Validated HPLC-UV method for amphotericin B quantification in a critical patient receiving AmBisome and treated with extracorporeal replacement therapies.

Amphotericin B (AMB) is a polyene macrolide antifungal agent used for treating invasive fungal infections. Liposomal AMB is a lipid dosage form, available as AmBisome, which reduces the toxicity of the drug. A simple HPLC-UV method was developed for the determination of AMB in plasma to study its pharmacokinetic profile in a critical patient receiving AmBisome and treated with extracorporeal replacement therapies. Sample preparation was performed using plasma deproteinization and drug release from liposome by the addition of acetonitrile (ACN)/zinc sulfate and ultrasonication. Chromatographic separation was performed using a C18 column and a mobile phase consisting of phosphate buffer (pH 3.0)/ACN (65/35, v/v). The UV detector was set at 407 nm. The total run time analysis was 23 min. The method was validated according to the standard guidelines and applied to study the pharmacokinetics of AMB in a critical patient. The total run time analysis obtained was shorter than that of the previously reported methods, being useful for therapeutic drug monitoring or pharmacokinetic profile research.

Pharmacokinetic/Pharmacodynamic Analysis of Voriconazole Against Candida spp. and Aspergillus spp. in Allogeneic Stem Cell Transplant Recipients.

BACKGROUND: To evaluate the adequacy of different dosing regimens of voriconazole for the prophylaxis of invasive candidiasis and aspergillosis in adult allogeneic stem cell transplant recipients by means of population pharmacokinetic (PK) modelling and simulation. METHODS: Allogeneic stem cell transplant recipients receiving voriconazole were included in this observational study. A population PK model was developed. Three oral voriconazole-dosing regimens were simulated: 200, 300, and 400 mg twice daily. The pharmacodynamic target was defined as fAUC0-24/0.7. A probability of target attainment ≥90% was considered optimal. The cumulative fraction of response was defined as the fraction of patients achieving the pharmacodynamic target when a population of simulated patients is matched with a simulated population of different Candida spp. and Aspergillus spp. The percentage of patients with trough plasma concentrations at steady state (Ctrough) within the reference range (1-5.5 mg/L) was also calculated. RESULTS: A 2-compartment PK model was developed using data from 40 patients, which contributed 237 voriconazole plasma samples, including trough and maximum concentrations. Voriconazole 200, 300, and 400 mg twice daily achieved probability of target attainment ≥90% for minimal inhibitory concentration values ≤0.25, ≤0.38, and ≤0.50 mg/L, respectively. The cumulative fraction of response for A. niger, A. versicolor, and A. flavus increased >10% when increasing voriconazole dose from 200 to 400 mg twice daily (from 72.5% to 89.5% for A. niger; from 77.7% to 88.7% for A. versicolor; and from 82.4% to 94.9% for A flavus). The percentage of patients with Ctrough within the reference range increased 15% when voriconazole dose was increased from 200 to 300 mg twice daily. CONCLUSIONS: The PK simulations in this study suggest that transplant recipients on voriconazole prophylaxis against invasive candidiasis or aspergillosis are likely to achieve the target concentrations associated with the desired treatment outcomes if the maintenance dose is 200 mg twice daily. However, Aspergillus spp. with high minimal inhibitory concentrations could require higher maintenance doses.

Stability of mycophenolate mofetil in polypropylene 5% dextrose infusion bags and chemical compatibility associated with the use of the Equashield® closed-system transfer device.

