Imatinib plasma concentrations variability in hemato-oncologic patients

Abstract Imatinib (Glivec~ has transformed the treatment and prognosis of chronic myeloid leukaemia (CML) and of gastrointestinal stromal tumor (GIST). However, the treatment must be taken indefinitely and is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occurs. Considering the large interindividual differences in the function of the enzymatic and transport systems involved in imatinib disposition, exposure to this drug can be expected to vary widely among patients. Among those known systems is a cytochrome P450 (CYI'3A4) that metabolizes imatinib, the multidrug transporter P-glycoprotein (P-gp; product of the MDR1 gene) that expels imatinib out of cells, and al-acid glycoprotein (AGP), a circulating protein binding imatinib in the plasma. The aim of this observational study was to explore the influence of these covariates on imatinib pharmacokinetics (PK), to assess the interindividual variability of the PK parameters of the drug, and to evaluate whether imatinib use would benefit from a therapeutic drug monitoring (TDM) program. A total of 321 plasma concentrations were measured in 59 patients receiving imatinib, using a validated chromatographic method developed for this study (HPLC-LTV). The results were analyzed by non-linear mixed effect modeling (NONMEM). A one-compartment pharmacokinetic model with first-order absorption appropriately described the data, and a large interindividual variability was observed. The MDK> polymorphism 3435C>T and the CYP3A4 activity appeared to modulate the disposition of imatinib, albeit not significantly. A hyperbolic relationship between plasma AGP levels and oral clearance, as well as volume of distribution, was observed. A mechanistic approach was built up, postulating that only the unbound imatinib concentration was able to undergo first-order elimination. This approach allowed determining an average free clearance (CL,~ of 13101/h and a volume of distribution (Vd) of 301 1. By comparison, the total clearance determined was 141/h (i.e. 233 ml/min). Free clearance was affected by body weight and pathology diagnosis. The estimated variability of imatinib disposition (17% for CLu and 66% for Vd) decreased globally about one half with the model incorporating the AGP impact. Moreover, some associations were observed between PK parameters of the free imatinib concentration and its efficacy and toxicity. Finally, the functional influence of P-gp activity has been demonstrated in vitro in cell cultures. These elements are arguments to further investigate the possible usefulness of a TDM program for imatinib. It may help in individualizing the dosing regimen before overt disease progression or development of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug. Résumé L'imatinib (Glivec ®) a révolutionné le traitement et le pronostic de la leucémie myéloïde chronique (LMC) et des tumeurs stromales d'origine digestive (GIST). Il s'agit toutefois d'un traitement non dénué d'inconvénients et de toxicité, et qui doit être pris indéfiniment. Par ailleurs, une résistance, ou des échappements au traitement, sont également rencontrés. Le devenir de ce médicament dans l'organisme dépend de systèmes enzymatiques et de transport connus pour présenter de grandes différences interindividuelles, et l'on peut s'attendre à ce que l'exposition à ce médicament varie largement d'un patient à l'autre. Parmi ces systèmes, on note un cytochrome P450 (le CYP3A4) métabolisant l'imatinib, la P-glycoprotéine (P-gp ;codée par le gène MDR1), un transporteur d'efflux expulsant le médicament hors des cellules, et l'atglycoprotéine acide (AAG), une protéine circulante sur laquelle se fixe l'imatinib dans le plasma. L'objectif de la présente étude clinique a été de déterminer l'influence de ces covariats sur la pharmacocinétique (PK) de l'imatinib, d'établir la variabilité interindividuelle des paramètres PK du médicament, et d'évaluer dans quelle mesure l'imatinib pouvait bénéficier d'un programme de suivi thérapeutique (TDM). En utilisant une méthode chromatographique développée et validée à cet effet (HPLC-UV), un total de 321 concentrations plasmatiques a été dosé chez 59 patients recevant de l'imatinib. Les résultats ont été analysés par modélisation non linéaire à effets mixtes (NONMEM). Un modèle pharmacocinétique à un compartiment avec absorption de premier ordre a permis de décrire les données, et une grande variabilité interindividuelle a été observée. Le polymorphisme du gène MDK1 3435C>T et l'activité du CYP3A4 ont montré une influence, toutefois non significative, sur le devenir de l'imatinib. Une relation hyperbolique entre les taux plasmatiques d'AAG et la clairance, comme le volume de distribution, a été observée. Une approche mécanistique a donc été élaborée, postulant que seule la concentration libre subissait une élimination du premier ordre. Cette approche a permis de déterminer une clairance libre moyenne (CLlibre) de 13101/h et un volume de distribution (Vd) de 301 l. Par comparaison, la clairance totale était de 141/h (c.