Jesús Frías

Acceptability and characteristics of 124 human bioequivalence studies with active substances classified according to the Biopharmaceutic Classification System

AIM The aim of this study was to evaluate the acceptability of 124 bioequivalence (BE) studies with 80 active substances categorized according to the Biopharmaceutics Classification System (BCS) in order to establish if there were different probabilities of proving BE between the different BCS classes. METHODS We evaluated the differences between pharmaceutical products with active substances from different BCS classes in terms of acceptability, number of subjects in the study (n), the point estimates, and intra- and inter-subject coefficients of variation data from BE studies with generic products. RESULTS Out of 124 BE studies 89 (71.77%) were performed with pharmaceutical products containing active substances classified by the BCS. In all BCS classes there were non-bioequivalent pharmaceutical products: 4 out of 26 (15.38%) in class 1, 14 out of 28 (50%) in class 2, 3 out of 22 (13.63%) in class 3 and 1 out of 13 (7.69%) in class 4. When we removed those pharmaceutical products in which intra-subject variability was higher than predicted (2 in class 1 active substances, 9 in class 2 and 2 in class 3) there were still non-BE pharmaceutical products in classes 1, 2 and 3. CONCLUSIONS Comparisons between pharmaceutical products with active substances from the four BCS classes have not allowed us to define differential characteristics of each class in terms of n, inter and intra-subject variability for C(max) or AUC. Despite the usually employed test dissolution methodology proposed as quality control, pharmaceutical products with active substances from the four classes of BCS showed non-BE studies.

An Acenocoumarol Dosing Algorithm Using Clinical and Pharmacogenetic Data in Spanish Patients with Thromboembolic Disease

Appropriate dosing of coumarins is difficult to establish, due to significant inter-individual variability in the dose required to obtain stable anticoagulation. Several genetic and other clinical factors have been associated with the coumarins dose, and some pharmacogenetic-guided dosing algorithms for warfarin and acenocoumarol have been developed for mixed populations. We recruited 147 patients with thromboembolic disease who were on stable doses and with an international normalized ratio (INR) between 2 and 3. We ascertained the influence of clinical and genetic variables on the stable acenocoumarol dose by multiple linear regression analysis in a derivation cohort (DC; n = 117) and developed an algorithm for dosing that included clinical factors (age, body mass index and concomitant drugs) and genetic variations of VKORC1, CYP2C9, CYP4F2 and APOE. For purposes of comparison, a model including only clinical data was created. The clinical factors explained 22% of the dose variability, which increased to 60.6% when pharmacogenetic information was included (p<0.001); CYP4F2 and APOE variants explained 4.9% of this variability. The mean absolute error of the predicted acenocoumarol dose (mg/week) obtained with the pharmacogenetic algorithm was 3.63 vs. 5.08 mg/week with the clinical algorithm (95% CI: 0.88 to 2.04). In the testing cohort (n = 30), clinical factors explained a mere 7% of the dose variability, compared to 39% explained by the pharmacogenetic algorithm. Considering a more clinically relevant parameter, the pharmacogenetic algorithm correctly predicted the real stable dose in 59.8% of the cases (DC) vs. only 37.6% predicted by the clinical algorithm (95% CI: 10 to 35). Therefore the number of patients needed to genotype to avoid one over- or under-dosing was estimated to be 5.

Overuse of PPIs in Patients at Admission, During Hospitalisation, and at Discharge in a Terciary Spanish Hospital

Background: The first generic PPI was introduced in Spain in 2001, and since then their prescriptions have increased steadily by about 200%. Aim: To evaluate the frequency of use and the appropriateness of indications of PPIs in hospitalised patients, and possible factors predicting their use. We also evaluated relevant PPI-drug interactions and serious adverse drug reactions (SADRs). Methods: This was a cross-sectional, prescription-indication drug-utilisation study in hospitalised patients with follow-up until discharge. Sampling was random and stratified by services, and was calculated to obtain an error in the precision of prescription of ±4% with a 95% confidence interval with maximum variability (50%). Results: 328 patients were included; 28.65% were prescribed a PPI at admission, 82.62% were prescribed a PPI during hospitalisation, and 54.75% at discharge, with inappropriate indications in 74.47%, 61.25% and 80.24% respectively. The OR of being discharged with PPIs was 3.01(95% CI:2.17 – 4.18, p=0.000). The inappropriate indication most frequently seen at admission and at discharge was antiplatelet therapy. During hospitalisation it was prophylaxis for stress ulcer in patients at low risk. PPI prescription at admission remained at discharge in 75.90% of cases, 73.02% without an acceptable indication. Being > 64 years old, taking > 4 drugs, co-medication (NSAIDs, antiaggregation and anticoagulation), certain hospital departments and length of stay > 15 days predicted 83.7% of prescriptions at discharge. Four relevant PPIdrug interactions were found, and 2 resulted in SADRs, thus the incidence per 1, 000 patients was 2.66 (Poisson 95% CI:0.62-7.23). Conclusions: There was a very high frequency of overuse of PPIs in inpatients and outpatients. Hospitalisation did not represent an opportunity for better prescription of PPIs.

