Quantitative and qualitative control of antineoplastic preparations: Gravimetry versus HPLC.

This article compares gravimetry vs. high-performance liquid chromatography (HPLC) as quality control (QC) methods for paclitaxel, docetaxel and oxaliplatin preparations. We aimed at assessing the preparation method reliability in our hospital, evaluating compounding accuracy and estimating the influence of personnel training and standardized homogenization on compounding accuracy. Agreement, correlation, concordance, accuracy and precision between methods were evaluated for each drug. Conforming preparation percentages (CPs) at different tolerance limits (TLs) and compounding accuracy were calculated for each method and drug. Compounding accuracy was compared before and after personnel training and standardized homogenization implantation. SPSS v 20.0 and Ene v 2.0 were used. A total of 222 samples (58 docetaxel, 95 paclitaxel and 69 oxaliplatin) were analyzed. Gravimetry and HPLC are comparable methods. Overall CP was 81% for gravimetry at 10% TL and 85% for HPLC at 15% TL. Compounding accuracy is shown to be good for all methods and drugs. Homogenization optimization and personnel training make measurements more accurate for docetaxel and paclitaxel HPLC, but seem to worsen accuracy for docetaxel gravimetry. Gravimetry has shown to be a good alternative to HPLC for routine QC. Coupling with electronic methods should be considered in the future.

Comparative cost-effectiveness of bevacizumab-irinotecan-fluorouracil versus irinotecan-fluorouracil in first-line metastatic colorectal cancer.

PURPOSE: To evaluate the cost-effectiveness of the addition of bevacizumab to the irinotecan-fluorouracil (Douillard regimen-CPT-FUFA-) in first-line treatment of metastatic colorectal cancer in a single-institution population. METHODS: Controlled, nonrandomized retrospective observational study. Treatment-naïve metastatic colorectal cancer patients received CPT-FUFA (January 2000-December 2003; control group) and bevacizumab_CPT-FUFA (January 2007-December 2010; study group). Variables related to: patient, clinical response (number of disease progression or death events, progression-free survival) and treatment (antineoplastic dose reduction, incremental cost/treated patient associated with the addition of bevacizumab). STATISTICAL ANALYSIS: median progression-free survival (Kaplan-Meier method), and hazard ratio (Cox regression). Survival curves were compared (Mantel-Haenszel test). RESULTS: In all, 69 patients were included: 32 (57.2 years -95%CI: 54.0-60.5-, 65.6% men) in CPT-FUFA group and 37 (68.1 years - 95%CI: 65.5-70.7-, 78.4% men) in bevacizumab_CPT-FUFA group. The disease progression or death events were 29 (90.6%) in CPT-FUFA group and 34 (91.9%) in bevacizumab_CPT-FUFA group. Median progression-free survival was 10.1 months (95%CI: 7.1-12.2) in CPT-FUFA and 11.0 months (95%CI: 7.6-12.6) in bevacizumab_CPT-FUFA (hazard ratio = 1.22; 95%CI: 0.7-2.1). Dose reductions: irinotecan and fluorouracil 11% (range: 4-20) in 5/32 (15.6%) CPT-FUFA patients and 25% (range: 8-35) in 18/37 (48.6%) bevacizumab_CPT-FUFA patients; Bevacizumab 30% (range: 4-50) in 20/37 (54.1%) bevacizumab_CPT-FUFA patients. The incremental cost associated with the addition of bevacizumab was 12,696.5 (IC95%:10,860.8-14,532.1) euros/patient. CONCLUSION: The addition of bevacizumab to the irinotecan-fluorouracil regimen, does not improve progression-free survival in our study population but increases costs per treated patient. These results potentially compromise the cost-effectiveness of the Bevacizumab_CPT-FUFA regimen.

Effect of age on systemic exposure and haematological toxicity of carboplatin in advanced non-small cell lung cancer patients.

