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The evaluation of transporter-mediated drug-drug interactions (DDIs) during drug development and post-approval contributes to benefit-risk assessment and helps formulate clinical management strategies. The use of endogenous biomarkers, which are substrates of clinically relevant uptake and efflux transporters, to assess the transporter inhibitory potential of a drug has received widespread attention. Endogenous biomarkers, such as coproporphyrin (CP) I and III, have increased mechanistic understanding of complex DDIs. Other endogenous biomarkers are under evaluation, including, but not limited to, sulfated bile acids and 4-pyridoxic acid (PDA). The role of endogenous biomarkers has expanded beyond facilitating assessment of transporter-mediated DDIs and they have also been used to understand alterations in transporter activity in the setting of organ dysfunction and various disease states. We envision that endogenous biomarker-informed approaches will not only help to formulate a prudent and informed DDI assessment strategy but also facilitate quantitative predictions of changes in drug exposures in specific populations.
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The Commercially Insured health Plan Risk Index for Overdose or Serious Opioid-induced Respiratory Depression (CIP-RIOSORD) is an evidence-based tool to determine serious opioid-induced respiratory depression (OIRD) or overdose risk. The CIP-RIOSORD total score determines a risk class and estimates the probability for an OIRD event within the next 6 months. We performed a single-center, retrospective analysis to determine CIP-RIOSORD baseline scores and the most common predictive factors in patients with cancer. Patients (n = 160) were split into new consultations (n = 83, Group 1) versus the first documented follow-up consultation (n = 77, Group 2). Most patients were Caucasian women with metastatic gastrointestinal cancer. CIP-RIOSORD scores for Group 1 patients were 14.8 ± 15.2 (mean ± SD, risk class 4). Group 2 patients had higher CIP-RIOSORD scores (16.6 ± 14.9, risk class 4). For Group 1, the most common CIP-RIOSORD predictive factors were use of a long-acting opioid formulation (n = 24, 29%) and daily oral morphine equivalent (OME) ≥100 (n = 20, 24%); for Group 2, predictive factors were use of an antidepressant (n = 34, 44%) and a long-acting opioid formulation (n = 27, 35%). Based on the CIP-RIOSORD, there is a 15% probability of experiencing a serious OIRD event or overdose within the next 6 months.
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Analgésicos Opioides , Insuficiencia Respiratoria , Humanos , Femenino , Analgésicos Opioides/efectos adversos , Estudios Retrospectivos , Persona de Mediana Edad , Insuficiencia Respiratoria/inducido químicamente , Masculino , Anciano , Adulto , Dolor en Cáncer/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Factores de Riesgo , Sobredosis de Droga , Sobredosis de Opiáceos , Medición de RiesgoRESUMEN
OBJECTIVE: Fexofenadine is a probe drug used to phenotype P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3 activities. This study evaluated a limited sampling strategy using plasma concentrations and/or partial area under the concentration versus time curves (AUCs) to estimate systemic exposure and, potentially, P-gp and OATP1B1/3 activities. MATERIALS AND METHODS: Plasma concentration versus time data were obtained from 53 healthy adult participants (22 females) from four published studies. Participants were administered a single oral dose (120 mg) of fexofenadine during constitutive P-gp and OATP1B1/3 conditions. Concentration-time data were divided into a training (n = 18) and validation (n = 35) set. Backwards stepwise linear regression generated single-, 2-timepoint, and partial AUC limited sampling models (LSMs). Noncompartmental analysis methods were used to determine total AUC (AUC0-lNF) from intensive sampling. Coefficient of determination (r2) and bias and precision were assessed via relative percent mean prediction error (%MPE), relative percent mean absolute error (%MAE), and relative percent root mean square error (%RMSE). RESULTS: The geometric mean observed AUC0-INF was 1,680 ng×h/mL. The 2-, 5-, and 2- plus 5-hour LSMs met backwards stepwise linear regression significance (p < 0.15) to remain in the model but had unacceptable %RMSE (17 - 29%). The majority of partial AUC LSMs had unacceptable r2 (0.21 - 0.83), with all models having unacceptable %MAE (12 - 35%). CONCLUSION: Fexofenadine limited sampling strategy using single-timepoint, 2-timepoint, and partial AUCs were unable to accurately estimate AUC0-lNF and thus constitutive P-gp and OATB1B1/3 activities in healthy adults. Timepoints that were not measured or selected may have improved LSM performance.
