007). Setting a maximum tolerable threshold of CIPN8 = 30, optimal paclitaxel exposure target is shorter for rs7349683 homozygous (11.6 h) than heterozygous (12.6 h) or wild-type (13.6 h) patients. Total number of missense variants (median = 0, range 0-2) was associated with decreased PN sensitivity (ß-coefficient: -0.42, 95% confidence interval -0.72 to -0.12, P = .006). No association with treatment disruption was detected for the total number of missense variants or rs7349683. CONCLUSION: Isolating toxicity sensitivity by accounting for exposure is a novel approach, and rs7349683 represents a promising marker for PN sensitivity that may be used to individualize paclitaxel treatment.

8.
Pharmacogenomics J ; 19(6): 501-515, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31616046

RESUMO

Cytochrome P450 enzyme variant alleles have shown evidence that functional consequences differ between substrates. A systematic effort has not yet been made to confirm substrate-dependent activity. This review will discuss the challenges of assessing three examples (CYP2C8*3, CYP2D6*10, and CYP2C9*2) where substrate-dependent activity has been hypothesized with differing levels of evidence and their potential clinical implications. Data supports bidirectional substrate-dependent activity for CYP2C8*3. Although some data suggests CYP2D6*10 causes differences in the magnitude of effect across substrates, confirmatory studies are needed. Convincing evidence for CYP2C9*2 was lacking likely due to compensatory CYP450 metabolism or experimental variability. Confirmed substrate-dependent activity has the potential to impact clinical use of pharmacogenomics, and must be taken into consideration to ensure the goal of improving treatment through personalization is met. It is important for the pharmacogenomics community to begin thinking about this important topic and how it can be best accommodated in clinical practice.

10.
Support Care Cancer ; 27(10): 3729-3737, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31363906

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a number of chemotherapeutic agents. Drugs commonly implicated in the development of CIPN include platinum agents, taxanes, vinca alkaloids, bortezomib, and thalidomide analogues. As a drug response can vary between individuals, it is hypothesized that an individual's specific genetic variants could impact the regulation of genes involved in drug pharmacokinetics, ion channel functioning, neurotoxicity, and DNA repair, which in turn affect CIPN development and severity. Variations of other molecular markers may also affect the incidence and severity of CIPN. Hence, the objective of this review was to summarize the known biological (molecular and genomic) predictors of CIPN and discuss the means to facilitate progress in this field.


Assuntos
Antineoplásicos/efeitos adversos , Síndromes Neurotóxicas/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Bortezomib/efeitos adversos , Predisposição Genética para Doença/genética , Humanos , Taxoides/efeitos adversos , Alcaloides de Vinca/efeitos adversos
11.
Pharmacogenomics ; 20(8): 571-580, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31190621

RESUMO

Aim: This study tested for associations between SLCO1B1 polymorphisms and circulating estrogen levels in women with breast cancer treated with letrozole or exemestane. Patients & methods: Postmenopausal women with hormone-receptor positive breast cancer were genotyped for SLCO1B1*5 (rs4149056) and rs10841753. Pretreatment and on-treatment plasma estrogens and aromatase inhibitor (AI) concentrations were measured. Regression analyses were performed to test for pharmacogenetic associations with estrogens and drug concentrations. Results: SLCO1B1*5 was associated with elevated pretreatment estrone sulfate and an increased risk of detectable estrone concentrations after 3 months of AI treatment. Conclusion: These findings suggest SLCO1B1 polymorphisms may have an effect on estrogenic response to AI treatment, and therefore may adversely impact the anticancer effectiveness of these agents.

