Effect of truncating AUC at 12, 24 and 48 hr when evaluating the bioequivalence of drugs with a Long Half-Life

This is the peer reviewed version of the following article: Basic an Clinical Pharmacology and Toxicology 118.1 (2016): 53-7 which has been published in final form at http://dx.doi.org/10.1111/bcpt.12432. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."Bioequivalence studies of drugs with a long half-life require long periods of time for pharmacokinetic sampling. The latest update of the European guideline allows the area under the curve (AUC) truncated at 72 hr to be used as an alternative to AUC0-t as the primary parameter. The objective of this study was to evaluate the effect of truncating the AUC at 48, 24 and 12 hr on the acceptance of the bioequivalence criterion as compared with truncation at 72 hr in bioequivalence trials. The effect of truncated AUC on the within-individual coefficient of variation (CVw) and on the ratio of the formulations was also analysed. Twenty-eight drugs were selected from bioequivalence trials. Pharmacokinetic data were analysed using WinNonLin 2.0 based on the trapezoidal method. Analysis of variance (ANOVA) was performed to obtain the ratios and 90% confidence intervals for AUC at different time-points. The degree of agreement of AUC0-72 in relation to AUC0-48 and AUC0-24, according to the Landis and Koch classification, was 'almost perfect'. Statistically significant differences were observed when the CVw of AUC truncated at 72, 48 and 24 hr was compared with the CVw of AUC0-12. There were no statistically significant differences in the AUC ratio at any time-point. Compared to AUC0-72, Pearson's correlation coefficient for mean AUC, AUC ratio and AUC CVw was worse for AUC0-12 than AUC0-24 or AUC0-48. These preliminary results could suggest that AUC truncation at 24 or 48 hr is adequate to determine whether two formulations are bioequivalentThis study was partially funded by the Fundación Teófilo Hernando and Foundation for Biomedical Research at Hospital Universitario de La Princesa F Abad-Santos and D Ochoa have been consultants or investigators in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, Chemo, Farmalíder, Ferrer, GlaxoSmithKline, Janssen-Cilag, Kern, Normon, Servier, Teva, and Zambon

Toxic effects of methoxychlor on the episodic prolactin secretory pattern: Possible mediated effects of nitric oxide production

BACKGROUND: This work addresses the issue of whether methoxychlor (MTX) exposure may modify the ultradian secretion of prolactin through changes in the synthesis of nitric oxide (NO) induced by N(ω)-nitro-L-arginine methyl ester (L-NAME) in the hypothalamic-pituitary axis. Associated changes in dopamine (DA) content in the anterior (AH), mediobasal (MBH) and posterior hypothalamus (PH) and median eminence (ME) were evaluated. METHODS: Two groups of animals (MTX and MTX+L-NAME treated) received subcutaneous (sc) injections of MTX at a dose of 25 mg/kg/day for one month. The other two groups of animals (control and L-NAME treated) received sc vehicle injections (0.5 mL/day of sesame oil), during the same period of time to be used as controls. Forty hours before the day of the experiment, animals were anaesthetized with intrapritoneal injections of 2.5% tribromoethanol in saline and atrial cannulas were implanted through the external jugular vein. Plasma was continuously extracted in Hamilton syringes coupled to a peristaltic bomb in tubes containing phosphate-gelatine buffer (to increase viscosity). The plasma was obtained by decantation and kept every 7 minutes for the measurement of plasma prolactin levels through a specific radioimmnunoassay and DA concentration by high-pressure liquid chromatography (HPLC). RESULTS: Prolactin release in animals from all experimental groups analyzed was episodic. Mean plasma prolactin levels during the bleeding period, and the absolute pulse amplitude were increased after MTX or N(ω)-nitro-L-arginine methyl ester (L-NAME) administration. However MTX and L-NAME did not modify any other parameter studied with the exception of relative pulse amplitude in MTX treated rats. L-NAME administration to rats treated with the pesticide reduced mean plasma prolactin levels and the absolute amplitude of prolactin peaks. Peak duration, frequency and relative amplitude of prolactin peaks were not changed in the group of rats treated with MTX plus L-NAME as compared to either control or MTX treated rats. Whereas MTX decreased DA content in the ME and increased it in the AH, its content did not change in the MBH or PH, as compared to the values found in controls. Also, L-NAME administration decreased DA content in the ME as compared to controls. However, L- NAME administration to MTX exposed rats, markedly increased DA content in the ME as compared to either MTX treated or control rats. L-NAME administration increased DA content in the AH as compared to the values found in non-treated rats. However L-NAME administration to MTX exposed rats did not modify DA content as compared to either MTX treated or control rats. L-NAME administration did not modify DA content at the MBH nor in saline treated nor in MTX treated rats. However, the values of DA in the MBH in MTX plus L-NAME treated animals were statistically decreased as compared to L-NAME treated rats. In the PH, L-NAME administration increased DA content as compared to the values found in non-treated animals. L-NAME administration to MTX exposed rats also increased DA content as compared to either MTX treated or control rats. CONCLUSION: The results suggest the existence of an interaction between MTX and L-NAME in the modulation of the ultradian prolactin secretion at the pituitary levels. The possibility of an indirect effect mediated by changes in DA content at the ME requires further examination

