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Tsume Y.,University of Michigan | Langguth P.,Johannes Gutenberg University Mainz | Garcia-Arieta A.,Agencia Espanola de Medicamentos y Productos Sanitarios | Amidon G.L.,University of Michigan
Biopharmaceutics and Drug Disposition | Year: 2012

The FDA Biopharmaceutical Classification System guidance allows waivers for in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms only for BCS class I. Extensions of the in vivo biowaiver for a number of drugs in BCS class III and BCS class II have been proposed, in particular, BCS class II weak acids. However, a discrepancy between the in vivo BE results and in vitro dissolution results for BCS class II acids was recently observed. The objectives of this study were to determine the oral absorption of BCS class II weak acids via simulation software and to determine if the in vitro dissolution test with various dissolution media could be sufficient for in vitro bioequivalence studies of ibuprofen and ketoprofen as models of carboxylic acid drugs. The oral absorption of these BCS class II acids from the gastrointestinal tract was predicted by GastroPlus™. Ibuprofen did not satisfy the bioequivalence criteria at lower settings of intestinal pH of 6.0. Further the experimental dissolution of ibuprofen tablets in a low concentration phosphate buffer at pH 6.0 (the average buffer capacity 2.2 mmol l -1/pH) was dramatically reduced compared with the dissolution in SIF (the average buffer capacity 12.6 mmol l -1/pH). Thus these predictions for the oral absorption of BCS class II acids indicate that the absorption patterns depend largely on the intestinal pH and buffer strength and must be considered carefully for a bioequivalence test. Simulation software may be a very useful tool to aid the selection of dissolution media that may be useful in setting an in vitro bioequivalence dissolution standard. Copyright © 2012 John Wiley & Sons, Ltd. Copyright © 2012 John Wiley & Sons, Ltd. Source

Romero A.,Molecular Oncology Laboratory | Martin M.,Hospital General Universitario Gregorio Maranon | Cheang M.C.U.,Lineberger Comprehensive Cancer Center | Garcia-Asenjo J.A.L.,Hospital Universitario Principe Of Asturias | And 7 more authors.
American Journal of Pathology | Year: 2011

Anthracyclines are frequently used for the treatment of breast cancer and topoisomerase II alpha (TOP2A) is considered to be the molecular target. Numerous studies have evaluated the predictive value of TOP2A using different methodological approaches and inconsistent results have been reported. Indeed, the correlation between techniques for the assessment of TOP2A status has not been well evaluated. In this study, we determined TOP2A status in 61 breast tumor samples by realtime PCR, DNA microarrays, immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH), and then evaluated these results with clinical-pathological features and breast cancer intrinsic subtypes. First, we observed a statistical significant correlation of TOP2A gene expression between real-time PCR and microarrays (Pearson coefficient, 0.816; P < 0.001), and both predicted TOP2A IHC results fairly well (area under the curve > 0.74). In contrast, poor agreement between FISH and IHC data was observed (k: 0.134). Secondly, TOP2A expression was found significantly associated with cell proliferation, and with the highly proliferative Luminal B, Her2-enriched and Basal-like intrinsic subtypes. In conclusion, TOP2A expression in breast cancer was associated with high proliferation and aggressive tumor subtypes and appears to be independent of its amplification status. All of these features should be taken into consideration when assessing the predictive value of TOP2A for anthracycline-based chemotherapy. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. Source

Catala-Lopez F.,Agencia Espanola de Medicamentos y Productos Sanitarios | Garcia-Altes A.,Fundacion Institute Investigacion En Servicios Of Salud
Revista Espanola de Salud Publica | Year: 2010

Background: Economic evaluation has been promoted as a tool to guide decision-making processes regarding healthcare resources' allocation and in the adoption of healthcare technologies. We analyzed the evolution and the main characteristics of economic evaluations of healthcare interventions done during the period 1983-2008 in Spain. Methods: Observational descriptive study. We performed A systematic review in the main bibliographic databases (PubMed/MEDLINE, SCOPUS, ISI Web of Knowledge, CRD, IME, IBECS) and manually through Internet in journals and public reports. There were predefined inclusion and exclusion criteria, and a set of variables to analyze the characteristics of the selected reports. Results: In total, 477 studies fulfilled the inclusion criteria. Some of the studies characteristics were: cost-effectiveness analysis (62.5%), decision analysis techniques (34.0%), healthcare system perspective (42.1%), therapeutic interventions (70.0%) and non explicit financing (44.0%). The geographical distribution for Spanish regions of the first authors was: Catalonia (29.3%), Community of Madrid (23.7%), Andalusia (6.7%) and Region of Valencia (6.3%). A total of 50.9% of the principal authors were employed at hospital centers. The most common disease conditions were: cardiovascular diseases (15.7%), infectious and parasitic diseases (15.3%) and malignant neoplasms (13.2%). A total of 82.2 % of the reports provided recommendations for decision making. Conclusions: An increasing number of studies was observed. Identified reports combined heterogeneity in the quality of the information brought with regard to analysis methods, data sources, type of interventions, or disease conditions. It is suggested to do more efforts for improving the quantity and quality of reports in public health interventions. Source