12.
Pharmacogenomics ; 20(6): 421-432, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30983501

RESUMO

Aim: This study evaluated the impact of CYP3A5 genotype and other patient characteristics on sublingual (SL) tacrolimus exposure and compared the relationship with oral administration. Patients & methods: Tacrolimus concentrations were retrospectively collected for adult lung transplant recipients, who were genotyped for CYP3A5*3, CYP3A4*22, CYP3A7*1C, and POR*28. Regression analyses were performed to determine covariates that impacted the SL and oral tacrolimus concentration/dose ratios. Results: An interaction of CYP3A5 genotype and CYP3A inhibitor increased the SL concentration/dose, while cystic fibrosis decreased the SL concentration/dose. The oral concentration/dose was independently associated with these covariates and was increased by serum creatinine and number of tacrolimus doses. Conclusion: This study suggests personalized dosing strategies for tacrolimus likely need to consider characteristics beyond CYP3A5 genotype.

13.
Breast Cancer Res Treat ; 175(2): 297-303, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30747308

RESUMO

PURPOSE: UGT2B17 gene deletion (UGT2B17*2) has been reported to affect bone health as well as the pharmacokinetics of aromatase inhibitor (AI) drugs such as exemestane. The goal of this study was to assess associations between UGT2B17 gene deletion and bone health prior to and after 24 months of AI treatment in postmenopausal women with hormone receptor positive (HR+) breast cancer. METHODS: Bone health in women with HR+ breast cancer enrolled on the prospective randomized Exemestane and Letrozole Pharmacogenetics (ELPh) trial was determined by measuring bone turnover markers (BTM) and bone mineral density (BMD) pre-treatment and after 3 BTM and 24 BMD months of treatment with either the steroidal AI exemestane or the nonsteroidal AI letrozole. DNA samples were genotyped for UGT2B17*2. RESULTS: Of the 455 subjects included in the analyses, 244 (53.6%) carried at least one copy of UGT2B17*2. UGT2B17*2 was associated with lower pre-treatment BMD at the hip (P = 0.01) and spine (P = 0.0076). Letrozole treatment was associated with a greater decrease in BMD of the hip (P = 0.03) and spine (P = 0.03) than exemestane. UGT2B17 genotype was not associated with changes in BMD from 24 months of AI treatment, though in UGT2B17*2 homozygous patients, there was a trend toward greater decreases in BMD of the spine from treatment with letrozole compared with exemestane (P = 0.05). CONCLUSION: UGT2B17*2 may be associated with lower baseline BMD in women with HR+ breast cancer. Exemestane is less detrimental to bone health than letrozole in postmenopausal women treated with AI, and this effect may be confined to patients carrying UGT2B17*2, though this finding requires independent validation.


Assuntos
Androstadienos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Glucuronosiltransferase/genética , Letrozol/administração & dosagem , Antígenos de Histocompatibilidade Menor/genética , Androstadienos/efeitos adversos , Inibidores da Aromatase/administração & dosagem , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/genética , Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Deleção de Genes , Estudos de Associação Genética , Genótipo , Humanos , Letrozol/efeitos adversos , Pessoa de Meia-Idade , Farmacogenética , Pós-Menopausa/efeitos dos fármacos , Pós-Menopausa/genética , Tamoxifeno/administração & dosagem
14.
Pharmacogenomics ; 20(2): 95-104, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30520341

RESUMO

AIM: First, evaluate if patients carrying putatively diminished activity CYP2C8 genotype have longer paclitaxel exposure (e.g., time above threshold concentration of 0.05 µM [Tc >0.05]). Second, screen additional pharmacogenes for associations with Tc >0.05. Methods: Pharmacogene panel genotypes were translated into genetic phenotypes for associations with Tc >0.05 (n = 58). RESULTS: Patients with predicted low-activity CYP2C8 had shorter Tc >0.05 after adjustment for age, body surface area and race (9.65 vs 11.03 hrs, ß = 5.47, p = 0.02). This association was attributed to CYP2C8*3 (p = 0.006), not CYP2C8*4 (p = 0.58). Patients with predicted low-activity SLCO1B1 had longer Tc >0.05 (12.12 vs 10.15 hrs, ß = 0.85, p = 0.012). CONCLUSION: Contrary to previous publications, CYP2C8*3 may confer increased paclitaxel metabolic activity. SLCO1B1 and CYP2C8 genotype may explain some paclitaxel pharmacokinetic variability.