Biomonitoring of Human Exposure to Prestige Oil: Effects on DNA and Endocrine Parameters

Since 1960, about 400 tankers spilled more than 377765 tons of oil, with the Prestige accident (Galician coast, NW Spain, November 2002) the most recent. Taking into account the consistent large number of individuals exposed to oil that exists all over the world, it seems surprising the absence in the literature of studies focused on the chronic effects of this exposure on human health. In this work we evaluated the level of DNA damage by means of comet assay, and the potential endocrine alterations (prolactin and cortisol) caused by Prestige oil exposure in a population of 180 individuals, classified in 3 groups according to the tasks performed, and 60 controls. Heavy metals in blood were determined as exposure biomarkers, obtaining significant increases of aluminum, nickel and lead in the exposed groups as compared to controls. Higher levels of genetic damage and endocrine alterations were also observed in the exposed population. DNA damage levels were influenced by age, sex, and the use of protective clothes, and prolactin concentrations by the last two factors. Surprisingly, the use of mask did not seem to protect individuals from genetic or endocrine alterations. Moreover, polymorphisms in genes encoding for the main enzymes involved in the metabolism of oil components were analyzed as susceptibility biomarkers. CYP1A1-3′UTR and EPHX1 codons 113 and 139 variant alleles were related to higher damage levels, while lower DNA damage was observed in GSTM1 and GSTT1 null individuals

Effect of food on the pharmacokinetics of omeprazole, pantoprazole and rabeprazole

Background: The pharmacokinetics of proton pump inhibitors (PPIs) may be affected by food intake. We aimed to evaluate the effect of food on the pharmacokinetics of omeprazole, rabeprazole, and pantoprazole. Setting: The study population comprised 186 healthy volunteers participating in 6 bioequivalence clinical trials. Method: Subjects were evaluated to determine the effect of a high-fat breakfast on the pharmacokinetics of omeprazole (n = 36), rabeprazole (n = 69), and pantoprazole (n = 81). Main outcome measure: Drug plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. Results: Food affected the pharmacokinetics of omeprazole (increased Tmax and decreased AUC and Cmax), pantoprazole (increased Tmax and decreased AUC), and rabeprazole (increased Tmax, Cmax and half-life). Food increased variability in Tmax for all 3 drugs, delaying absorption around 3 to 4 h and until 20 h in some subjects. Conclusion: As food delays the absorption of PPIs and increases their variability, it would be better to administer these drugs under fasting conditions. Trial registration: European Union Drug Regulating Authorities Clinical Trials Database: EudraCT: 2004-003863-59 (registration date 05/MAR/2004), EudraCT 2006-001162-17 (registration date 17-MAR-2006), EudraCT: 2007-002489-37 (registration date 12-JUN-2007), EudraCT: 2007-002490-31 (registration date 12-JUN-2007), EudraCT: 2010-024029-19 (registration date 23-NOV-2010).The analysis, interpretation of data and the manuscript writing was partially funded by Fundación Teófilo Hernando, a nonprofit foundation linked to Universidad Autónoma de Madri

Association between genetic polymorphisms and response to anti-TNFs in patients with inflammatory bowel disease

