Novel Genetic Variants Explaining Severe Adverse Drug Events after Clinical Implementation of DPYD Genotype-Guided Therapy with Fluoropyrimidines: An Observational Study.

Fluoropyrimidines (FPs) are commonly prescribed in many cancer streams. The EMA and FDA-approved drug labels for FPs recommend genotyping the DPYD*2A (rs3918290), *13 (rs55886062), *HapB3 (rs56038477), alleles, and DPYD rs67376798 before treatment starts. We implemented the DPYD genotyping in our daily clinical routine, but we still found patients showing severe adverse drug events (ADEs) to FPs. We studied among these patients the DPYD rs1801265, rs17376848, rs1801159, rs1801160, rs1801158, and rs2297595 as explanatory candidates of the interindividual differences for FP-related toxicities, examining the association with the response to FPs . We also studied the impact of DPYD testing for FP dose tailoring in our clinical practice and characterized the DPYD gene in our population. We found a total acceptance among physicians of therapeutic recommendations translated from the DPYD test, and this dose tailoring does not affect the treatment efficacy. We also found that the DPYD*4 (defined by rs1801158) allele is associated with a higher risk of ADEs (severity grade ≥ 3) in both the univariate (O.R. = 5.66; 95% C.I. = 1.35-23.67; p = 0.014) and multivariate analyses (O.R. = 5.73; 95% C.I. = 1.41-28.77; p = 0.019) among FP-treated patients based on the DPYD genotype. This makes it a candidate variant for implementation in clinical practice.

Azathioprine dose tailoring based on pharmacogenetic information: Insights of clinical implementation.

Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and rheumatoid arthritis), and in patients receiving organ transplants. Thiopurine-S-methyltransferase (TPMT) is a cytoplasmic trans-methylase catalyzing the S-methylation of thiopurines. The active metabolites obtained from thiopurines are hydrolyzed into inactive forms by the Nudix hydrolase 15 (NUDT15). The TPMT*2 (defined by rs1800462), *3A (defined by rs1800460 and rs1142345), *3B (defined by rs1800460), *3C (defined by rs1142345), *6 (defined by rs75543815), and NUDT15 rs116855232 genetic variant have been associated, with the highest level of evidence, with the response to azathioprine, and, the approved drug label for azathioprine and main pharmacogenetic dosing guidelines recommend starting with reduced initial doses in TPMT intermediate metabolizer (IM) patients and considering an alternative treatment in TPMT poor metabolizer (PM) patients. This study aims to assess the clinical impact of azathioprine dose tailoring based on TPMT genotyping studying the azathioprine toxicity and efficacy, treatment starts, and dose adjustments during follow-up, comparing TPMT IM/PM and normal metabolizer (NM) patients. It also studied the association of NUDT15 rs116855232 with response to azathioprine in patients receiving a tailored treatment based on TPMT and characterized the TMPT and NUDT15 studied variants in our population. Results show that azathioprine dose reduction in TPMT IM patients (TPMT*1/*2, *1/*3A, or *1/*3C genotypes) is related to lower toxicity events compared to TPMT NM (TPMT *1/*1 genotype), and lower azathioprine dose adjustments during follow-up without showing differences in the efficacy. The results support the hypothesis of existing other genetic variants affecting azathioprine toxicity.

Intact charge variant analysis of ziv-aflibercept by cationic exchange liquid chromatography as a proof of concept: Comparison between volatile and non-volatile salts in the mobile phase.