Assuntos
Citocromo P-450 CYP2C8/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Neoplasias/tratamento farmacológico , Paclitaxel/efeitos adversos , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/efeitos adversos , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Neoplasias/patologia , Paclitaxel/administração & dosagem , Variantes Farmacogenômicos/genética , Fenótipo
15.
BMC Cancer ; 18(1): 1155, 2018 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-30466416

RESUMO

BACKGROUND: Drug-drug interactions (DDIs) in subjects enrolling in clinical trials can impact not only safety of the patient but also study drug outcomes and data validity. This makes it critical to adequately screen and manage DDIs. The study objective was to determine the prevalence of DDIs involving study medications in subjects enrolling in National Clinical Trials Network (NCTN) clinical trials at a single institution. DDIs were evaluated based on study protocol recommendations for concomitant medication use (i.e. exclude, avoid or use caution), screening via DDI tool, and pharmacist review. METHODS: Subjects enrolled in NCTN trials of commercially available agents between January 2013 and August 2017 were included if a complete medication list was available. Complete medication lists were collected from the date of enrollment or the next available date then screened utilizing protocol guidance and the DDI screening tool, Lexicomp® Drug Interactions (Wolters Kluwer, Hudson, OH). Interactions were reviewed for clinical relevance: defined as a DDI that would require a medication change to ensure study agent safety and efficacy at enrollment. RESULTS: One hundred and twenty-eight subjects enrolled in 35 clinical trials were included. Protocol guidance detected 15 unique DDI pairs that should be avoided or used with caution in 10.2% (13/128) of subjects. The majority of these subjects did not have a clinically relevant DDI (69.2%, 9/13) based on pharmacist review. Lexicomp® detected moderate to major DDIs in 24.2% (31/128) of subjects, with 9.4% (12/128) having a clinically relevant DDI. CONCLUSIONS: This study confirms a high prevalence of DDIs present in subjects enrolling in oncology clinical trials. Further efforts should be made to improve methods to detect and manage DDIs in patients enrolling on clinical trials to ensure patient safety and trial data validity.


Assuntos
Interações Medicamentosas , Neoplasias/epidemiologia , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Oncologia , Neoplasias/tratamento farmacológico , Prevalência
16.
Breast Cancer Res Treat ; 171(3): 657-666, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29946863

RESUMO

PURPOSE: Approximately 25% of breast cancer patients experience treatment delays or discontinuation due to paclitaxel-induced peripheral neuropathy (PN). Currently, there are no predictive biomarkers of PN. Pharmacometabolomics is an informative tool for biomarker discovery of drug toxicity. We conducted a secondary whole blood pharmacometabolomics analysis to assess the association between pretreatment metabolome, early treatment-induced metabolic changes, and the development of PN. METHODS: Whole blood samples were collected pre-treatment (BL), just before the end of the first paclitaxel infusion (EOI), and 24 h after the first infusion (24H) from sixty patients with breast cancer receiving (80 mg/m2) weekly treatment. Neuropathy was assessed at BL and prior to each infusion using the sensory subscale (CIPN8) of the EORTC CIPN20 questionnaire. Blood metabolites were quantified from 1-D-1H-nuclear magnetic resonance spectra using Chenomx® software. Metabolite concentrations were normalized in preparation for Pearson correlation and one-way repeated measures ANOVA with multiple comparisons corrected by false discovery rate (FDR). RESULTS: Pretreatment histidine, phenylalanine, and threonine concentrations were inversely associated with maximum change in CIPN8 (ΔCIPN8) (p < 0.02; FDR ≤ 25%). Paclitaxel caused a significant change in concentrations of 2-hydroxybutyrate, 3-hydroxybutyrate, pyruvate, o-acetylcarnitine, and several amino acids from BL to EOI and/or 24H (p < 0.05; FDR ≤ 25%), although these changes were not associated with ΔCIPN8. CONCLUSIONS: Whole blood metabolomics is a feasible approach to identify potential biomarker candidates of paclitaxel-induced PN. The findings suggest that pretreatment concentrations of histidine, phenylalanine, and threonine may be predictive of the severity of future PN and paclitaxel-induced metabolic changes may be related to disruption of energy homeostasis.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Metabolômica , Paclitaxel/administração & dosagem , Doenças do Sistema Nervoso Periférico/sangue , Adulto , Idoso , Biomarcadores/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Feminino , Histidina/sangue , Humanos , Espectroscopia de Ressonância Magnética , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia , Fenilalanina/sangue , Treonina/sangue
17.
Am J Health Syst Pharm ; 75(10): 607-612, 2018 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-29748299