Tumor necrosis factor (TNF) is a major proinflammatory cytokine involved in the immune response in inflammatory bowel disease (IBD). Anti-TNF drugs such as infliximab and adalimumab are used to treat IBD; however, approximately 30% of patients do not respond to treatment. Individual genetic differences could contribute to lack of efficacy. Genetic studies have tried to uncover the factors underlying differences in response, however, knowledge remains limited, and the results obtained should be validated, so that pharmacogenetic information can be applied in clinical practice. In this review, we gather current knowledge in the pharmacogenetics of anti-TNF drugs in patients with IBD. We observed a connection between the major genes described as possible predictors of response to anti-TNF drugs in IBD and the cytokines and molecules involved in the T helper (Th) 17 pathwayThis study was supported by Fundación Teófilo Hernando. Rocío Prieto-Pérez has a grant from Universidad Autónoma de Madrid (research personnel in training (FPI) program 2013)

Evaluation of the relationship between pharmacokinetics and the safety of aripiprazole and its cardiovascular effects in healthy volunteers

The aim of this study was the evaluation of the possible relationship between pharmacokinetics and the safety of aripiprazole as well as its influence on blood pressure (BP), heart rate (HR), and corrected QT (QTc) interval. Methods: The study population comprised 157 healthy volunteers from 6 bioequivalence clinical trials. Subjects were administered a single 10-mg oral dose of each formulation separated by a 28-day washout period. Plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. Blood pressure was measured at the following times: predose and 0.5, 2, 4, 6, and 8 hours postdose. An electrocardiogram was recorded at predose, 4, and 8 hours postdose. Results: Area under the curve (AUC), maximum plasma concentration, half-life, and distribution volume corrected for weight were higher in women. Aripiprazole treatment produced a decrease of BP (9.3 mm Hg on systolic and 6.2 mm Hg on diastolic pressure) and an increase in HR (12.1 beats per minute) and QTc interval (9.1 milliseconds). There were sex differences in BP, HR, and QTc interval. Women and subjects with higher AUC and maximum plasma concentration values were more prone to experience adverse drug reactions and gastrointestinal adverse reactions. The AUC was related with systolic BP and diastolic BP decrease and HR increase but there was no relationship between aripiprazole concentrations and QTc increase. Conclusions: Aripiprazole decreases BP and increases HR and QTc interval. Pharmacokinetics, pharmacodynamics, and safety of aripiprazole are affected by sex. There is a directly proportional relationship between pharmacokinetic parameters and adverse drug reactions and effect on BP and HRThis study was partially funded by Fundación Teófilo Hernando and Foundation for Biomedical Research at Hospital Universitario de La Princes

Polymorphisms associated with adalimumab and infliximab response in moderate-to-severe plaque psoriasis

Aims. This study evaluated the influence of pharmacogenetics in psoriatic patients treated with adalimumab and/or infliximab. Materials & methods: Prospective observational study evaluating the association of 124 polymorphisms with the response to adalimumab or infliximab (PASI75) in patients with moderate-to-severe plaque psoriasis at 3 months (n = 95) and 6 months of treatment (n = 90). Significant SNPs for univariate analysis were subjected to multivariate analysis. Results: Five SNPs were associated with PASI75 at 3 months: rs6661932 (IVL), rs2546890 (IL-12B), rs2145623 (NFKBIA), rs9304742 (ZNF816A) and rs645544 (SLC9A8). Furthermore, rs1061624 (TNFR1B) was associated with PASI75 at 6 months. Conclusion: Nevertheless, these biomarkers should be validated in large-scale studies before implementation in clinical practice

Baixem de les tarimes i connectem: recerca en història medieval i innovació docent

We would like to introduce our group of research, [CONTRA TAEDIUM], created by professionals from different fields, that have contributed in this article. Our purpose is to expose our reflections based on our own experiences, not only in research, but also in teaching. We propose new forms of writing history in order to understand the dairy life of the women and men of the past, from birth to death. We would like to point out that interacting all types of sources is essential to understand our history. But, what really makes sense is to bring our students in the historical methodology and involve them in their education. Moreover, it is necessary to design new teaching materials using the new technologies, although it requires team-work and a great, but satisfying, effor