Ziv-aflibercept (ziv-AFL) is a complex fusion protein which is widely used in hospitals for the treatment of colorectal metastatic cancer. Charge variants are critical attributes for assessing post-transitional modifications (PMTs) that have to be controlled during the development and manufacture of these proteins and until their administration to patients. Cation exchange (CEX) chromatography is a charge-sensitive analytical method that is well suited for analysing charge variants in proteins. The aim of this paper is to analyse the charge variants of ziv-AFL in the medicine (Zaltrap®) when fresh and when degraded. Two CEX chromatographic methods were compared for this purpose. The former was an adaptation of the method used in the first published study in which charge variants were analysed via pH gradient elution using volatile, low ionic strength buffers with direct coupling to high-resolution Orbitrap mass spectrometry. The second method was developed and optimized during our research using the salt-mediated pH gradient mode and classical non-volatile, high ionic strength buffers which were incompatible with direct coupling with mass detection. Fresh and controlled degraded samples of ziv-AFL were used to evaluate the capacity of both CEX chromatographic strategies for detecting charge variants in ziv-AFL. In the controlled degradation study the samples of the medicine were subjected to three stress factors: temperature of 60 °C for three hours, freeze/thaw process -two cycles-, and exposure to light for twelve hours. The CEX chromatographic method with non-volatile salts in the mobile phase enabled better detection of charge variants degraded ziv-AFL samples than the method using volatile salts with lower ionic strength. In addition, the complexity of the mass spectra data generated made it impossible to identify the multicharge variant species of ziv-AFL. Although charge variants were not separated in ziv-AFL fresh sample, our results indicate that the method with non-volatile salts in the mobile phase could be used to characterize and track changes in the charge variant UV chromatographic profile of ziv-AFL in fresh and degraded samples, even though it cannot be coupled to a mass detector and there is therefore no information about mass. The increase of basic protein degraded compounds were the most important degradation pattern detected in ziv-AFL (Zaltrap®).

Impact of single nucleotide polymorphisms on the efficacy and toxicity of EGFR tyrosine kinase inhibitors in advanced non-small cell lung cancer patients.

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the treatment of choice for advanced-stage (IIIB-IV) NSCLC patients with mutations in EGFR. However, EGFR-TKIs clinical outcomes vary from person to person and these inter-individual differences may be due to genetic factors such as single nucleotide polymorphisms (SNPs). SNPs in genes involved in EGFR-TKIs pharmacodynamics, metabolism and mechanism of action have been demonstrated to be associated with response, survival and toxicity in advanced NSCLC patients treated with EGFR-TKIs. Here we review the influence of gene polymorphisms in the EGFR pathway on clinical outcome and toxicity to EGFR-TKIs in advanced NSCLC patients. The EGFR-216 polymorphism has reported a strong association between response and/or survival to EGFR-TKIs in Caucasian population. Similarly, the effect of EGFR-CA repeats polymorphisms on survival of advanced NSCLC patients treated with EGFR-TKIs have been confirmed both in Caucasian and Asian population. The influence on toxicity of the -216, -191, CA repeats, Arg497Lys and Asp994Asp polymorphisms in EGFR have also been confirmed. Polymorphisms in AKT (rs1130214 and rs1130233) and SMAD3 (rs6494633, rs11071938 and rs11632964) have been associated with survival in advanced NSCLC patients treated with EGFR-TKIs. However, data come from a limited number of studies and need to be confirmed. Finally, polymorphisms in genes coding proteins of the membrane transporters and cytochrome P450 enzymes have been less extensively investigated. There are few studies with small samples, which complicated the generalization of their role in EGFR-TKIs treatment.

Cutaneous leishmaniasis associated with TNF-α blockers: a case report.

Leishmaniasis is a chronic protozoan disease that is found in diverse geographical areas of the world. Leishmania spp. are endemic in the Mediterranean coasts of southern Europe. Tumour necrosis factor alpha (TNF-α) plays an important role in the defence of the host against infection by Leishmania spp. In this case report we describe Leishmania infection caused by a monoclonal antibody against TNF-α: infliximab. A 51-year-old patient with psoriatic arthritis treated with infliximab, 5 mg/kg every 6 weeks as immunomodulatory treatment and methotrexate 10 mg weekly as a conventional disease-modifying antirheumatic drug, visited his otorhinolaryngologist owing to a lesion in his left nostril. The lesion was diagnosed as cutaneous leishmaniasis so treatment with infliximab was suspended. The patient was then treated with liposomal amphotericin B and showed a total recovery of the lesion; liposomal amphotericin B was maintained at 5 mg/kg monthly.