Blazquez-Perez A.,Agencia Espanola de Medicamentos y Productos Sanitarios | San Miguel R.,Complejo Hospitalario de Navarra | Mar J.,Clinical Management Service
PharmacoEconomics | Year: 2013

Background: Chronic hepatitis C is the leading cause of chronic liver disease, representing a significant burden in terms of morbidity, mortality and costs. A new scenario of therapy for hepatitis C virus (HCV) genotype 1 infection is being established with the approval of two effective HCV protease inhibitors (PIs) in combination with the standard of care (SOC), peginterferon and ribavirin. Objective: Our objective was to estimate the cost effectiveness of combination therapy with new PIs (boceprevir and telaprevir) plus peginterferon and ribavirin versus SOC in treatment-naive patients with HCV genotype 1 according to data obtained from clinical trials (CTs). Methods: A Markov model simulating chronic HCV progression was used to estimate disease treatment costs and effects over patients' lifetimes, in the Spanish national public healthcare system. The target population was treatment-naive patients with chronic HCV genotype 1, demographic characteristics for whom were obtained from the published pivotal CTs SPRINT and ADVANCE. Three options were analysed for each PI based on results from the two CTs: universal triple therapy, interleukin (IL)-28B-guided therapy and dual therapy with peginterferon and ribavirin. A univariate sensitivity analysis was performed to evaluate the uncertainty of certain parameters: age at start of treatment, transition probabilities, drug costs, CT efficacy results and a higher hazard ratio for all-cause mortality for patients with chronic HCV. Probabilistic sensitivity analyses were also carried out. Results: Incremental cost-effectiveness ratios (ICERs) of €2012 per quality-adjusted life-year (QALY) gained were used as outcome measures. According to the base-case analysis, using dual therapy as the comparator, the alternative IL28B-guided therapy presents a more favorable ICER (€18,079/QALY for boceprevir and €25,914/QALY for telaprevir) than the universal triple therapy option (€27,594/QALY for boceprevir and €33,751/QALY for telaprevir), with an ICER clearly below the efficiency threshold for medical interventions in the Spanish setting. Sensitivity analysis showed that age at the beginning of treatment was an important factor that influenced the ICER. A potential reduction in PI costs would also clearly improve the ICER, and transition probabilities influenced the results, but to a lesser extent. Probabilistic sensitivity analyses showed that 95 % of the simulations presented an ICER below €40,000/QALY. Post hoc estimations of sustained virological responses of the IL28B-guided therapeutic option represented a limitation of the study. Conclusion: The therapeutic options analysed for the base-case cohort can be considered cost-effective interventions for the Spanish healthcare framework. Sensitivity analysis estimated an acceptability threshold of the IL28B-guided strategy of patients younger than 60 years. © 2013 Springer International Publishing Switzerland. Source

Background and objective: We evaluated and quantified by meta-analysis techniques the incidence of contrast-induced nephropathy (CIN) in patients at risk undergoing computed tomography (CT). Material and methods: We conducted a systematic review of randomized controlled clinical trials designated to evaluate the nephrotoxicity related to iso-osmolar contrast media (IOCM) compared to low-osmolar contrast media (LOCM). Main electronic databases searched included PubMed/MEDLINE, EMBASE, ISI Web of Knowledge and Virtual Health Library (BVS-BIREME), as well as abstracts presented at related scientific societies meetings. Prior to data extraction, definitions of nephrotoxicity and risk population were established. Besides meta-analysis, the global agreement between CIN definitions was evaluated with Mantel-Haenszel stratified test. Results: Five studies were included with 716 randomized patients. When CIN was defined as increased serum creatinine (SCr) <25%, the relative risk (RR) was 0.71 (CI95%: 0.401.26)in favor of IOCMand when it was defined as SCr <0.5 mg/dL it showed a RR 1.48 (CI95%: 0.375.87)favoring LOCMin the four studies used this criterion. Mantel-Haenszel stratified test was χ2=2.51 (p=0.8). Conclusion: In patients with renal failure undergoing CT there is a similar risk of CIN with the administration of any contrast media studied. CIN incidence depends on the chosen criteria and is lower with the definition of SCr <0.5 mg/dL at 2472 h. No agreement was found between CIN definitions were adopted. © 2009 Elsevier España, S.L. All rights reserved. Source

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