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Fenotipo , Femenino , Humanos , Área Bajo la CurvaRESUMEN
BACKGROUND: Fexofenadine is a recommended in vivo probe drug for phenotyping P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) 1B1/3 transporter activities. This study evaluated a limited sampling strategy using a population pharmacokinetic approach to estimate plasma fexofenadine exposure as an index of P-gp and OATP activities. METHODS: In a previous study, a single oral dose of fexofenadine (120 mg) was administered alone or in combination with grapefruit juice, Panax ginseng , or Echinacea purpurea to healthy adult participants. Serial plasma samples were collected up to 72 hours after administration and fexofenadine concentrations were measured. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling. Limited sampling models (LSMs) using single and 2-timepoint fexofenadine concentrations were compared with full profiles from intense sampling using empirical Bayesian post hoc estimations of systemic exposure derived from the population pharmacokinetic model. Predefined criteria for LSM selection and validation included a coefficient of determination (R 2 ) ≥ 0.90, relative percent mean prediction error ≥ -5 to ≤5%, relative percent mean absolute error ≤ 10%, and relative percent root mean square error ≤ 15%. RESULTS: Fexofenadine concentrations (n = 1520) were well described using a 2-compartment model. Grapefruit juice decreased the relative oral bioavailability of fexofenadine by 25%, whereas P. ginseng and E. purpurea had no effect. All the evaluated single timepoint fexofenadine LSMs showed unacceptable percent mean prediction error, percent mean absolute error, and/or percent root mean square error. Although adding a second time point improved precision, the predefined criteria were not met. CONCLUSIONS: Identifying novel fexofenadine LSMs to estimate P-gp and OATP1B1/3 activities in healthy adults for future transporter-mediated drug-drug interaction studies remains elusive.
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Citrus paradisi , Transportadores de Anión Orgánico , Adulto , Humanos , Teorema de Bayes , Terfenadina/farmacocinética , Preparaciones FarmacéuticasRESUMEN
The chaplain is an essential member of the palliative care (PC) team, yet, standard methods to document chaplain assessments are lacking. The study team performed a retrospective analysis of chaplaincy documentation in an outpatient PC clinic at an academic medical center over 6 months (April 2017 to October 2017). The study team identified unique adult patients with cancer, then manually extracted variables from the electronic medical record. The primary objective was to assess the number of spiritual assessments documented by the chaplain. Secondary objectives included descriptive analysis of identified spiritual needs. Out of the 376 total patient encounters, 292 (77.8%) included documentation of a chaplain's spiritual assessment. The most frequent spiritual need was self-worth/community (n = 163, 55.8%).This study demonstrates that chaplains can effectively document Spiritual AIM-based screening and assessment. Moreover, this may be an effective documentation method across institutions to facilitate chaplain-based data.
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Servicio de Capellanía en Hospital , Neoplasias , Centros Médicos Académicos , Adulto , Servicio de Capellanía en Hospital/métodos , Clero , Documentación , Humanos , Neoplasias/terapia , Estudios Retrospectivos , EspiritualidadRESUMEN
The trillions of microbes that make up the gut microbiome are an important contributor to health and disease. With respect to xenobiotics, particularly orally administered compounds, the gut microbiome interacts directly with drugs to break them down into metabolic products. In addition, microbial products such as bile acids interact with nuclear receptors on host drug-metabolizing enzyme machinery, thus indirectly influencing drug disposition and pharmacokinetics. Gut microbes also influence drugs that undergo enterohepatic recycling by reversing host enzyme metabolic processes and increasing exposure to toxic metabolites as exemplified by the chemotherapy agent irinotecan and non-steroidal anti-inflammatory drugs. Recent data with immune checkpoint inhibitors demonstrate the impact of the gut microbiome on drug pharmacodynamics. We summarize the clinical importance of gut microbe interaction with digoxin, irinotecan, immune checkpoint inhibitors, levodopa, and non-steroidal anti-inflammatory drugs. Understanding the complex interactions of the gut microbiome with xenobiotics is challenging; and highly sensitive methods such as untargeted metabolomics with molecular networking along with other in silico methods and animal and human in vivo studies will uncover mechanisms and pathways. Incorporating the contribution of the gut microbiome to drug disposition, pharmacokinetics, and pharmacodynamics is vital in this era of precision medicine.