Trends in endpoint selection and result interpretation in advanced non-small cell lung cancer clinical trials published between 2000 and 2012: A retrospective cohort study.

BACKGROUND: The objective of this review was to investigate trends in clinical trial design, specifically, the primary outcomes used, interpretation of results, and the magnitude of the benefits described in phase III controlled clinical trials in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). METHODS: Seventy-six trials published between 2000 and 2012 were selected from a total of 122 identified in a structured search. RESULTS: Overall survival (OS) was evaluated as the primary study endpoint in 50 (65.8%) trials, followed by progression-free survival (PFS) in 15 (19.7%), and other variables, such as toxicity, quality of life (QoL), and response rate in 11 (14.5%). Ten (66.7%) out of 15 clinical trials using PFS as the primary endpoint were published between 2010 and 2012. Median overall survival (mOS) was 9.90 months (interquartile range: 3.5) with an increase of 0.384 months per year of publication (P < 0.001). A statistically significant improvement in mOS was obtained in only 13 (18.8%) trials. A total of 41 (53.9%) studies concluded that the result was positive. Of these, only 16 (39.1%) showed a statistically significant benefit in OS. QoL was assessed in 46 trials (60.5%) and of these, 10 (21.7%) reported significant improvements. CONCLUSIONS: These findings raise important questions about how clinical benefits are measured in clinical trials in advanced NSCLC. Appropriate clinically relevant outcome variables should be established and validated, and post-marketing studies should be requested by regulatory authorities to ensure meaningful clinical benefits in OS and QoL.

Extravasation accidents with liposomal/liposomal pegylated anthracyclines treated with dexrazoxane: an overview and outcomes.

The extravasation of chemotherapeutic agents is a challenge for oncologic care teams. The management of nonliposomal (conventional) anthracyclines is well established in clinical practice guidelines, including general measures and specific antidotes, such as dexrazoxane. However, there is little scientific evidence on the management of liposomal and pegylated liposomal anthracyclines. The aim of this paper was to review the scientific literature on the extravasation of liposomal and pegylated liposomal anthracyclines and determine the clinical impact of this type of extravasation, focusing on dexrazoxane. The literature was searched using two databases: PubMed and Embase. Three searches were conducted, using liposomal anthracycline extravasation, pegylated liposomal anthracycline extravasation, and liposomal doxorubicin extravasation as keywords, respectively. Seven articles fulfilled the study eligibility criteria and included seventeen cases in humans. Extravasation occurred with three drugs: liposomal doxorubicin in nine (53%) patients, liposomal daunorubicin in four (23.5%) patients, and pegylated liposomal doxorubicin in four (23.5%) patients. General measures for extravasations were applied in all patients, but only three patients received dexrazoxane. All cases were completely resolved at 2-3 months, except for one patient, in whom dexrazoxane was not used. In animals, dexrazoxane decreased both the frequency of wounds produced by pegylated liposomal doxorubicin and their extent. The pharmacokinetic profiles of liposomal and pegylated liposomal anthracyclines differ from those of conventional anthracyclines, modifying their effectiveness and safety. General measures may be inadequate to heal areas affected by extravasation, which may require the administration of dexrazoxane. However, each case should be evaluated individually for the administration of dexrazoxane in off-label use until scientific evidence is available on its effectiveness and safety as an antidote for these formulations of anthracyclines.

Pomalidomide in the treatment of multiple myeloma: design, development and place in therapy.