Stability studies are necessary in healthcare settings as they facilitate fast, cost-effective and efficient work related to batch manufacturing and availability of supplies. We studied the stability of 1-10 mg/mL mycophenolate mofetil (MMF) in polypropylene 5% dextrose infusion bags prepared from Cellcept® and with a generic brand name (Micofenolato de Mofetilo Accord) at different storage temperatures. To ensure chemical compatibility during preparation, we also tested MMF sorption to the Equashield® closed-system drug transfer device used in this step. For this, a validated stability-indicating high-performance liquid chromatography method was developed for the quantification and identification of MMF in the infusion bags. The analytical selectivity of the assay was determined by subjecting an MMF sample to extreme values of pH, oxidative stress and heat conditions to force degradation. Protected from light, 1-10 mg/mL MMF in infusion polypropylene bags prepared from reconstituted Cellcept® 500 mg or Accord 500 mg in 5% dextrose was stable for at least 35 days when stored at 2-8°C or between -15 and -25°C, and for 14 days when stored at 25°C. MMF loss owing to chemical sorption to the Equashield® closed-system drug transfer device set was negligible.

Effectiveness, toxicity, and economic evaluation of vinflunine for the treatment of patients with transitional cell carcinoma in the Spanish outpatient setting.

The aim of this study was to evaluate the effectiveness and toxicity profile of the vinflunine chemotherapy regimen and to examine the cost-effectiveness relation in a real-world sample of patients with transitional cell carcinoma of the bladder. This is a multicenter, observational, retrospective cohort study. To assess the effectiveness and safety of vinflunine treatment, progression-free survival, overall survival, and adverse events were registered. An economic evaluation was performed and cost-effectiveness ratios were calculated. A total of 37 patients were included in the study, with a mean age of 67 (SD=9) years. The median progression-free survival was 2.61 months (95% confidence interval 1.79-4.23) and the median overall survival was 5.72 months (95% confidence interval 3.34-10.35). An objective response was achieved in eight (22%) patients. Statistically significant differences were found between patients treated with vinflunine as a second-line therapy and those treated with vinflunine as a third-line therapy (P=0.036). The most commonly reported analytical adverse event was anemia (n=34; 92%), and the most severe was neutropenia (n=19; 51%), with nine patients developing grade 4 neutropenia (9/19; 47%). The total cost of vinflunine treatment was &OV0556;553 873, with a median of &OV0556;8524 (interquartile range, &OV0556;9220) per patient. The median-based cost-effectiveness ratio was &OV0556;44 789 (&OV0556;31 706-58 022) per progression-free year gained and &OV0556;22 750 (&OV0556;14 526-34 085) per life-year gained. The data from this study fill an important need for information on the relative value of this treatment in terms of cost-effectiveness and might help achieve an optimal quality healthcare system.

A pharmacokinetic approach to model-guided design of infliximab schedules in ulcerative colitis patients.

BACKGROUND: Infliximab, an anti-tumour necrosis factor approved for treatment of Crohn´s disease and ulcerative colitis, is administered at predefined interdose intervals. On insufficient response or loss of response, treatment can be intensified. The lack or loss of response is likely related to complex pharmacokinetics of infliximab. AIMS: To explore optimal dosing strategies of infliximab in treatment-naïve patients with ulcerative colitis through predictive Monte Carlo simulations based on a validated population PK model. METHODS: A population of 2,000 treatment-naïve patients was generated by Montecarlo simulation. Six dosing strategies for maintenance therapy were simulated on this population. Strategies 1 and 2 consisted on 5 mg/kg and 6 mg/kg doses, respectively, and 8 weeks inter-dose interval. Strategies 3 and 4 used Individualized doses, adjusted to albumin level, sex and body weight, and a fix interdose interval of 8 weeks to achieve a target trough concentration of 5 mg/L or 6 mg/L, respectively. Strategies 5 and 6 used a fix dose of 5 mg/kg and individualized inter-dose intervals, adjusted to the same covariates, to achieve a target concentration, of 5 mg/L or 6 mg/L, respectively. RESULTS: Strategies 2-6 reached trough levels statistically higher than strategy 1 (p < 0.05). Strategy 5 proved to be the best dosing strategy. It was associated with a higher proportion of responder patients than strategy 1 (62 % vs. 40 %) without reaching higher peak concentrations. CONCLUSIONS: Optimization of maintenance treatment of colitis with infliximab by a pharmacokinetic approach could benefit infliximab-naive patients with ulcerative colitis.