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Microbioma Gastrointestinal , Animales , Humanos , Medicina de Precisión , XenobióticosRESUMEN
PURPOSE: S-warfarin is used to phenotype cytochrome P450 (CYP) 2C9 activity. This study evaluated S-warfarin limited sampling strategy with a population pharmacokinetic (PK) approach to estimate CYP2C9 activity in healthy adults. METHODS: In 6 previously published studies, a single oral dose of warfarin 10 mg was administered alone or with a CYP2C9 inducer to 100 healthy adults. S-warfarin concentrations were obtained from adults during conditions when subjects were not on any prescribed medications. A population PK model was developed using non-linear mixed effects modeling. Limited sampling models (LSMs) using single- or 2-timepoint concentrations were compared with full PK profiles from intense sampling using empiric Bayesian post hoc estimations of S-warfarin AUC derived from the population PK model. Preset criterion for LSM selection and validation were a correlation coefficient (R2) >0.9, relative percent mean prediction error (%MPE) >-5 to <5%, relative percent mean absolute error (%MAE) ≤ 10%, and relative percent root mean squared error (%RMSE) ≤ 15%. RESULTS: S-warfarin concentrations (n=2540) were well described with a two-compartment model. Mean apparent oral clearance was 0.56 L/hr and volume of distribution was 35.5 L. Clearance decreased 33% with the CYP2C9 *3 allele and increased 42% with lopinavir/ritonavir co-administration. During CYP2C9 constitutive conditions, LSMs at 48 hr and at 72 hr as well as 2-timepoint LSMs were within acceptable limits for R2, %MPE, %MAE, and %RMSE. During CYP2C9 induction, S-warfarin LSMs had unacceptable %MPE, %MAE, and %RMSE. CONCLUSIONS: Phenotyping studies with S-warfarin in healthy subjects can utilize a single- and/or a 2-timepoint LSM with a population PK approach to estimate constitutive CYP2C9 activity.
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Inductores del Citocromo P-450 CYP2C9/farmacología , Citocromo P-450 CYP2C9/metabolismo , Lopinavir/farmacología , Modelos Biológicos , Ritonavir/farmacología , Warfarina/farmacología , Factores de Edad , Área Bajo la Curva , Teorema de Bayes , Citocromo P-450 CYP2C9/genética , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Femenino , Genotipo , Voluntarios Sanos , Humanos , Masculino , Tasa de Depuración Metabólica , Fenotipo , Factores Sexuales , Warfarina/administración & dosificaciónRESUMEN
PURPOSE: Advance care planning (ACP) is a clinical skill that can be taught. An opportunity exists to teach how to conduct ACP to clinicians not typically engaged in these conversations to increase the likelihood that patients and caregivers engage in ACP. We conducted a prospective study exploring the feasibility of a pharmacist-led ACP intervention. METHODS: We completed a prospective, single-center study from July 2015 to July 2017. We included patients of age ≥ 18 years with incurable cancer referred to the palliative care clinic. A trained pharmacist led an ACP discussion with the patient and selected proxy. We defined feasibility as completion of ≥ 30 pharmacist-led ACP discussions over the study period. Additionally, we defined an informed healthcare proxy as someone who understood three key end-of-life (EOL) treatment preferences: the patient's personal definition of quality of life, desired resuscitation status, and preferred location of death (in or out of the hospital). Patients were followed until the end of the study or death. For those patients who died, the pharmacist contacted the proxy for follow-up and explored satisfaction with the ACP intervention. RESULTS: Thirty-four patients completed the study. All selected proxies completed the intervention and were able to understand the three EOL preferences. At the time of the patient's death (n = 20), proxies reported that 66.6% received their preferred resuscitation status and 72.2% died in their preferred location. Proxy satisfaction with the ACP process was 7.6 ± 2.5 (mean ± SD) on a 11-point Likert scale. CONCLUSION: These findings indicate the potential for pharmacists to lead and engage in ACP in the outpatient setting.