Multiple myeloma is a very heterogeneous disease with variable survival. Despite recent progress and the widespread use of new agents, patients with relapsed and refractory disease have a poor outcome. Immunomodulatory drugs play a key role in both the front-line and the relapsed/refractory setting. The combination of pomalidomide (POM) and dexamethasone is safe and effective in relapsed and refractory patients, even in those with high-risk cytogenetic features. Furthermore, it can be used in most patients without the need to adjust according to the degree of renal failure. In order to further improve the results, POM-based triplet therapies are currently used. This article highlights the most relevant issues of POM and POM-based combinations in the relapsed/refractory multiple myeloma setting, from a pharmacological and clinical point of view.

Trends in phase III randomized controlled clinical trials on the treatment of advanced non-small-cell lung cancer.

The objective of this review was to analyze trends in outcomes and in the quality of phase III randomized controlled trials on advanced NSCLC published between 2000 and 2012, selecting 76 trials from a total of 122 retrieved in a structured search. Over the study period, the number of randomized patients per trial increased by 14 per year (P = 0.178). The sample size significantly increased between 2000 and 2012 in trials of targeted agents (460.1 vs. 740.8 patients, P = 0.009), trials of >1 drug (360.4 vs. 584.8, P = 0.014), and those including patients with good performance status (675.3 vs. 425.6; P = 0.003). Quality of life was assessed in 46 trials (60.5%), and significant improvements were reported in 10 of these (21.7%). Platinum-based regimens were the most frequently investigated (86.8% of trials). Molecular-targeted agents were studied in 25.0% of chemotherapy arms, and the percentage of trials including these agents increased each year. The median (interquartile range) overall survival (MOS) was 9.90 (3.5) months with an increase of 0.384 months per year of publication (P < 0.001). A statistically significant improvement in MOS was obtained in only 13 (18.8%) trials. The median progression-free survival was 4.9 (1.9) months, with a nonsignificant increase of 0.026 months per year (P > 0.05). There has been a continuous but modest improvement in the survival of patients with advanced NSCLC over the past 12 years. Nevertheless, the quality of clinical trials and the benefit in outcomes should be carefully considered before the incorporation of novel approaches into clinical practice.

Medication reconciliation at admission to surgical departments.

RATIONALE, AIMS AND OBJECTIVES: We aim to determine the prevalence of reconciliation errors (REs) at admission to surgery departments, report their potential clinical impact and analyse possible risk factors. METHODS: Prospective observational study was conducted for 8 months in a regional public hospital in Spain. The study included patients consecutively hospitalized in the Department of Orthopedic Surgery and Traumatology or Department of Angiology and Vascular Surgery from May through December 2010. At 24-48 hours after hospital admission, the pre-admission pharmacological treatment of patients was compared with the medication received in hospital to identify REs, which were classified by type and potential severity. Multivariate logistic regression analysis was conducted with the presence of RE as dependent variable. RESULTS: The study included 176 patients, 60.8% of whom were aged >65 years and consumed a mean of 5.55 (±4.33) drugs. 55.1% had ≥1 RE, with a mean of 3.21 REs per patient [95% confidence interval (CI; 2.72-3.70)]. The most frequent RE was drug omission (84.1%). No clinical risk was posed by 50.5% of the REs. Multivariate analysis evidenced fourfold higher risk of an RE in patients admitted for elective versus emergency surgery and a 1.35-fold higher risk in patients receiving a larger number of drugs. CONCLUSIONS: There was a high prevalence of REs among patients admitted to the surgical departments, most frequently the omission of a drug. The risk of an RE was higher in patients admitted for elective versus emergency surgery, as well as with the receipt of a larger number of drugs before admission.

Influence of the HER2 Ile655Val polymorphism on trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients: a meta-analysis.