à.d. 233 ml/min). La CLlibre est affectée par le poids corporel et le type de pathologie. La variabilité interindividuelle estimée pour le devenir de l'imatinib (17% sur CLlibre et 66% sur Vd) diminuait globalement de moitié avec le modèle incorporant l'impact de l'AAG. De plus, une certaine association entre les paramètres PK de la concentration d'imatinib libre et l'efficacité et la toxicité a été observée. Finalement, l'influence fonctionnelle de l'activité de la P-gp a été démontrée in nitro dans des cultures cellulaires. Ces divers éléments constituent des arguments pour étudier davantage l'utilité potentielle d'un programme de TDM appliqué à l'imatinib. Un tel suivi pourrait aider à l'individualisation des régimes posologiques avant la progression manifeste de la maladie ou l'apparition de toxicité, améliorant tant l'efficacité que la tolérabilité de ce médicament. Résumé large public L'imatinib (un médicament commercialisé sous le nom de Glivec ®) a révolutionné le traitement et le pronostic de deux types de cancers, l'un d'origine sanguine (leucémie) et l'autre d'origine digestive. Il s'agit toutefois d'un traitement non dénué d'inconvénients et de toxicité, et qui doit être pris indéfiniment. De plus, des résistances ou des échappements au traitement sont également rencontrés. Le devenir de ce médicament dans le corps humain (dont l'étude relève de la discipline appelée pharmacocinétique) dépend de systèmes connus pour présenter de grandes différences entre les individus, et l'on peut s'attendre à ce que l'exposition à ce médicament varie largement d'un patient à l'autre. Parmi ces systèmes, l'un est responsable de la dégradation du médicament dans le foie (métabolisme), l'autre de l'expulsion du médicament hors des cellules cibles, alors que le dernier consiste en une protéine (dénommée AAG) qui transporte l'imatinib dans le sang. L'objectif de notre étude a été de déterminer l'influence de ces différents systèmes sur le comportement pharmacocinétique de l'imatinib chez les patients, et d'étudier dans quelle mesure le devenir de ce médicament dans l'organisme variait d'un patient à l'autre. Enfin, cette étude avait pour but d'évaluer à quel point la surveillance des concentrations d'imatinib présentes dans le sang pourrait améliorer le traitement des patients cancéreux. Une telle surveillance permet en fait de connaître l'exposition effective de l'organisme au médicament (concept abrégé par le terme anglais TDM, pour Therapeutic Drag Monitoring. Ce projet de recherche a d'abord nécessité la mise au point d'une méthode d'analyse pour la mesure des quantités (ou concentrations) d'imatinib présentes dans le sang. Cela nous a permis d'effectuer régulièrement des mesures chez 59 patients. Il nous a ainsi été possible de décrire le devenir du médicament dans le corps à l'aide de modèles mathématiques. Nous avons notamment pu déterminer chez ces patients la vitesse à laquelle l'imatinib est éliminé du sang et l'étendue de sa distribution dans l'organisme. Nous avons également observé chez les patients que les concentrations sanguines d'imatinib étaient très variables d'un individu à l'autre pour une même dose de médicament ingérée. Nous avons pu aussi mettre en évidence que les concentrations de la protéine AAG, sur laquelle l'imatinib se lie dans le sang, avait une grande influence sur la vitesse à laquelle le médicament est éliminé de l'organisme. Ensuite, en tenant compte des concentrations sanguines d'imatinib et de cette protéine, nous avons également pu calculer les quantités de médicament non liées à cette protéine (= libres), qui sont seules susceptibles d'avoir une activité anticancéreuse. Enfin, il a été possible d'établir qu'il existait une certaine relation entre ces concentrations, l'effet thérapeutique et la toxicité du traitement. Tous ces éléments constituent des arguments pour approfondir encore l'étude de l'utilité d'un programme de TDM appliqué à l'imatinib. Comme chaque patient est différent, un tel suivi pourrait aider à l'ajustement des doses du médicament avant la progression manifeste de la maladie ou l'apparition de toxicité, améliorant ainsi tant son efficacité que son innocuité.