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Planificación Anticipada de Atención , Farmacéuticos , Adolescente , Directivas Anticipadas , Humanos , Estudios Prospectivos , Calidad de VidaRESUMEN
Determining factors that contribute to interindividual and intra-individual variability in pharmacokinetics (PKs) and drug metabolism is essential for the optimal use of drugs in humans. Intestinal microbes are important contributors to variability; however, such gut microbe-drug interactions and the clinical significance of these interactions are still being elucidated. Traditional PKs can be complemented by untargeted mass spectrometry coupled with molecular networking to study the intricacies of drug metabolism. To show the utility of molecular networking on metabolism we investigated the impact of a 7-day course of cefprozil on cytochrome P450 (CYP) activity using a modified Cooperstown cocktail and assessed plasma, urine, and fecal data by targeted and untargeted metabolomics and molecular networking in healthy volunteers. This prospective study revealed that cefprozil decreased the activities of CYP1A2, CYP2C19, and CYP3A, decreased alpha diversity and increased interindividual microbiome variability. We further demonstrate a relationship between the loss of microbiome alpha diversity caused by cefprozil and increased drug and metabolite formation in fecal samples. Untargeted metabolomics/molecular networking revealed several omeprazole metabolites that we hypothesize may be metabolized by both CYP2C19 and bacteria from the gut microbiome. Our observations are consistent with the hypothesis that factors that perturb the gut microbiome, such as antibiotics, alter drug metabolism and ultimately drug efficacy and toxicity but that these effects are most strongly revealed on a per individual basis.
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Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Microbioma Gastrointestinal/efectos de los fármacos , Omeprazol/farmacocinética , Adulto , Anciano , Antibacterianos/administración & dosificación , Cefalosporinas/administración & dosificación , Estudios Cruzados , Citocromo P-450 CYP1A2/genética , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Interacciones Farmacológicas , Heces/microbiología , Femenino , Voluntarios Sanos , Humanos , Masculino , Metabolómica , Persona de Mediana Edad , Omeprazol/administración & dosificación , Pruebas de Farmacogenómica , Variantes Farmacogenómicas , Estudios Prospectivos , Adulto Joven , CefprozilRESUMEN
PURPOSE: Opioid-induced constipation (OIC) is a distressing physical symptom for patients with cancer taking opioids. Total opioid consumption may contribute to developing worsening OIC-related symptoms. We completed a retrospective analysis examining the association of total daily opioid consumption on self-reported constipation in patients with cancer. METHODS: In over 5 clinic visits, we collected self-reported constipation scores and 24-h oral morphine equivalents (OME). We examined the association between OME and the presence of constipation (i.e., score > 3) and the relationship of OME between patients with or without constipation. RESULTS: Of 297 patients with cancer, we observed 57.8% with constipation and 42.4% without constipation at the first clinic visit. Age was similar in both groups (54.2 ± 14.5 vs. 56.4 ± 14.8 years [mean ± SD]) and the majority of patients were women (63.7% vs. 61.1%). The most common cancer type in patients with constipation was non-colorectal gastrointestinal (n = 25, 14.6%), while in patients without constipation was colorectal gastrointestinal (n = 25; 19.8%). Across visits, we observed weak or no association between OME and self-reported constipation (r = 0.01-0.27). At the first visit, higher mean OME was seen in patients who self-reported constipation (133.4 vs 76; p < 0.05). Age, sex, metastatic disease, and stimulant laxative use were not associated with constipation. CONCLUSIONS: We observed weak to no association between OME and constipation in patients with cancer. These results suggest a lack of a clear association between total opioid consumption and self-reported constipation.