A pharmacovigilance program from laboratory signals for the detection and reporting of serious adverse drug reactions in hospitalized patients.

The detection and reporting of serious adverse drug reactions (SADRs) have become important components of monitoring and evaluation activities performed in hospitals. We present the implementation of a prospective pharmacovigilance program based on automatic laboratory signals (ALSs) at a hospital. We also report the general findings after the first year of operation of the program, which involved ALSs that indicate various SADRs: agranulocytosis, aplastic anemia, liver injury, thrombocytopenia, hyponatremia, and rhabdomyolysis. The number of hospitalizations during the year was 54,525, and 1,732 patients experienced at least one ALS. The review of electronic medical records (EMRs) showed that no alternative cause (i.e., no non‐SADR explanation) for the ALS was identified in 520 (30%) of the patients. After the individual ALS–patient evaluation, a total of 110 SADRs (6.35% of those identified after reviewing EMRs and 21.15% of those requiring individual patient evaluations) were identified. In other words, in order to identify a single SADR, we had to review the electronic records of approximately 16 patients and personally visit 5 patients.

Hipertensión arterial y política de salud en España

José R. Banegas a,b, , Albert Jovell , Benjamı́n Abarca , Manuel Aguilar Diosdado , Luis Aguilera , Pedro Aranda , Vicente Bertoméu , Pedro Capilla , Pedro Conthe , Fernando De Álvaro , Antonio Fernández-Pro , Xavier Formiguera , Jesús Frı́as , Lucı́a Guerrero , José L. Llisterri , José M. Lobos , Juan F. Macı́as , Ángel L. Martı́n De Francisco , Jesús Millán , Juan C. Morales , Vicente Palomo , Alex Roca-Cusachs , Javier Román , Carlos Sanchis , Antonio Sarriá , Julián Segura , Álex De La Sierra , Luis Verde , Julio Zarco n y Luis M. Ruilope a,u a Asociación de la Sociedad Española de Hipertensión y Liga Española para la Lucha contra la Hipertensión Arterial b Universidad Autónoma de Madrid, CIBERESP (CIBER de Epidemiologı́a y Salud Pública), Madrid c Foro Español de Pacientes d Sociedad Española de Medicina General e Sociedad Española de Diabetes f Sociedad Española de Medicina de Familia y Comunitaria g Sociedad Española de Cardiologı́a h Consejo General de Colegios Oficiales de Farmacéuticos i Sociedad Española de Medicina Interna j Sociedad Española de Nefrologı́a en el Comité Español Interdisciplinario para la Prevención Cardiovascular k Sociedad Española para el Estudio de la Obesidad l Departamento de Farmacologı́a y Terapéutica, Universidad Autónoma de Madrid, Madrid m Asociación de Enfermerı́a de Hipertensión y Riesgo Cardiovascular (EHRICA) n Sociedad Española de Médicos de Atención Primaria o Comité Español Interdisciplinar de Prevención Cardiovascular (CEIP) p Sociedad Española de Geriatrı́a y Gerontologı́a q Sociedad Española de Nefrologı́a r Sociedad Española de Arteriosclerosis s Sociedad Española de Farmacéuticos de Atención Primaria t Ibermutuamur-Corporación Mutua-Proyectos Sanitarios u Agencia de Evaluación de Tecnologı́as Sanitarias. Instituto de Salud Carlos III, Madrid v Asociación para la Prevención del Riesgo Cardiovascular (PRECAR) x Sociedad Española de Directivos de Atención Primaria, España

Evaluation of the influence of sex and CYP2C19 and CYP2D6 polymorphisms in the disposition of citalopram.

We investigate the impact of sex and genotype on citalopram disposition in 35 healthy volunteers who received an oral dose of 20mg citalopram within a single-dose bioequivalence study. CYP2C19*2 and *3, and CYP2D6*4 mutations were determined by Real-Time PCR. The influence of sex and genotype was analyzed by a linear mixed model for repeated measures, including formulation, period, sequence, sex, CYP2C19 and CYP2D6 as fixed effects and subject nested sequence*sex*CYP2C19*CYP2D6 as the random one. Pharmacokinetic parameters were log-transformed and AUC(infinity) and C(max) adjusted to the administered dose/weight. The model yields a statistical significance in AUC(infinity) and CL/F for CYP2C19 and CYP2D6. Gender, formulation, sequence or period effects were not statistically significant. AUC(infinity) of CYP2C19*1/*2 and CYP2C19*2/*2 carriers is 44% and 118% higher than wild type, respectively; CYP2D6 volunteers carrying 1/4 have an AUC 23% higher than wild type. Our data also suggest that the influence of CYP2D6 on AUC(infinity) is very low when it is in association with CYP2C19*1/*1 while its influence is more apparent in association with CYP2C19*1/*2. In conclusion, we demonstrate the influence of CYP2C19 and CYP2D6 in the disposition of citalopram, and we suggest that the influence of CYP2D6 is more probable in volunteers with at least one defective allele of CYP2C19.