The aim of this study was to evaluate systemic exposure to carboplatin and its haematological toxicity in patients with advanced non-small cell lung cancer both older and younger than 70 years when the target area under the curve (AUC) in elderly patients was reduced by 20%. For this purpose, a population pharmacokinetic model was developed and the haematological toxicity of the drug was assessed. A total of 33 patients received carboplatin on day 1 and gemcitabine (1250 mg/m(2) ) on days 1 and 8. This schedule was repeated every 21 days. The Calvert-Crokcoft-Gault formula was employed to calculate a dose of carboplatin with a target AUC of 5 mg/min./mL in patients under 70 years and 4 mg/min./mL in patients aged 70 or older. The data of 24 patients were treated for population modelling performed with the nonmem (University of California, San Francisco, CA, USA) approach. Haematological toxicity was evaluated for all 33 patients enrolled in the study. The carboplatin systemic exposure measured by the AUC (mg/min./mL) was 5.98 (5.45; 6.51) and 5.36 (5.02; 5.69) for the younger patients and older groups, respectively. No significant differences were observed between the two groups with respect to rates of grade 3+ anaemia, neutropenia or thrombocytopenia. In clinical practice, a target AUC of 4 mg/min./mL carboplatin is applied to patients aged 70 and over, but the actual systemic exposure to the drug is higher. This supports a target AUC of 4 mg/min./mL carboplatin for patients older than 70 years when the dose is calculated by means of the Calvert-Crokcoft-Gault formula.

Impact of nutritional status on the oral bioavailability of leucine administered to rats as part of a standard enteral diet.

BACKGROUND: To investigate the absorption and relative bioavailability of leucine administered orally as part of an enteral diet in well and malnourished animals. METHODS: Two groups - RN (regular nutrition) and PCR (protein-calorie restricted) - were fed with different diets for 23-25 days. Rats from each group were assigned randomly to one of three treatments (water, T-Diet Plus Standard(®) (problem) or Isosource ST(®) (reference)) administered in single (N = 76) or multiple (N = 39) doses. Blood samples were assayed for leucine content. Area under the curve (AUC) was calculated by non-compartmental analysis. Log-transformed AUC(s) were statistically compared by analysis of variance, and 90% confidence intervals (CI 90%) of the ratio of the log-transformed AUC(s) between problem and reference diets, and between enteral diet and water were determined. RESULTS: The AUC (last) between the problem and reference diets was not statistically different. 90% CIs for single and multiple doses were 58.4-137.5% and 78-134.6% for RN and 76.7-172.2% and 72-167.2% for PCR, respectively. Leucine absorption was 12% higher among malnourished animals when multiple doses were administered, but the differences detected were not statistically different. CONCLUSIONS: In spite of the different composition of proteins in the enteral diets tested, the absorption of leucine, even though slightly higher in the malnourished state, is similar in both of them.

Potential risk of medication discrepancies and reconciliation errors at admission and discharge from an inpatient medical service.

BACKGROUND: Medication discrepancies, defined as unexplained variations among drug regimens at care transitions, are common. Some are unintended and cause reconciliation errors that are potentially detrimental for patients. OBJECTIVE: To determine the prevalence of medication discrepancies and reconciliation errors at admission and discharge in hospitalized patients and explore risk factors for reconciliation errors and their potential clinical impact. METHODS: An observational prospective study was conducted at a general teaching hospital. Patients who were admitted to the internal medicine service and were receiving chronic preadmission treatment were included in the study. Preadmission treatment was compared with the treatment prescribed on admission (first 48 hours) and at hospital discharge, and discrepancies and reconciliation errors were identified. The primary endpoint was the presence of reconciliation errors at admission and/or discharge. Potential risk factors (patient-, medication-, and system-related) for reconciliation errors were analyzed using a multivariate logistic regression model. RESULTS: Of the 120 patients enrolled in the study between April and August 2009, 109 (90.8%) showed 513 discrepancies. The prevalence of patients with reconciliation errors was 20.8% (95% CI 13.6 to 28.1). Intended medication discrepancies were more frequent at admission (96.6%) than at discharge (75.5%), while reconciliation errors were more frequent at discharge (24.5%) than at admission (3.4%). The prevalence ratio (admission vs discharge) was 2.4 (95% CI 1.9 to 3.0) for discrepancies and 0.65 (95% CI 0.32 to 1.32) for reconciliation errors. The logistic regression analysis revealed an association between the number of discrepancies at admission (OR 1.21; 95% CI 1.01 to 1.44) and age (OR 1.05; 95% CI 0.99 to 1.10) and an increased risk of reconciliation errors. CONCLUSIONS: Medication reconciliation strategies should focus primarily on avoiding errors at discharge. Since medication discrepancies at admission may predispose patients to reconciliation errors, early detection of such discrepancies would logically reduce the risk of reconciliation errors. Medication reconciliation programs must implement a process for gathering accurate preadmission drug histories and must submit this information to a critical assessment of patients' needs.