RESUMO

PURPOSE: The frequency and process for drug interaction (DI) screening at sites enrolling patients into SWOG clinical trials were studied. METHODS: Survey invitations were e-mailed to 180 SWOG head clinical research associates to determine the frequency of and personnel involved in DI assessment in subjects who were screened for and enrolled in clinical trials at their sites. Descriptive statistics were performed to evaluate the data. RESULTS: A total of 83 surveys recorded a response to at least 1 question, yielding an overall response rate of 46.1%. At least 72 completed surveys were submitted, for a completion rate of 40.0%. The majority of sites (51%) reported that DI screening only occurred during eligibility assessment when a DI was included in the protocol exclusion criteria. The pharmacist was "always" involved in DI screening during eligibility assessment at 17% of sites. Clinical research coordinators (56%) and research nurses (45%) were the predominant personnel who performed DI screening to assess eligibility for trial enrollment. A subset of sites (3-6%) reported not having access to a pharmacist. Fewer than 10% of sites reported that they "always" use drug information services, websites, resources, or literature searches, though many tools were used "often" or "sometimes" by more than 20% of sites. CONCLUSION: A survey revealed that DI screening was not being systematically conducted within SWOG clinical trials. When DI screening did occur, it was primarily conducted by clinical research coordinators or study nurses. Pharmacist-led DI screening was not the current practice within SWOG sites surveyed and was precluded by a lack of pharmacists' availability or involvement.


Assuntos
Ensaios Clínicos como Assunto/métodos , Interações Medicamentosas , Assistência Farmacêutica/organização & administração , Farmacêuticos/organização & administração , Humanos , Neoplasias/tratamento farmacológico , Papel Profissional , Inquéritos e Questionários
18.
J Oncol Pract ; 14(6): e368-e374, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29787332

RESUMO

PURPOSE: Patients with cancer are an especially vulnerable population to potential drug-drug interactions (DDIs). This makes it important to adequately screen them for DDIs. The objective of this study was to compare the abilities of nine DDI screening tools to detect clinically relevant interactions with oral oncolytics. METHODS: Subscription-based tools (ie, PEPID, Micromedex, Lexicomp, Facts & Comparisons) and free tools (ie, Epocrates Free, Medscape, Drugs.com, RxList, WebMD) were compared for their abilities to detect clinically relevant DDIs for 145 drug pairs including an oral oncology agent. Clinical relevance was determined by a pharmacist using Stockley's Drug Interactions. Descriptive statistics were calculated for each tool, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), and then compared grouped by free or subscription-based tools for the secondary analysis and analyzed via generalized estimating equations. RESULTS: For individual metrics, PPV had overall higher values (0.88 to 0.97) relative to the low values included for sensitivity (0.65 to 0.96), specificity (0.53 to 0.93) and NPV (0.38 to 0.83). The top-performing subscription and free tools, Lexicomp and Drugs.com, had no statistically significant differences in performance. Overall, subscription tools had a significantly higher sensitivity (0.85 ± 0.017 v 0.78 ± 0.017; P = .0082) and NPV (0.57 ± 0.039 v 0.48 ± 0.032; P = .031) than free tools. No differences were observed between the specificity and PPV. CONCLUSION: Due to the low performance of some tools for sensitivity, specificity, and NPV, individual performance should be examined and prioritized on the basis of the intended use when selecting a DDI tool. If a strong-performing subscription-based tool is unavailable, a strong-performing free option, like Drugs.com, is available.