Salivary cotinine concentrations in daily smokers in Barcelona, Spain: a cross-sectional study

Background: Characterizing and comparing the determinant of cotinine concentrations in different populations should facilitate a better understanding of smoking patterns and addiction. This study describes and characterizes determinants of salivary cotinine concentration in a sample of Spanish adult daily smoker men and women. Methods: A cross-sectional study was carried out between March 2004 and December 2005 in a representative sample of 1245 people from the general population of Barcelona, Spain. A standard questionnaire was used to gather information on active tobacco smoking and passive exposure, and a saliva specimen was obtained to determine salivary cotinine concentration. Two hundred and eleven adult smokers (>16 years old) with complete data were included in the analysis. Determinants of cotinine concentrations were assessed using linear regression models. Results: Salivary cotinine concentration was associated with the reported number of cigarettes smoked in the previous 24 hours (R2 = 0.339; p < 0.05). The inclusion of a quadratic component for number of cigarettes smoked in the regression analyses resulted in an improvement of the fit (R2 = 0.386; p < 0.05). Cotinine concentration differed significantly by sex, with men having higher levels. Conclusion: This study shows that salivary cotinine concentration is significantly associated with the number of cigarettes smoked and sex, but not with other smoking-related variables.

Concentrations of resveratrol and derivatives in foods and estimation of dietary intake in a Spanish population: European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain cohort

Resveratrol has been shown to have beneficial effects on diseases related to oxidant and/or inflammatory processes and extends the lifespan of simple organisms including rodents. The objective of the present study was to estimate the dietary intake of resveratrol and piceid (R&P) present in foods, and to identify the principal dietary sources of these compounds in the Spanish adult population. For this purpose, a food composition database (FCDB) of R&P in Spanish foods was compiled. The study included 40 685 subjects aged 35-64 years from northern and southern regions of Spain who were included in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain cohort. Usual food intake was assessed by personal interviews using a computerised version of a validated diet history method. An FCDB with 160 items was compiled. The estimated median and mean of R&P intake were 100 and 933 mg/d respectively. Approximately, 32% of the population did not consume RΠ The most abundant of the four stilbenes studied was trans-piceid (53·6 %), followed by trans-resveratrol (20·9 %), cis-piceid (19·3 %) and cis-resveratrol (6·2 %). The most important source of R&P was wines (98·4 %) and grape and grape juices (1·6 %), whereas peanuts, pistachios and berries contributed to less than 0·01 %. For this reason the pattern of intake of R&P was similar to the wine pattern. This is the first time that R&P intake has been estimated in a Mediterranean country.

Plasma homocysteine and vitamin B12 serum levels, red blood cell folate concentrations, C677T methylenetetrahydrofolate reductase gene mutation and risk of recurrent miscarriage: a case-control study in Spain.