Multidisciplinary system for detecting medication errors in antineoplastic chemotherapy.

OBJECTIVE: To analyze medication errors (MEs) in a multidisciplinary system with a Computerized Pharmacotherapy Process (CPP) in cancer patients. DESIGN: A longitudinal, prospective 2-year (January 2003 -to December 2004) cohort study was made in adult patients administered antineoplastic treatment in Services of Oncology and Haematology. MEs were identified by double cross-validation of each stage of the pharmacotherapeutic process (prescription, preparation, dispensing, administration, and follow-up) carried out by the multidisciplinary team (physician, pharmacist, nurse) with CPP assistance. VARIABLES: Number of MEs per 1000 patient-days, percentage according to the stage of the pharmacotherapeutic process and the severity of intercepted ME (scored from 1 = no damage to the patient, to 5 = patient death). RESULTS: A total of 1311 patients were receiving treatment, and MEs were identified in 225. Out of a total of 13,158 patient-days, 276 MEs were detected, equivalent to 20.9 MEs per 1000 patient-days; of these, 16.8 MEs per 1000 patient-days (80%) were intercepted and did not affect any patient. The detected ME distribution according to pharmacotherapeutic stage was: prescription 75.7%, preparation 21.0%, dispensing 1.8%, administration 1.1%, and follow-up 0.4%. ME distribution according to severity was: grade 1 : 15.9%, grade 2 : 49.6%, grade 3 : 33.7%, grade 4 : 0.7%, and grade 5 : 0%. The system intercepted 98.9% of all MEs with severity >or=3 (MEs with a potential for causing patient damage). CONCLUSIONS: The multidisciplinary system with a well-established CPP detects 20.9 MEs per 1000 patient-days and intercepts 98.8% of all MEs with a potential for causing patient damage.

Individualización de Carboplatino en el anciano con cáncer de pulmón no microcítico avanzado / Individual dosing of carboplatin in elderly patients with advanced non small cell lung cancer

El cáncer de pulmón no microcítico (CPNM) se diagnostica mayoritariamenteen pacientes mayores de 65 años. Los pacientes ancianos presentan una elevadacomorbilidad asociada al tratamiento antineoplásico que demanda la individualizaciónde las pautas posológicas. Las opciones de tratamiento son abundantes y elcarboplatino (CbPt) se encuentra entre los fármacos de primera línea. La dosis de CbPt se establece con la fórmula de Calvert (estándar) que requiere la medidaexacta de la función renal.El objetivo de este trabajo es aportar un modelo farmacocinético que permitaindividualizar las dosis de CbPt en ancianos con CPNM avanzado y evaluar suexactitud y precisión respecto al estándar.Los modelos farmacocinéticos para el CbPt no unido a las proteínas plasmáticas,obtenidos con las concentraciones plasmáticas de una población de 24 pacientesvarones con CPNM, indican que la edad es la covariable biométrica más estrechamenterelacionada con el aclaramiento plasmático de CbPt, sin dejar por ellode ser un factor de confusión. El error relativo medio (ERM) de la dosis ha sidopara los pacientes adultos (edad < 65 años) del 5% (1-9%) y para los pacientesancianos del 25% (19-30%). Por consiguiente, la dosificación de CbPt con la fórmulade Calvert conduce a una sobredosificación en los pacientes ancianos, produciendomayor exposición al fármaco de la deseada. El alcance clínico de estoshallazgos requiere su validación en una nueva población de pacientes

