Lung cancer is a major cause of cancer-related mortality worldwide, both in men and women. The vast majority of patients are diagnosed with non-small-cell lung cancer (NSCLC, 80–85% of lung cancer cases). Therapeutics named immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment in the last decade. They are monoclonal antibodies, and those directed against PD-1 (programmed cell death protein 1) or PD-L1 (programmed cell death-ligand 1) have been used in the treatment of lung cancer and significantly improved the prognosis of NSCLC patients. However, during treatment with ICIs, immune-related adverse events (irAEs) can occur in any organ and any tissue. At the same time, although cardiac irAEs are relatively rare compared to irAEs in other organs, they have a high mortality rate. The two most common clinical manifestations of immunotherapy-related cardiotoxicity are myocarditis and pericarditis. Various types of arrhythmias have been reported in patients treated with ICIs, including the occurrence of life-threatening complete atrioventricular block or ventricular tachyarrhythmias. Here, we aim to summarize the incidence, clinical manifestations, underlying mechanisms, diagnosis, and treatment strategies for ICI-associated cardiotoxicity as these issues become very important in view of the increasing use of ICI in the treatment of lung cancer.

https://www.mdpi.com/1422-0067/21/19/7195/pdf

Immune Checkpoint Inhibitors and Cardiac Toxicity in Patients Treated for Non-Small Lung Cancer: A Review

Purpose: The aim of this study was to develop a simple, rapid and sensitive reverse phase high performance liquid chromatography (RP-HPLC) method for quantification of sirolimus (SRL) in pharmaceutical dosage forms. Methods: The chromatographic system employs isocratic elution using a Knauer- C18, 5 mm, 4.6 × 150 mm. Mobile phase consisting of acetonitril and ammonium acetate buffer set at flow rate 1.5 ml/min. The analyte was detected and quantified at 278nm using ultraviolet detector. The method was validated as per ICH guidelines. Results: The standard curve was found to have a linear relationship (r2 > 0.99) over the analytical range of 125–2000ng/ml. For all quality control (QC) standards in intraday and interday assay, accuracy and precision range were -0.96 to 6.30 and 0.86 to 13.74 respectively, demonstrating the precision and accuracy over the analytical range. Samples were stable during preparation and analysis procedure. Conclusion: Therefore the rapid and sensitive developed method can be used for the routine analysis of sirolimus such as dissolution and stability assays of pre- and post-marketed dosage forms.

/pdf/development-and-validation-of-an-hplc-method-for-the-19e5zj95do.pdf

Development and Validation of an HPLC Method for the Analysis of Sirolimus in Drug Products

Background. Although high-performance liquid chromatography (HPLC) is the method of choice for blood sirolimus determination, the microparticle enzyme immunoassay (MEIA) run on the IMx® analyser is widely used in therapeutic monitoring of this immunosuppressant agent. The aim of our study was to evaluate the possible determination of sirolimus using the fluorescence polarization immunoassay (FPIA) commercialized for everolimus quantification.Methods. Sirolimus concentrations were determined in whole-blood samples from liver and kidney transplant recipients using the Innofluor® Certican® FPIA (Seradyn Inc.) run on a TDx® analyser (Abbott Laboratories), Sirolimus MEIA run on an IMx® analyser (Abbott Laboratories), and HPLC (UV detection) methods.Results. The Innofluor® FPIA has a similar cross-reactivity with everolimus and sirolimus, and the within- and between-run coefficients of variation obtained for sirolimus determination were 2.7%–13.3%. In analysing different blood samples from liver and kidney tran...

Determination of blood sirolimus concentrations in liver and kidney transplant recipients using the Innofluor® fluorescence polarization immunoassay: Comparison with the microparticle enzyme immunoassay and high-performance liquid chromatography-ultraviolet method

Globally, 69.6 million individuals were infected with hepatitis C virus (HCV) infection in 2016. Of the six major HCV genotypes (GT), the most predominant one is GT1, worldwide. The prevalence of HCV in Central Asia, which includes most of the Commonwealth of Independent States (CIS), has been estimated to be 5.8% of the total global burden. The predominant genotype in the CIS and Ukraine regions has been reported to be GT1, followed by GT3. Inadequate HCV epidemiological data, multiple socio-economic barriers, and the lack of region-specific guidelines have impeded the optimal management of HCV infection in this region. In this regard, a panel of regional experts in the field of hepatology convened to discuss and provide recommendations on the diagnosis, treatment, and pre-, on-, and posttreatment assessment of chronic HCV infection and to ensure the optimal use of cost-effective antiviral regimens in the region. A comprehensive evaluation of the literature along with expert recommendations for the management of GT1-GT6 HCV infection with the antiviral agents available in the region has been provided in this review. This consensus document will help guide clinical decision-making during the management of HCV infection, further optimizing treatment outcomes in these regions.