Assuntos
Antineoplásicos/efeitos adversos , Serviços de Informação sobre Medicamentos , Interações Medicamentosas , Informática Médica/métodos , Administração Oral , Antineoplásicos/administração & dosagem , Humanos , Informática Médica/normas , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
19.
Pharmacogenomics ; 19(6): 563-576, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29629825

RESUMO

Tacrolimus is prescribed to the majority of transplant recipients to prevent graft rejection, and although patients are maintained on oral administration, nonoral routes of administration are frequently used in the initial post-transplant period. CYP3A5 genotype is an established predictor of oral tacrolimus dose requirements, and clinical guideline recommendations exist for CYP3A5-guided dose selection. However, the association between CYP3A5 and nonoral tacrolimus administration is currently poorly understood, and differs from the oral tacrolimus relationship. In addition to CYP3A5, other pharmacogenes associated with CYP3A activity, including CYP3A4, CYP3A7 and POR have also been identified as predictors of tacrolimus exposure. This review will describe the current understanding of the relationship between these pharmacogenes and tacrolimus pharmacokinetics after oral and nonoral administration.


Assuntos
Citocromo P-450 CYP3A/genética , Rejeição de Enxerto/genética , Transplante de Rim/efeitos adversos , Tacrolimo/efeitos adversos , Administração Oral , Vias de Administração de Medicamentos , Genótipo , Rejeição de Enxerto/complicações , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/patologia , Humanos , Testes Farmacogenômicos , Polimorfismo de Nucleotídeo Único/genética , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética
20.
Clin Cancer Res ; 24(15): 3602-3610, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-29703818

RESUMO

Purpose: Paclitaxel exposure, specifically the maximum concentration (Cmax) and amount of time the concentration remains above 0.05 µmol/L (Tc>0.05), has been associated with the occurrence of paclitaxel-induced peripheral neuropathy. The objective of this study was to validate the relationship between paclitaxel exposure and peripheral neuropathy.Experimental Design: Patients with breast cancer receiving paclitaxel 80 mg/m2 × 12 weekly doses were enrolled in an observational clinical study (NCT02338115). Paclitaxel plasma concentration was measured at the end of and 16-26 hours after the first infusion to estimate Cmax and Tc>0.05 Patient-reported peripheral neuropathy was collected via CIPN20 at each dose, and an 8-item sensory subscale (CIPN8) was used in the primary analysis to test for an association with Tc>0.05 Secondary analyses were conducted using Cmax as an alternative exposure parameter and testing each parameter with a secondary endpoint of the occurrence of peripheral neuropathy-induced treatment disruption.Results: In 60 subjects included in the analysis, the increase in CIPN8 during treatment was associated with baseline CIPN8, cumulative dose, and relative dose intensity (P < 0.05), but neither Tc>0.05 (P = 0.27) nor Cmax (P = 0.99). In analyses of the secondary endpoint, cumulative dose (OR = 1.46; 95% confidence interval (CI), 1.18-1.80; P = 0.0008) and Tc>0.05 (OR = 1.79; 95% CI, 1.06-3.01; P = 0.029) or Cmax (OR = 2.74; 95% CI, 1.45-5.20; P = 0.002) were associated with peripheral neuropathy-induced treatment disruption.Conclusions: Paclitaxel exposure is predictive of the occurrence of treatment-limiting peripheral neuropathy in patients receiving weekly paclitaxel for breast cancer. Studies are warranted to determine whether exposure-guided dosing enhances treatment effectiveness and/or prevents peripheral neuropathy in these patients. Clin Cancer Res; 24(15); 3602-10. ©2018 AACR.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/sangue , Idoso , Neoplasias da Mama/sangue , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Pessoa de Meia-Idade , Paclitaxel/sangue , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia , Resultado do Tratamento
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