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Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Dolor en Cáncer/tratamiento farmacológico , Estreñimiento Inducido por Opioides/etiología , Administración Oral , Adulto , Anciano , Dolor en Cáncer/epidemiología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Morfina/administración & dosificación , Morfina/efectos adversos , Neoplasias/tratamiento farmacológico , Neoplasias/epidemiología , Estreñimiento Inducido por Opioides/epidemiología , Estudios Retrospectivos , Autoinforme/estadística & datos numéricosRESUMEN
INTRODUCTION: The scope of pharmacy practice has evolved over the last few decades to focus on the optimization of medication therapy. Despite this positive impact, the lack of reimbursement remains a significant barrier to the implementation of innovative pharmacist practice models. SUMMARY: We describe the successful development, implementation and outcomes of three types of pharmacist collaborative care models: (1) a pharmacist with physician oversight, (2) pharmacist-interprofessional teams and (3) physician-pharmacist teams. The outcome measurement of these pharmacist care models varied from the design phase to patient volume measurement and to comprehensive quality dashboards. All of these practice models have been successfully funded by affiliated health systems or grants. CONCLUSIONS: The expansion of pharmacist services delivered by clinical faculty has several benefits to affiliated health systems: (1) significant improvements in patient care quality, (2) access to experts in specialty areas, and (3) the dissemination of outcomes with national and international recognition, increasing the visibility of the health system.
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We have previously described a midazolam limited sampling strategy employing a population pharmacokinetic (PK) approach to estimate constitutive cytochrome P450 (CYP) 3A activity. This study evaluated expansion of this approach to estimate CYP3A constitutive, inhibitory, and induction activities. Midazolam concentrations (n = 4441) from adults (n = 152) were obtained from previous studies after single, oral, or intravenous administration with intensive sample collection. Data were fit to a 2-compartment population PK model that incorporated CYP3A conditions as covariates for clearance (CL), volume of distribution, and bioavailability (F). Limited sampling models using single- or 2-time point concentrations were compared with full PK profiles using the empiric Bayesian post hoc estimations of midazolam area under the plasma concentration-time curve derived from the population PK model. Ketoconazole, rifampin, and pleconaril were significant covariates of CL, while ketoconazole, rifampin, and grapefruit juice were significant covariates for F. Typical midazolam CL and F estimates were 32.9 L/h and 0.31 for the constituent state, while the ratio of inducer/inhibitor for midazolam CL and CL/F for the induced/inhibited (rifampin/ketoconazole) states were 14.2 and 85.3. Upon comparison to the population PK model, the majority of evaluated single- and 2-time point limited sampling models estimated area under the plasma concentration-time curve had unacceptable r2 and/or unacceptable bias and precision. Exclusively during CYP3A inhibitory conditions, the 4- and 6-hour limited sampling model had acceptable limits of r2 , bias, and precision. Consequently, development of a single- or 2-time point midazolam limited sampling model for general, widespread use to simultaneously evaluate various CYP3A conditions remains elusive.
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Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/efectos de los fármacos , Citocromo P-450 CYP3A/metabolismo , Midazolam/farmacocinética , Administración Oral , Adulto , Área Bajo la Curva , Teorema de Bayes , Disponibilidad Biológica , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Femenino , Humanos , Inyecciones Intravenosas , Cinética , Masculino , Midazolam/administración & dosificaciónAsunto(s)
Analgésicos Opioides/administración & dosificación , Antineoplásicos/efectos adversos , Benzodiazepinas/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Náusea/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Dolor en Cáncer/tratamiento farmacológico , Esquema de Medicación , Femenino , Humanos , Persona de Mediana Edad , Náusea/inducido químicamente , Vómitos/inducido químicamente , Vómitos/tratamiento farmacológicoRESUMEN
OBJECTIVE: To review effective approaches for non-pain symptom management for cancer patients focusing on treatment of nausea and vomiting, constipation, diarrhea, anorexia/cachexia, fatigue, and dyspnea. DATA SOURCES: Peer-reviewed articles, clinical practice guidelines, professional organization position statements. CONCLUSION: Oncology nurses are key advocates for optimal symptom management. Maximizing palliation of symptoms improves quality of life and prolongs survival. IMPLICATIONS FOR NURSING PRACTICE: To provide an evidence-based approach to symptom management, oncology nurses require a deep understanding of symptom pathophysiology while anticipating side effects, educating patients and caregivers, considering psychosocial/spiritual factors, exploring treatment expectations, and clarifying goals of treatment.