Consensus on management of hepatitis C virus infection in resource-limited Ukraine and Commonwealth of Independent States regions.

Measurement of sirolimus as a guide to therapy is widely accepted. Since the commercial introduction of the drug, the only method available to measure blood concentrations has been high-performance liquid chromatography (HPLC). Only a limited number of centers have the facilities to perform this technique and, as a result, the measurement of the drug has been performed in central laboratories, often some distance from the clinical centers. This article describes a single-center assessment of a new immunoassay to measure sirolimus, including a comparison between immunoassay results and a chromatographic technique. Calibration accuracy was good, reproducibility at 11 ng/mL was better than 6%, and sensitivity was better than 2 ng/mL; all these parameters are appropriate for routine clinical use. There was a mean positive bias of almost 20% for the measurement of sirolimus in clinical samples from kidney transplant patients receiving the drug, compared with HPLC. This bias was most likely due to cross-reactivity with metabolites of the drug and was of the order noted when an earlier configuration of this immunoassay was used in clinical practice. We conclude that, despite the analytical bias, this immunoassay offers a viable alternative to the use of HPLC and would be an assay suitable for implementing at local centers.

A microparticle enzyme immunoassay to measure sirolimus

http://revistafarmaciahospitalaria.sefh.es/gdcr/index.php/fh/article/download/1025/1025

Comparación de la cromatografía líquida de alta resolución frente al enzimoinmunoensayo de micropartículas para la determinación de sirolimus en trasplante renal

Infliximab en artritis reumatoide. Utilización en un hospital de tercer nivel

Background and importance In naive treated populations with advanced non-small cell lung cancer (NSCLC), pembrolizumab monotherapy is the recommended option for patients whose tumours express PD-L1 with a tumour proportion score (TPS) ≥50%. In a population previously treated with platinum based chemotherapy double, pembrolizumab (PD-L1 1%) is a valid option in those who have not been treated with firstline immunotherapy. Aim and objectives To analyse the effectiveness and safety of patients with NSCLC treated with pembrolizumab in clinical practice. Material and methods This was a multicentre, observational, retrospective study carried out between January 2017 and June 2019. All patients with NSCLC undergoing treatment with pembrolizumab as monotherapy were included. Patient data were taken from the clinical records. Variables included were age, sex, stage, line of treatment, dose administered and functional status (PS) according to the ECOG scale. Efficacy endpoints was progression free survival (PFS) assessed by RECIST 1.1 criteria. Adverse events (AEs) were also assessed. Analysis of PFS was performed using the Kaplan–Meier curve. Results Thirty-eight patients were included with NSCLC: 81.58% were men, mean age was 62.34±11.68 years, 97.36% (n=37) had ECOG PS 0–1 and 100% had NSCLC stage IV. The percentage of patients who started pembrolizumab as firstline therapy was 50% and their tumours expressed PD-L1 ≥50% TPS, 42.10% had pembrolizumab as secondline therapy and 7.90% as thirdline therapy. The median administered dose was 160 mg (108–200); 8 patients (21.05%) are still receiving treatment. Causes of treatment suspension in the remaining patients were disease progression (60.53%) or death (18.42%). Median PFS of patients who started pembrolizumab as firstline therapy was 10 months (95% CI 7.1–12.92); in those treated as secondline and thirdline, median PFS was 4.2 months (95% CI 3.12–5.27). AEs included asthenia grades 1–2 in 15.79%, arthralgia grades 1–2 in 13.16%, dermatitis in 7.89%, diarrhoea in 7.89%, hypothyroidism in 5.26%, pneumonitis in 5.26%, vomiting in 5.26%, anorexia in 5.26%, constipation in 5.26% and myalgia in 2.63%. Conclusion and relevance Median PFS in our study was similar to the results of Keynote-024 (pembrolizumab as firstline treatment) 10 versus 10.3 months and Keynote-010 (pembrolizumab in previously treated patients) 4.2 versus 3.9 months. Pembrolizumab was safe and well tolerated; the safety profile was similar to that described in clinical trials. References and/or acknowledgements 1. doi: 10.1016/S0140-6736(15)01281-7 2. doi: 10.1016/S1470-2045(17)30690-3. No conflict of interest.

https://ejhp.bmj.com/content/ejhpharm/27/Suppl_1/A93.2.full.pdf

4CPS-099 Real world evidence of pembrolizumab as monotherapy in non-small cell lung cancer: effectiveness and safety study