Efficacy and marginal cost of treatment with tocilizumab in COVID-19 patients. / Resultados en la práctica asistencial y coste marginal del tratamiento con tocilizumab en pacientes COVID-19.

OBJECTIVE: To describe the marginal cost and survival of patients treated with tocilizumab in a university hospital under real-life conditions and to evaluate factors that could influence costs and health outcomes will be evaluated. METHODS: Observational, single-center, retrospective study of a cohort of adult patients infected with SARS-CoV-2 treated with tocilizumab. The one-year restricted mean survival time was analyzed in life-years gained (LYG). The influence of sex, age and severity on patient survival was evaluated. The marginal cost/LYG and marginal cost/survivor ratios were calculated. RESULTS: 508 patients (66 ± 13 years; 32% women) were included. Seventeen percent were admitted to the ICU. Overall survival was 77%. Age older than 71.5 years (HR = 1.08; 95% CI 1.07-1.10; p < 0.001) and ICU admission at initiation of treatment (HR = 2.01; 95% CI 1.30-3.09; p = 0.002) were identified as risk factors. The total budgetary impact of tocilizumab in the period analyzed was 206,466 euros. The patients with the highest cost per unit of health outcome were those admitted to the ICU and those over 71.5 years, with a marginal cost/LYG of € 966 and a marginal cost/survivor of € 1,136. CONCLUSION: The efficiency of treatment with tocilizumab is associated with the age and severity of the patients. The figures are lower in all subgroups than the thresholds usually used in cost-effectiveness evaluations. The results of the present study suggest that early first dose of tocilizumab is an efficient strategy.

Health Outcomes and Primary Adherence to Secondary Prevention Treatment after St-Elevation Myocardial Infarction: a Spanish Cohort Study.

This retrospective observational study aimed to establish the first prescription and its dispensation (primary adherence) in the first 30 days of the four pharmacotherapeutic classes recommended after a type 1 STEMI episode, determine the potential risk factors for lack of primary adherence, and evaluate the potential impact of primary adherence on cardiovascular outcomes. Of the 613 patients analyzed, 576 were included (64.7 ± 13.8 years, 73.8% men) between January 2008 and December 2013. Primary adherence exceeded 90% in all groups. Complete primary adherence was higher in high-drug coverage patients and was lower in patients with cardiovascular or neuropsychiatric diseases. According to competing risk analysis, 1-year cardiovascular mortality was significantly lower in patients with complete primary adherence than in those without complete prescription or adherence, 1.8% versus 5.6% (HR = 0.286; p = 0.012). Complete primary adherence did not prevent a 1-year cardiovascular event, 5.6% versus 5.5% (p = 0.904).

Secondary adherence to beta-blockers after ST-elevation myocardial infarction without ventricular dysfunction. / Impacto pronóstico de la adherencia secundaria a betabloqueantes tras infarto de miocardio con elevación del segmento ST sin disfunción ventricular.

INTRODUCTION AND OBJECTIVES: Adequate medication intake affects treatment effectiveness. The aim of this study was to establish the impact of prescription and secondary adherence to beta-blockers on medium- and long-term and long-term cardiovascular outcomes, after a first type 1 ST-elevation myocardial infarction (STEMI) episode without heart failure or left ventricular ejection fraction ≥ 40%. METHODS: A retrospective observational study was conducted in a cohort of patients admitted from 2008 to 2013 to the University Clinical Hospital in Valencia. Competing risk analysis assessed the relationship between cardiovascular mortality or new vascular event with beta-blocker prescription and secondary adherence, defined as a proportion of days covered. RESULTS: During after the first year following discharge, beta-blocker prescription was not significantly associated with better health outcomes in the 460 patients included. However, cardiovascular mortality was lower in adherent patients compared to non-adherent patients, at 0.6% vs. 6.6% (HR = 0.083; 95% CI, 0.015-0.448; p = 0.003), and in adherent patients compared to those who did not receive the treatment due to lack of prescription or lack of adherence, with 0.6% vs. 4.8% (HR = 0.115; 95% CI, 0.022-0.587; p = 0.009). These results were not observed when the complete follow-up period was analysed (median 46.7 months). CONCLUSIONS: Secondary adherence to beta-blockers improves 1-year prognosis after STEMI with preserved left ventricular function.