Proton pump inhibitors are associated with hypersensitivity reactions to drugs in hospitalized patients: a nested case-control in a retrospective cohort study.

Previous research has shown that gastric acid suppression by antacid drugs can promote allergic reactions to acid‐labile food proteins. No data are available about whether antacid drugs can promote drug hypersensitivity reactions. The most potent and longer lasting inhibition of gastric secretion is provided by proton pump inhibitors (PPIs). We hypothesized that gastric acid suppression by proton pump inhibitors could be causative of drug hypersensitivity reactions during hospitalization.

Digoxin level and clinical manifestations as determinants in the diagnosis of digoxin toxicity.

The aim of this study was to determine the relative importance of different risk factors in the diagnosis of digitalis toxicity. The authors recruited inpatients for whom serum digoxin level was requested and prospectively followed them for a week to ascertain if they showed digitalis toxicity. The predictive value of different factors for the assessment of digoxin toxicity was analyzed by multiple logistic regression. Forty-one toxic and 58 nontoxic patients were included. In the univariant analysis, intoxicated patients were older, most were women, and they had worse renal function and higher digoxin level; but there were no differences in serum electrolytes or other risk factors. In the multivariant analysis, digoxin level was the only independent factor related to digitalis toxicity. A different risk of toxicity for each clinical manifestation was found for a certain digoxin level. Patients with signs of automaticity in the electrocardiogram had a higher likelihood of being intoxicated than patients with gastrointestinal symptoms, atrioventricular block, or bradycardia. Therefore, in the population evaluated in this study, digoxin level is the key independent factor in digoxin intoxication, although the probability of being intoxicated is also a function of the type of clinical manifestations. A graphic approximation of this probability based on these two factors is presented.

Activated charcoal increases digoxin elimination in patients

Digoxin continues to be an important cause of drug toxicity. On the basis of a healthy volunteer study, activated charcoal has been proposed as a treatment for digoxin chronic intoxication. In order to evaluate the effect of activated charcoal on digoxin elimination in intoxicated patients during routine practice, we reviewed all Serum Digoxin Level Requests for adult in-patients from 1991 to 1993, with digoxin levels > 2.5 ng/ml. Of a total of 39 cases, 23 had been treated with activated charcoal while 16 had not. Digoxin elimination half-life during activated charcoal therapy was 36 h (S.D. 14 h; 95% C.I. 30-42 h) while in the non-treated group it was 68 h (S.D. 19 h, 95% C.I. 57-78). Calculated total body clearance of digoxin was 55 ml/min (S.D. 17 ml/min; 95% C.I. 45-64 ml/min) for the non-treated group versus 98 ml/min (S.D. 34 ml/min; 95% C.I. 83-113 ml/min) for the group receiving charcoal, representing an 78% increase in digoxin elimination.

Symptomatic thromboembolic events in patients treated with intravenous-immunoglobulins: Results from a retrospective cohort study

AIMS To estimate the incidence and predictors of symptomatic arterial and venous thromboembolic events (TEE) from intravenous immunoglobulin (IVIg) therapy according to its indications. METHODS We performed a retrospective cohort study of patients seen at our institution and treated with IVIg over a 36-month period. Indications, comorbility and comedication associated with TEE were identified by a stepwise logistic regression analysis. RESULTS Of 303 patients included with at least one infusion of IVIg over three years, TEE were identified in a total of 50 patients treated with IVIg, for an incidence of 16.9% (CI 95%: 13.0-21.6); 27 (54%) arterial (9.1%;CI 95%: 6.3-13.0%) and 23 (46%) venous TEE (7.8%; CI95%: 5.2-11.4%), overall mortality was 32%. Per indication there were more patients with autoimmune conditions, secondary immunodeficiency, dysimmune neuropathies, acute rejection of solid organ transplantation and sepsis. Patients with TEE were significantly older, were more likely to be men, they had more comorbid conditions; the doses of IVIg were high (589.4mg/kg/day vs 387.0mg/kg/day, p<0.001) and differences in comedication were found. The stepwise logistic regression analysis retained high doses of IVIg (OR 3.03; CI 95%: 1.49-5.67) and diuretics therapy (OR 1.69; CI 95%: 1.06-3.97) when combined with the usual comorbid confounders. CONCLUSIONS The incidence of TEE from IVIg therapy remains high at one in six patients treated. The most remediable factor is a high daily IVIg load. Decreasing the daily IVIg dose together with carefully weighing diuretics therapy and comorbid risk factors may be the keys to saving lives.