Background: Hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) gene mutation have been postulated as a possible cause of recurrent miscarriage (RM). There is a wide variation in the prevalence of MTHFR polymorphisms and homocysteine (Hcy) plasma levels among populations around the world. The present study was undertaken to investigate the possible association between hyperhomocysteinemia and its causative genetic or acquired factors and RM in Catalonia, a Mediterranean region in Spain. Methods: Sixty consecutive patients with ≥ 3 unexplained RM and 30 healthy control women having at least one child but no previous miscarriage were included. Plasma Hcy levels, MTHFR gene mutation, red blood cell (RBC) folate and vitamin B12 serum levels were measured in all subjects. Results: No significant differences were observed neither in plasma Hcy levels, RBC folate and vitamin B12 serum levels nor in the prevalence of homozygous and heterozygous MTHFR gene mutation between the two groups studied. Conclusions: In the present study RM is not associated with hyperhomocysteinemia, and/or the MTHFR gene mutation.

Alterations of Na, K and Rb concentrations in Mycenaean pottery and a proposed explanation using X-ray diffraction

One of the most important reference groups for Mycenaean pottery is the Mycenae/Berbati (MB). In several studies, a second group has been identified (MBKR). The chemical compositions were similar to MB, but with important differences in the Na, K and Rb contents. The present study suggests that these differences are due to selective alteration and contamination processes that are indirectly determined by the original firing temperature. Therefore, groups MB and MBKR should be considered as a single reference group.

Serum Vitamin D Concentrations Are Not Associated with Insulin Resistance in Swiss Adults.

BACKGROUND: Low vitamin D status has been associated with an increased risk of developing type 2 diabetes and insulin resistance (IR), although this has been recently questioned. OBJECTIVE: We examined the association between serum vitamin D metabolites and incident IR. METHODS: This was a prospective, population-based study derived from the CoLaus (Cohorte Lausannoise) study including 3856 participants (aged 51.2 ± 10.4 y; 2217 women) free from diabetes or IR at baseline. IR was defined as a homeostasis model assessment (HOMA) index >2.6. Fasting plasma insulin and glucose were measured at baseline and at follow-up to calculate the HOMA index. The association of vitamin D metabolites with incident IR was analyzed by logistic regression, and the results were expressed for each independent variable as ORs and 95% CIs. RESULTS: During the 5.5-y follow-up, 649 (16.9%) incident cases of IR were identified. Participants who developed IR had lower baseline serum concentrations of 25-hydroxyvitamin D3 [25(OH)D3 (25-hydroxycholecalciferol); 45.9 ± 22.8 vs. 49.9 ± 22.6 nmol/L; P < 0.001], total 25(OH)D3 (25(OH)D3 + epi-25-hydroxyvitamin D3 [3-epi-25(OH)D3]; 49.1 ± 24.3 vs. 53.3 ± 24.1 nmol/L; P < 0.001), and 3-epi-25(OH)D3 (4.2 ± 2.9 vs. 4.3 ± 2.5 nmol/L; P = 0.01) but a higher 3-epi- to total 25(OH)D3 ratio (0.09 ± 0.05 vs. 0.08 ± 0.04; P = 0.007). Multivariable analysis adjusting for month of sampling, age, and sex showed an inverse association between 25(OH)D3 and the likelihood of developing IR [ORs (95% CIs): 0.86 (0.68, 1.09), 0.60 (0.46, 0.78), and 0.57 (0.43, 0.75) for the second, third, and fourth quartiles compared with the first 25(OH)D3 quartile; P-trend < 0.001]. Similar associations were found between total 25(OH)D3 and incident IR. There was no significant association between 3-epi-25(OH)D3 and IR, yet a positive association was observed between the 3-epi- to total 25(OH)D3 ratio and incident IR. Further adjustment for body mass index, sedentary status, and smoking attenuated the association between 25(OH)D3, total 25(OH)D3, and the 3-epi- to total 25(OH)D3 ratio and the likelihood of developing IR. CONCLUSION: In the CoLaus study in healthy adults, the risk of incident IR is not associated with serum concentrations of 25(OH)D3 and total 25(OH)D3.

Improved predictive mapping of indoor radon concentrations using ensemble regression trees based on automatic clustering of geological units.