Osimertinib in first-line treatment of advanced EGFR-mutated non-small-cell lung cancer: a cost-effectiveness analysis.

Aim: Osimertinib improves progression-free survival in first-line EGFR mutation-positive non-small-cell lung cancer. Materials & methods: A Markov cohort model including costs, utilities and disutilities, was conducted to estimate quality-adjusted life-year (QALY) and incremental cost-effectiveness ratio when treating with osimertinib versus standard first-line tyrosine kinase inhibitors (TKIs). Results: Osimertinib presented higher QALYs (0.61) compared with standard EGFR-TKIs (0.42). Osimertinib costs were €83,258.99, in comparison with €29,209.45 for the standard EGFR-TKIs. An incremental cost-effectiveness ratio of €273,895.36/QALY was obtained for osimertinib. Conclusion: Osimertinib was more effective in terms of QALYs gained than comparators (erlotinib-gefitinib). However, to obtain a cost-effectiveness alternative, a discount greater than 60% in osimertinib acquisition cost is required.

Validated HPLC-UV detection method for the simultaneous determination of ceftolozane and tazobactam in human plasma.

AIM: A simple, rapid, economical and sensitive HPLC-UV method was developed for the simultaneous quantification of ceftolozane and tazobactam in plasma samples. METHODOLOGY: After deproteinization followed by a liquid-liquid back-extraction, the compounds were separated on a C18 column (150 mm × 4.6 mm, 5 µm) with UV-visible detection at 220 nm. The mobile phase consisted of acetonitrile and potassium dihydrogenphosphate buffer at pH 3.0 (8:92, v/v), delivered isocratically at a flow rate of 1.0 ml/min and at a column oven temperature of 30°C. Cefepime was used as an internal standard. RESULTS: Linearity was achieved in the concentration range of 0.50-100.00 µg/ml for ceftolozane and 0.25-50.00 µg/ml for tazobactam. The intra- and interday precision showed good reproducibility with coefficients of variation of less than 9.26% for ceftolozane and 9.62% for tazobactam. CONCLUSION: The sample preparation procedure avoids expensive or time-consuming steps used by other previously published methods. The methodology was validated according to standard guidelines and was used for quantification of ceftolozane and tazobactam in plasma samples from critically ill patients.

[Single preoperative dose of metronidazole plus gentamicin for antimicrobial prophylaxis in colorectal surgery]. / Dosis única preoperatoria de metronidazol más gentamicina para profilaxis antibiótica en cirugía colorrectal.

BACKGROUND AND OBJECTIVE: To prove that a single-preoperative dose (SD) of metronidazole plus gentamicin guarantees the same clinical effectiveness than the same dose administered in a multiple-perioperative schedule (MD), with a reduction of the direct costs. PATIENTS AND METHOD: A retrospective cohort study with patients undergoing elective colorectal surgery between 1995 and 2003 was designed. Patients in the cohort of cases received a SD of metronidazole 1500 mg plus gentamicin 240 mg between 1999 and 2003. Patients included in the cohort of controls received the same dose of antibiotics in a MD schedule between 1995 and 1997. Clinical effectiveness was evaluated as length of stay, mortality and rate of surgical-related infections. Economic analysis was performed using direct costs of therapy exclusively. RESULTS: 414 patients were included in the cohort of MD and 978 were included in the cohort of SD. Total length of stay (standard deviation) was 15.1 (16.2 days), with a significant reduction in the SD cohort versus the MD cohort: 14.0 (15.4) days versus 17.5 (17.8) days (p < 0.001). No differences in mortality (overall rate 3.2%) or surgical infection rate (overall rate 8.6%) between cohorts were found. SD schedule produces a 35% cost-reduction per procedure. CONCLUSIONS: Attending the clinical effectiveness, no differences between SD and MD cohorts were found. Therefore, according to logistics advantages and costs reduction, the SD of antibiotic is considered the most efficient option.