Non small cell lung cancer (NSCLC) is frequently diagnosed in patients olderthan age 65 years. Elderly patients often have comorbidities associated with theantineoplasic treatment that request individualization of the chemotherapy. Treatmentoptions are numerous and carboplatin (CbPt) is in the first line of treatment.Conventional doses of CbPt are individually adjusted applying the Calvert formulae(standar) that demands the accurate measure of renal function.The aim of this study is to develop a pharmacokinetic model in order to individualisethe dose of CbPt in elderly patients in advanced NSCLC, and to characterizeits bias and precision respect to the standard.The pharmacokinetic models for the unbound fraction of CpPt were obtainedfrom concentration-time data of ultrafiltrate plasma samples of twenty-four advancedNSCLC men patients enrolled in the study. Age was significantly related to thecarboplatin clearance, although is a confusion factor. The mean dose error, inpercentage, was 5% (1-9%) in adult patients (Age< 65 years) and 25% (19-30%) inelderly patients. Consequently, CbPt the dose regimen in enderly patients, establishedby means of Calvert’s formula is overestimated and the exposure to the antineoplasticis higher than desired. The clinical relevance of these results requiresthe validation of the model with a new population group

Compromiso del farmacéutico con la calidad farmacoterapéutica y la seguridad del paciente / Pharmacists´ commitment to pharmacotherapeutic quality and patient safety

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Pharmaceutical validation as a process of improving the quality of antineoplastic treatment.

OBJECTIVE: To quantify the improvement added by standardization of pharmaceutical validation (PV) of antineoplastic treatment to the processes of prescription and preparation of the pharmacotherapeutic sequence, in terms of prevention and reduction of medication errors (ME). DESIGN: Prospective cohort study during two years (from 2001-2002) for oncohaematologic patients (inpatients and outpatients) that compared the percentage of medication errors detected and resolved and the number of medication errors with potential clinical significance (severity value >or=4) intercepted during PV in both years. RESULTS: During the PV processes, 202 ME were identified and resolved, which is the equivalent of 16.88 ME/1,000 patient-days. In 2001 14.08 ME/1,000 patient-days were detected and 19.83 ME/1,000 patient-days in 2002. This means that the effectiveness of the identification method increased by 41%. The number of ME intercepted with clinical significance (severity value >or=4) increased in a statistically significant manner by 2.18 times in 2002. CONCLUSION: This study shows that the standardization of PV is an effective method of improving the quality of antineoplastic treatment use, by increasing the ability to intercept ME.

Procedimientos para la práctica clínica orientada a problemas farmacoterapéuticos / Clinical practice procedures oriented to Pharmaco-therapeutic problems

La normalización de la metodología para la práctica clínica orientada a problemas terapéuticos, desde una visión global de la asistencia del paciente y de la mejora del proceso farmacoterapéutico, facilita su trazabilidad y garantiza la obtención de los mejores resultados posibles en los pacientes al reducir la variabilidad en su aplicación. El objetivo de este trabajo es proponer una metodología para la práctica clínica orientada a problemas terapéuticos que se incardina en el circuito clásico de mejora continua de la calidad (Plan, Do, Check, Act) al diferenciar las fases: a. identificación de pacientes con problemas relacionados con los medicamentos; b. determinación del origen del problema terapéutico y mejora del proceso farmacoterapéutico; c. evaluación de resultados, y d. documentación y trazabilidad. Este procedimiento facilita la integración de la asistencia del paciente individual (prevención y resolución de problemas relacionados con los medicamentos) con la mejora en la gestión de los procesos origen de dichos problemas (prevención de errores de medicación y/o fallos del sistema de medicación) (AU)