PURPOSE: According to estimations around 230 people die as a result of radon exposure in Switzerland. This public health concern makes reliable indoor radon prediction and mapping methods necessary in order to improve risk communication to the public. The aim of this study was to develop an automated method to classify lithological units according to their radon characteristics and to develop mapping and predictive tools in order to improve local radon prediction. METHOD: About 240 000 indoor radon concentration (IRC) measurements in about 150 000 buildings were available for our analysis. The automated classification of lithological units was based on k-medoids clustering via pair-wise Kolmogorov distances between IRC distributions of lithological units. For IRC mapping and prediction we used random forests and Bayesian additive regression trees (BART). RESULTS: The automated classification groups lithological units well in terms of their IRC characteristics. Especially the IRC differences in metamorphic rocks like gneiss are well revealed by this method. The maps produced by random forests soundly represent the regional difference of IRCs in Switzerland and improve the spatial detail compared to existing approaches. We could explain 33% of the variations in IRC data with random forests. Additionally, the influence of a variable evaluated by random forests shows that building characteristics are less important predictors for IRCs than spatial/geological influences. BART could explain 29% of IRC variability and produced maps that indicate the prediction uncertainty. CONCLUSION: Ensemble regression trees are a powerful tool to model and understand the multidimensional influences on IRCs. Automatic clustering of lithological units complements this method by facilitating the interpretation of radon properties of rock types. This study provides an important element for radon risk communication. Future approaches should consider taking into account further variables like soil gas radon measurements as well as more detailed geological information.

Ribavirin Concentrations Do Not Predict Sustained Virological Response in HIV/HCV-Coinfected Patients Treated with Ribavirin and Pegylated Interferon in the Swiss HIV Cohort Study.

BACKGROUND: Ribavirin (RBV) is an essential component of most current hepatitis C (HCV) treatment regimens and still standard of care in the combination with pegylated interferon (pegIFN) to treat chronic HCV in resource limited settings. Study results in HIV/HCV-coinfected patients are contradicting as to whether RBV concentration correlates with sustained virological response (SVR). METHODS: We included 262 HCV treatment naïve HIV/HCV-coinfected Swiss HIV Cohort Study (SHCS) participants treated with RBV and pegIFN between 01.01.2001-01.01.2010, 134 with HCV genotype (GT) 1/4, and 128 with GT 2/3 infections. RBV levels were measured retrospectively in stored plasma samples obtained between HCV treatment week 4 and end of therapy. Uni- and multivariable logistic regression analyses were used to evaluate the association between RBV concentration and SVR in GT 1/4 and GT 2/3 infections. The analyses were repeated stratified by treatment phase (week 4-12, 13-24, >24) and IL28B genotype (CC versus CT/TT). RESULTS: SVR rates were 35.1% in GT 1/4 and 70.3% in GT 2/3 infections. Overall, median RBV concentration was 2.0 mg/L in GT 1/4, and 1.9 mg/L in GT 2/3, and did not change significantly across treatment phases. Patients with SVR had similar RBV concentrations compared to patients without SVR in both HCV genotype groups. SVR was not associated with RBV levels ≥2.0 mg/L (GT 1/4, OR 1.19 [0.5-2.86]; GT 2/3, 1.94 [0.78-4.80]) and ≥2.5 mg/L (GT 1/4, 1.56 [0.64-3.84]; GT 2/3 2.72 [0.85-8.73]), regardless of treatment phase, and IL28B genotype. CONCLUSION: In HIV/HCV-coinfected patients treated with pegIFN/RBV, therapeutic drug monitoring of RBV concentrations does not enhance the chance of HCV cure, regardless of HCV genotype, treatment phase and IL28B genotype.

