Comparison of the everolimus concentrations measured in whole blood with everolimus QMS or sirolimus CMIA.

Few years ago, it was proposed that everolimus blood levels could be determined with the commercially available sirolimus chemiluminescence magnetic microparticle immunoassay (CMIA). More recently, a highly specific microsphere system (QMS) has been approved by FDA for therapeutic drug monitoring in humans. Aim of the present study was to compare the results of everolimus assay performed with everolimus QMS and with sirolimus CMIA. The two methods were compared with Passing-Bablok regression and Bland-Altman plot analysis. The Passing-Bablok regression analysis showed that although the results obtained with the two techniques were significantly correlated, CMIA-measured differed from QMS-measured everolimus concentrations by both a systematic and a proportional error. Specifically, at blood levels lower than 5 ng/mL CMIA were lower than QMS-measured everolimus concentrations. On the opposite, at everolimus blood concentrations higher than 10 ng/mL CMIA-estimated values became progressively higher than QMS-measured everolimus concentrations. The analysis of the Bland Altman plot showed a less than optimal agreement of the two tests (5.59% of the data point outside the ±1.96 SD interval). Moreover, the relationship between the difference between EveroQMS and EveroCMIA and their average was clearly concentration dependent with positive and negative values at concentration values lower and higher than 5 ng/mL respectively. In conclusion, our finding showed that the values of everolimus concentrations measured with sirolimus CMIA differ from those detected with the FDA-approved everolimus QMS further suggesting that sirolimus CMIA should not be used anymore for everolimus therapeutic drug monitoring.

Emerging Role of the Spleen in the Pharmacokinetics of Monoclonal Antibodies, Nanoparticles and Exosomes.

After being absorbed, drugs distribute in the body in part to reach target tissues, in part to be disposed in tissues where they do not exert clinically-relevant effects. Therapeutically-relevant effects are usually terminated by drug metabolism and/or elimination. The role that has been traditionally ascribed to the spleen in these fundamental pharmacokinetic processes was definitely marginal. However, due to its high blood flow and to the characteristics of its microcirculation, this organ would be expected to be significantly exposed to large, new generation drugs that can hardly penetrate in other tissues with tight endothelial barriers. In the present review, we examine the involvement of the spleen in the disposition of monoclonal antibodies, nanoparticles and exosomes and the possible implications for their therapeutic efficacy and toxicity. The data that we will review lead to the conclusion that a new role is emerging for the spleen in the pharmacokinetics of new generation drugs, hence suggesting that this small, neglected organ will certainly deserve stronger attention by pharmacologists in the future.

Sublingual administration improves systemic exposure of tacrolimus in kidney transplant recipients: comparison with oral administration.

BACKGROUND: Tacrolimus (TCR) is an immunosuppressive drug used by oral administration. Intravenous (IV) TCR administration is required under conditions of gastrointestinal diseases or abdominal surgery at the onset of paralytic ileus. The infusion formulation needs a large dilution and therefore a careful technical management during continuous infusion by 24 h and may determine anaphylaxis, cardiac arrhythmia, QT prolongation and torsades de pointes. Sublingual (SL) TCR administration was suggested as an alternative route. DESIGN: The aim of this study was to compare in the same kidney transplanted patients the TCR pharmacokinetic profiles by both the routes coupled with the pharmacoeconomic analysis. The study enrolled eight subjects undergoing renal transplantation and treated with TCR and methylprednisolone. TCR was administered by oral route at the scheduled dosage while the 50% of oral dosage was used by SL route, taking into account the absence of liver first pass. RESULTS: Except for AUC, which resulted significantly increased after oral administration, all exposure parameters were not significantly different between the two routes of administration. Analysis of dose-adjusted exposure parameters showed significant increases in AUC and Cmin after SL administration confirming a better bioavailability of the SL route compared with oral route. Cost saving was obtained using the SL rather than the IV route of TCR delivery. CONCLUSION: When oral administration of TCR is not advised, SL delivery represents an attractive option to IV administration.

Hematocrit Values Predict Carotid Intimal-Media Thickness in Obese Patients With Non-Alcoholic Fatty Liver Disease: A Cross-Sectional Study.

BACKGROUND: Literature data suggest with some criticism that full-fledged cardiovascular (CV) events (acute or chronic) are likely predicted by blood components, which are reported to be associated with the presence/severity of non-alcoholic fatty liver disease (NAFLD). This study was aimed at determining which marker(s) derived from blood count, such as white blood cells, neutrophils, neutrophil/lymphocyte ratio, platelet count, hemoglobin, mean corpuscular volume, hematocrit values were associated with ear or subclinical atherosclerosis, in obese patients of various classes suffering from NAFLD. METHODS: One hundred consecutive obese patients presenting NAFLD at ultrasound, with low prevalence of co-morbidities and no history or instrumental features of CV diseases, underwent carotid intima-media thickness (IMT) assessment by Doppler ultrasonography. All of them were studied taking into account anthropometric parameters, the metabolic profile, and inflammatory markers. RESULTS: White blood cells and neutrophil count showed no statistical association with IMT, which was predicted by the amount of visceral adiposity, as appreciated by ultrasonography. After adjusting for visceral adiposity and smoking status, only age and hematocrit contextually predicted early atherosclerosis, evaluated as IMT. Visceral adiposity was a confounding factor in foreseeing IMT. CONCLUSION: Hematocrit values along with the patient's age suggest an initial atherosclerosis, evaluated as IMT, and if this finding is confirmed in larger cohorts, could be added to other canonical CV risk factors. Inferences can be enhanced by future prospective studies that aim to identify the relationships between incident cardio-metabolic cases and this hematologic parameter.

Reticulocyte Hemoglobin Content Helps Avoid Iron Overload in Hemodialysis Patients: A Retrospective Observational Study.

BACKGROUND/AIM: Anemia in patients suffering from end-stage renal failure is currently treated with Erythropoiesis-Stimulating Agents (ESA). This treatment needs sufficient iron supplementation to avoid an inadequate dosage of ESA. Nowadays modern analytical instruments allow to accurately calculate the content of Hemoglobin (Hb) in reticulocytes (CHr), that can be used as a guide for prescribing patients with the appropriate amount of iron. PATIENTS AND METHODS: Patients, undergoing hemodialysis, were retrospectively selected from the database and were divided in two groups: group A received intravenous (IV) iron and subcutaneously ESA, and their dosages were adjusted on the basis of the following parameters: Hb, Mean corpuscular haemoglobin (MCH), CHr with consequent MCH/CHr ratio and reticulocyte count determined by the ADVIA 120 Hematology System of Siemens; group B patients were administered IV iron and ESA monitoring iron storage, Hb and ferritin. The aforementioned parameters and the administered amount of iron and ESA were monitored at baseline, four and eight months from the begining of the study. RESULTS: For ESA supplementation, no difference was observed between the groups at the various observed times. Despite similar Hb levels, the patients of group A needed significant lower doses of IV iron (-57.8%) avoiding risks of organ toxicity and obtaining consequent cost saving of nearly 1 €/patient/month. CONCLUSION: The use of CHr and its related parameters allows the avoidance of overdosage of IV iron, which can potentially damage organs, and the reduction of health care direct and indirect costs.