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Enfermería de Cuidados Paliativos al Final de la Vida/organización & administración , Neoplasias/enfermería , Rol de la Enfermera , Enfermería Oncológica/organización & administración , Manejo del Dolor/enfermería , Cuidados Paliativos/organización & administración , Atención Integral de Salud/organización & administración , Humanos , Relaciones Enfermero-Paciente , Calidad de la Atención de SaludRESUMEN
BACKGROUND: Limited sampling strategy (LSS) is a validated method to estimate pharmacokinetic (PK) parameters from a reduced number of samples. Omeprazole is used to phenotype in vivo cytochrome P450 (CYP) 2C19 activity. This study examined an LSS using 2 estimation methods to determine apparent oral clearance (CL/F) and thus CYP2C19 activity. METHODS: Data from 7 previously published studies included healthy subjects receiving a single, oral dose of omeprazole with intensive PK sampling. CL/F was estimated using noncompartmental analysis (NCA) and population PK modeling. LSS was simulated by selecting the 1, 2, 4, and/or 6-hour postdose time points. Linear regression was performed to assess whether CL/F estimated from limited sampling could accurately predict CL/F from the full PK profile. RESULTS: Median CL/F was 23.7 L/h by NCA and 19.3 L/h by population PK modeling. In comparing the LSS NCA estimated versus observed CL/F, all evaluated linear regression models had unacceptable coefficients of determination (r, range: 0.14-0.81). With the population PK approach, 737 plasma concentrations (n = 71) and CYP2C19 genotype data were described with a 1-compartment structural model with mixed zero and first-order absorption and lag time. In comparing the population PK LSS estimated versus observed CL/F, all evaluated linear regression models had unacceptable r (range: 0.02-0.74). Post hoc comparison of CYP2C19 poor metabolizers versus CYP2C19 extensive metabolizers resulted in significantly lower CL/F in poor metabolizers versus extensive metabolizers. CONCLUSIONS: Omeprazole LSS performed poorly in estimating CL/F using 2 separate estimation approaches and does not seem to be a suitable method for determining CYP2C19 activity.
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Citocromo P-450 CYP2C19/metabolismo , Omeprazol/farmacocinética , Tamaño de la Muestra , Adulto , Antiulcerosos/sangre , Antiulcerosos/farmacocinética , Simulación por Computador , Citocromo P-450 CYP2C19/genética , Genotipo , Voluntarios Sanos , Humanos , Modelos Biológicos , Omeprazol/sangreRESUMEN
Pain is a significant physical symptom that can be observed across the spectrum of hematopoietic stem cell transplant (HSCT) care. Pain assessment should include evaluation of the physical and functional components of pain. Management varies based on the type of HSCT-specific pain syndrome. Future directions for management of pain syndromes include the early integration of palliative care. The purpose of this review is to summarize various pain syndromes and management approaches in adult HSCT patients.
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Trasplante de Células Madre Hematopoyéticas , Manejo del Dolor/métodos , Dolor , Enfermedades del Sistema Nervioso Periférico , Adulto , Humanos , Dolor/etiología , Dolor/fisiopatología , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Enfermedades del Sistema Nervioso Periférico/terapia , SíndromeRESUMEN
Midazolam is the preferred probe to phenotype cytochrome P450 (CYP) 3A activity. This study evaluated a single-concentration, midazolam limited sampling strategy utilizing a population pharmacokinetic (PK) approach to estimate area under the curve, and thus CYP3A activity. Midazolam concentrations from adults during CYP3A constitutive conditions were obtained from previous studies after single, oral or intravenous administration. Population PK modeling was conducted by nonlinear mixed-effects modeling. Potential covariates of clearance, volume of distribution, and bioavailability were evaluated. A limited sampling model at 1, 2, 4, or 6 hours was selected and fitted with post hoc estimation with the final population PK model. Preset criterion for the limited sampling model selection was a coefficient of determination ≥0.9. Bias and precision were also evaluated. The studies provided 2122 observations from 152 healthy adults. Midazolam concentrations were adequately described by a two-compartment model with first order absorption. Age and sex were significant covariates of central volume (V2 ) and were retained in the final model. An estimate (interindividual variability) of midazolam clearance was 32.5 L/hr (52.9%), covariate of central volume was 67 L (39.1%), and oral bioavailability was 0.33 (45.5%). The final population parameter estimates were within the 95% confidence intervals and were similar to the median bootstrap estimates. Upon comparison to the population PK model, the 4-hour limited sampling model estimated area under the curve had an acceptable coefficient of determination and acceptable bias and precision limits. A 4-hour, but not the 1-, 2-, and 6-hour, single concentration accurately estimated midazolam area under the curve during constitutive CYP3A conditions in healthy adults.