The mediterranean diet pattern and its main components are associated with lower plasma concentrations of tumor necrosis factor receptor 60 in patients at high risk for cardiovascular disease

Adherence to aMediterranean diet (MD) is associated with a reduced risk of coronary heart disease. However, themolecular mechanisms involved are not fully understood. The aim of this studywas to compare the effects of 2MD with those of a lowfat- diet (LFD) on circulating inflammatory biomarkers related to atherogenesis. A total of 516 participants included in the PreventionwithMediterraneanDiet Studywere randomized into 3 intervention groups [MD supplementedwith virgin olive oil (MD-VOO); MD supplemented with mixed nuts (MD-Nuts); and LFD]. At baseline and after 1 y, participants completed FFQ and adherence to MD questionnaires, and plasma concentrations of inflammatory markers including intercellular adhesion molecule-1(ICAM-1), IL-6, and 2 TNF receptors (TNFR60 and TNFR80) were measured by ELISA. At 1 y, the MD groups had lower plasma concentrations of IL-6, TNFR60, and TNFR80 (P , 0.05), whereas ICAM-1, TNFR60, and TNFR80 concentrations increased in the LFD group (P , 0.002). Due to between-group differences, participants in the 2 MD groups had lower plasma concentrations of ICAM-1, IL-6, TNFR60, and TNFR80 compared to those in the LFD group (P # 0.028). When participants were categorized in tertiles of 1-y changes in the consumption of selected foods, those in the highest tertile of virgin olive oil (VOO) and vegetable consumption had a lower plasma TNFR60 concentration compared with those in tertile 1 (P,0.02).Moreover, the only changes in consumption thatwere associated with 1-y changes in the geometricmean TNFR60 concentrations were those of VOO and vegetables (P = 0.01). This study suggests that a MD reduces TNFR concentrations in patients at high cardiovascular risk.

Effects of oral supplementation of iron on hepcidin blood concentrations among non-anaemic female blood donors: a randomized controlled trial.

BACKGROUND AND OBJECTIVES: Hepcidin is the main hormone that regulates iron balance. Its lowering favours digestive iron absorption in cases of iron deficiency or enhanced erythropoiesis. The careful dosage of this small peptide promises new diagnostic and therapeutic strategies. Its measurement is progressively being validated and now its clinical value must be explored in different physiological situations. Here, we evaluate hepcidin levels among premenopausal female donors with iron deficiency without anaemia. MATERIALS AND METHODS: In a preceding study, a 4-week oral iron treatment (80 mg/day) was administered in a randomized controlled trial (n = 145), in cases of iron deficiency without anaemia after a blood donation. We subsequently measured hepcidin at baseline and after 4 weeks of treatment, using mass spectrometry. RESULTS: Iron supplementation had a significant effect on plasma hepcidin compared to the placebo arm at 4 weeks [+0·29 nm [95% CI: 0·18 to 0·40]). There was a significant correlation between hepcidin and ferritin at baseline (R(2) = 0·121, P < 0·001) and after treatment (R(2) = 0·436, P < 0·001). Hepcidin levels at baseline were not predictive of concentration changes for ferritin or haemoglobin. However, hepcidin levels at 4 weeks were significantly higher (0·79 nm [95% CI: 0·53 to 1·05]) among ferritin responders. CONCLUSIONS: This study shows that a 4-week oral treatment of iron increased hepcidin blood concentrations in female blood donors with an initial ferritin concentration of less than 30 ng/ml. Apparently, hepcidin cannot serve as a predictor of response to iron treatment but might serve as a marker of the iron repletion needed for erythropoiesis.

The attenuation of concentrations model: a new method for assessing mercury mobility in sediments

In this work we propose a new approach for the determination of the mobility of mercury in sediments based on spatial distribution of concentrations. We chose the Tainheiros Cove, located in the Todos os Santos Bay, Brazil, as the study area, for it has a history of mercury contamination due to a chloro-alkali plant that was active during 12 years. Twenty-six surface sediment samples were collected from the area and mercury concentrations were measured by cold vapour atomic absorption spectrophotometry. A contour map was constructed from the results, indicating that mercury accumulated in a "hot spot" where concentrations reach more than 1 µg g-1. The model is able to estimate mobility of mercury in the sediments based on the distances between iso-concentration contours that determines an attenuation of concentrations factor. Values of attenuation ranged between 0.0729 (East of the hot spot, indicating higher mobility) to 0.7727 (North of the hot spot, indicating lower mobility).