Experimental evidence suggests that in acute haemorrhagic pancreatitis in the dog the percentage of the cardiac output distributed to the pancreas falls. Histological evidence indicates arteriovenous shunt flow, but this has not been confirmed by flow measurements. It has recently been reported that in experimental preparations in which pancreatic blood flow is measured through the superior pancreaticoduodenal artery after ligation of other (accessory) vessels, perfusion is reduced in distal regions of the gland. There are no data regarding regional perfusion measurements in acute pancreatitis or the effect of ligating accessory vessels. This study therefore evaluates blood flow and regional perfusion in haemorrhagic pancreatitis in various preparations of the canine pancreas. Perfusion was assessed by measuring the clearance of Krypton-85 after injection into the arterial blood supply of the pancreas. Arterial blood flow was measured by the electromagnetic flow technique. The results show that perfusion in different regions of the gland is similar both before and during disease. If accessory vessels are ligated, however, only perfusion in the head of the gland is maintained. No arteriovenous shunt flow was shown. The percentage of the cardiac output being distributed to the gland did not change in any of the experiments; this contradiction to previous reports may arise from the effective control of acid base balance in this study. 

4CPS-073 Desensitisation to ibrutinib in a patient with serious late reaction: a case report

Background Hepatitis C is a serious disease with high prevalence, leading the causes of liver transplantation. The development of well-tolerated and highly effective direct-acting antivirals (DAAs) for hepatitis C virus (HCV) has dramatically changed the therapeutic landscape. Purpose Assessing the effectiveness of sofosbuvir/ledipasvir (SOF/LDV), dasabuvir/paritaprevir/ombitasvir/ritonavir (DSV/PTV +R /OBV) and sofosbuvir/simeprevir (SOF+SIM) used in the treatment of the hepatitis C virus genotype-1 infection. Material and methods Retrospective and observational study during 2015. Inclusion criteria: patients with HCV genotype-1 infection treated for 12 weeks either with SOF/LDV or SOF+SMV or PTV +R /OBV/DSV during study period. Exclusion criteria: patients with no data available, deaths or without therapeutic adherence. Outcomes collected: demographics: age and sex. Clinical data: basal viral load (BVL), SVR at week 12 (SVR12), defined as HCV RNA titres lower than 15 IU/mL. METAVIR score: F0 to F4. Subgenotype, liver transplant, HIV co-infection, previous treatments for HCV. Data were collected from the medical records of patients. Results Treatment with SOF/LDV: 39 patients were included (64.1% males) with a mean age of 60.3±9.1 years. Subgenotypic distribution was: 15.4% gt-1, 28.2% gt. 1-A, 56.4% gt. 1-B. According to METAVIR score: F4 to F3 (74.35%), F2 to F1 (25.65%). 17.9% patients were HIV-coinfected and 25.6% were liver transplanted. 51.3% were pretreated with ribavirin/peginterferon and 76.9%% had BVL>than 800,000 UI/ml. All patients (39) achieved SVR12. Treatment with PTV +R /OBV/DSV: 52 patients (67.32% male) were included with mean age 55.2±10 years. Subgenotypic distribution: 11.5% gt-1, 21.1% gt. 1-A, 67.4% gt. 1-B. Degree of fibrosis: F4 to F3 (75%), F2 to F1 (25%). HIV-coinfected patients 30.8%, and 30.7% pretreated with ribavirin/peginterferon. 57.7% had BVL>800,000 UI/ml. 98% (51/52) patients achieved SVR12. Treatment with SOF+SMV: 61 patients (59% males) were included, with mean age of 56.3±10 years. Subgenotypic distribution: 23% gt-1, 21.3% gt. 1-A, 55.7% gt. 1-B. METAVIR score: F4 to F3 (88.5%). F2 to F1 (11.5%). 70.5% had BVL>800,000 UI/ml. 16.4% were coinfected, and 65.6% pretreated. 90.2% (55/61) achieved SVR12. Conclusion The SVR12 rates achieved in this study with the treatments SOF/LDV, SOF/SMV and PTV/OBV/r±RBV match the results obtained in published clinical trials ION–1,2,3; SAPPHIRE 1–2, PEARL 2–3–4, TURQUOISE 2–3 and COSMOS/OPTIMIST, respectively. These results indicate an excellent response to the AADs, and allow us to see a horizon of the eradication of VHC disease. No conflict of interest

I Muñoz Castillo

Papers

Comparación de la cromatografía líquida de alta resolución frente al enzimoinmunoensayo de micropartículas para la determinación de sirolimus en trasplante renal

Infliximab en artritis reumatoide. Utilización en un hospital de tercer nivel

4CPS-099 Real world evidence of pembrolizumab as monotherapy in non-small cell lung cancer: effectiveness and safety study

4CPS-073 Desensitisation to ibrutinib in a patient with serious late reaction: a case report

4CPS-087 Assessment of the direct acting antivirals used to treat the hepatitis c virus genotype 1 infection in a tertiary hospital