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Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Hipnóticos y Sedantes/farmacocinética , Midazolam/farmacocinética , Adulto , Área Bajo la Curva , Femenino , Humanos , Hipnóticos y Sedantes/metabolismo , Masculino , Midazolam/metabolismo , Persona de Mediana Edad , Modelos BiológicosRESUMEN
PURPOSE: Limited data exist regarding transfusion practices at end of life (EOL) for hematopoietic stem cell transplant (HSCT) patients. The purpose of this study was to examine red blood cell (RBC) and platelet transfusion practices in HSCT patients who enrolled or did not enroll in hospice. METHODS: This was a single-center, retrospective chart review in deceased HSCT patients. The primary objective was to determine the mean difference between the last transfusion and death in HSCT patients (n = 116) who enrolled or did not enroll in hospice. RESULTS: Sixteen (14%) and 100 (86%) patients were enrolled in hospice and not enrolled in hospice, respectively. Hospice patients observed a larger mean difference between death and last transfusion (45.9 ± 66.7 vs. 14.6 ± 48.1 days, p < 0.0001). A higher amount of platelet, but not RBC, transfusions occurred in patients not enrolled in hospice (p = 0.04). The last transfusion that occurred more than 96 h before death was observed in 12 (75%) and 22 (22%) in hospice and non-hospice patients, respectively. For HSCT patients not enrolled in hospice, 17 patients received a transfusion on the same day of death and 31 patients received the last transfusion 24 h before death. CONCLUSIONS: Blood transfusion practices differed in HSCT patients enrolled and not enrolled in hospice. For most patients not enrolled in hospice, the last transfusion occurred 24 h before death. Future efforts should explore if limited access to blood products is a barrier to hospice enrollment for HSCT patients.
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Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Transfusión de Plaquetas , Pautas de la Práctica en Medicina , Cuidado Terminal/métodos , Receptores de Trasplantes , Adulto , Anciano , Femenino , Neoplasias Hematológicas/epidemiología , Trasplante de Células Madre Hematopoyéticas/estadística & datos numéricos , Cuidados Paliativos al Final de la Vida/métodos , Cuidados Paliativos al Final de la Vida/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Transfusión de Plaquetas/estadística & datos numéricos , Pautas de la Práctica en Medicina/estadística & datos numéricos , Estudios Retrospectivos , Cuidado Terminal/estadística & datos numéricos , Receptores de Trasplantes/estadística & datos numéricosRESUMEN
PURPOSE: Advance care planning (ACP) in hematopoietic stem-cell transplantation (HSCT) is challenging, given the potential for cure despite increased morbidity and mortality risk.The aim of this study was to evaluate ACP and palliative care (PC) integration for patients who underwent HSCT. METHODS: A retrospective analysis was conducted and data were extracted from electronic medical records of patients who underwent HSCT between January 2011 and December 2015. Patients who received more than one transplant and who were younger than 18 years of age were excluded. The primary objective was to determine the setting and specialty of the clinician who documented the initial and final code status. Secondary objectives included evaluation of advance directive and/or completion of the Physician Orders for Life-Sustaining Treatment form, PC consultation, hospice enrollment, and location of death. RESULTS: The study sample comprised 39% (n = 235) allogeneic and 61% (n = 367) autologous HSCTs. All patients except one (n = 601) had code status documentation, and 99.2% (n = 596) were initially documented as full code. Initial and final code status documentation in the outpatient setting was 3% (n = 17) and 24% (n = 143), respectively. PC consultation occurred for 19% (n = 114) of HSCT patients, with 83% (n = 95) occurring in the hospital. Allogeneic transplant type and age were significantly associated with greater rates of advance directive and/or Physician Orders for Life-Sustaining Treatment completion. Most patients (85%, n = 99) died in the hospital, and few were enrolled in hospice (15%, n = 17). CONCLUSION: To our knowledge, this is the largest single-center study of ACP and PC integration for patients who underwent HSCT. Code status documentation in the outpatient setting was low, as well as utilization of PC and hospice services.