Stability of tacrolimus ophthalmic solution.

PURPOSE: The stability of 0.3-mg/mL tacrolimus ophthalmic solution at different storage temperatures was studied. METHODS: A sterile ophthalmic solution of 0.3 mg/mL tacrolimus was prepared in triplicate under aseptic conditions by diluting tacrolimus in eye drops. Three aliquots of this solution were transferred into polypropylene bottles and stored at 25, 2-8, or -15 to -25 °C. Samples were collected immediately after preparation and at selected time points and assayed in triplicate using high-performance liquid chromatography (HPLC). Samples were also visually examined for macroscopic changes. The 0.3-mg/mL tacrolimus solution was also exposed to acidic treatment and heat to force its degradation and to evaluate the selectivity of the analytic method. The tacrolimus ophthalmic solution was considered stable if at least 90% of the mean initial concentration remained when analyzed by HPLC. RESULTS: When stored at 2-8 °C and between -15 and -25 °C, at least 90% of the initial tacrolimus concentration remained throughout the 85-day study period. There were no significant differences in tacrolimus concentrations between the starting and ending points (p > 0.05). However, when tacrolimus solution was stored at 25 °C, the percentage of the initial tacrolimus concentration remaining had decreased to less than 90% on day 28. CONCLUSION: Tacrolimus diluted to 0.3 mg/mL in eye drop solution was stable for 20 days when stored at 25 °C and for at least 85 days when stored at 2-8 °C or between -15 and -25 °C in polypropylene bottles and protected from light.

[Retrospective analysis of adverse side-effects of medication in elderly patients at a primary care health centre]. / Análisis retrospectivo de los acontecimientos adversos por medicamentos en pacientes ancianos en un centro de salud de atención primaria.

OBJECTIVE: To describe the adverse drug events (ADEs) reported by doctors of a primary health care centre in the patient's medical record. DESIGN: A retrospective, descriptive study. SETTING: Burriana Health Centre (Castellón), Spain. PARTICIPANTS: All patients over 75 with a clinical history held on paper at the health centre, ie non-institutionalized patients seen on an out-patient basis, were checked. MEASUREMENTS: A total of 2044 paper-based medical records were analysed, in which 832 histories describing 1893 ADEs (90.4% unforeseen and 9.6% preventable) were found. This means that 41% of the patients experienced one or more adverse events, with an average of 2.28 ADEs per patient. RESULTS: Most ADEs (85.3%) were light, but 6% were classified as serious, with high digestive haemorrhage caused by NSAIDs standing out as the most common serious problem (37.3%). The pharmaco-therapeutic groups most involved in ADEs were cardiovascular therapy (29.4%), anti-infectious drugs (21.2%) and nervous system drugs (20.1%). Seventeen cases of intoxication were detected (0.9% total ADEs), with digoxin responsible for 67% of the serious intoxications. It was observed that ADEs occur with statistical significance most frequently in women (OR, 1.73; 95% CI, 1.42-2.10). After an age-stratified analysis, it was concluded that the only sub-group where the increase in risk was not significant was the group of people over 85 years old. CONCLUSIONS: ADEs create a serious public health problem, with negative effects on patients. Although most ADEs are unforeseen (90.4%), it is still worrying that 9.6% of the ADEs identified are preventable.