BACKGROUND: The HER2 655 A>G genetic variant has recently been associated with trastuzumab-induced cardiotoxicity in HER2 breast cancer patients. Considering previous results, the aim of our study was to validate the role of this polymorphism as a predictor of the cardiac toxicity of trastuzumab in breast cancer patients. METHODS: Our study population was composed of 78 HER2 breast cancer patients receiving trastuzumab. The HER2 655 A>G (rs1136201) genetic variant was genotyped using TaqMan allelic discrimination technology. Patients were classified on the basis of the occurrence of cardiotoxic events or the absence of cardiotoxic events during 1 year after the first infusion. RESULTS: The HER2 655 A>G polymorphism was significantly associated with cardiotoxicity: AG versus AA [P=0.012, odds ratio (OR)=5.12, 95% confidence interval (CI) 1.43-18.36], AG+GG versus AA (P=0.01, OR=5.72, 95% CI 1.50-21.76), AG versus AA+GG (P=0.005, OR=7.17, 95% CI 1.82-28.29). A meta-analysis combining these data with the results from previous studies confirmed this association. CONCLUSION: Our results support the role of the HER2 655 A>G polymorphism as a genetic marker of trastuzumab-induced cardiotoxicity in HER2-positive breast cancer patients.

FcGR genetic polymorphisms and the response to adalimumab in patients with rheumatoid arthritis.

AIM: The aim of our study was to explore the potential of FcGR genetic polymorphisms as a predictor of adalimumab efficacy in rheumatoid arthritis (RA) patients. MATERIALS & METHODS: The study population was composed of 302 Dutch RA patients receiving adalimumab therapy. The FcGR2A (R131>H; rs1801274) and FcGR3A (F158>V; rs396991) genetic variants were genotyped using the TaqMan(®) allelic discrimination technology. Treatment outcome was evaluated with the use of the 28-joint disease activity score criteria (DAS28) and good response and remission were classified according to European League Against Rheumatism (EULAR) criteria. RESULTS: Comparing allelic frequencies between responders and nonresponders, the presence of the FcGR2A*R allele was associated with EULAR good response at 14 weeks (p = 0.017, odds ratio: 1.53, 95% CI: 1.08-2.17). No significant association was found for FcGR3A, with good response or remission. The combined effect of both FcGR2A and FcGR3A SNPs showed a trend for association with EULAR good response (p-value = 0.041, odds ratio: 1.38, 95% CI: 1.01-1.89). CONCLUSION: Our results indicate that FcGR polymorphisms could be a determinant of adalimumab efficacy in RA patients. Original submitted 28 July 2014; Revision submitted 19 December 2014.

Lack of validation of genetic variants associated with anti-tumor necrosis factor therapy response in rheumatoid arthritis: a genome-wide association study replication and meta-analysis.

INTRODUCTION: In this study, our aim was to elucidate the role of four polymorphisms identified in a prior large genome-wide association study (GWAS) in which the investigators analyzed the responses of patients with rheumatoid arthritis (RA) to treatment with tumor necrosis factor inhibitors (TNFi). The authors of that study reported that the four genetic variants were significantly associated. However, none of the associations reached GWAS significance, and two subsequent studies failed to replicate these associations. METHODS: The four polymorphisms (rs12081765, rs1532269, rs17301249 and rs7305646) were genotyped in a total of 634 TNFi-treated RA patients of Spanish Caucasian origin. Four outcomes were evaluated: changes in the Disease Activity Score in 28 joints (DAS28) after 6 and 12 months of treatment and classification according to the European League Against Rheumatism (EULAR) response criteria at the same time points. Association with DAS28 changes was assessed by linear regression using an additive genetic model. Contingency tables of genotype and allele frequencies between EULAR responder and nonresponder patients were compared. In addition, we combined our data with those of previously reported studies in a meta-analysis including 2,998 RA patients. RESULTS: None of the four genetic variants showed an association with response to TNFi in any of the four outcomes analyzed in our Spanish patients. In addition, only rs1532269 yielded a suggestive association (P = 0.0033) with the response to TNFi when available data from previous studies were combined in the meta-analysis. CONCLUSION: Our data suggest that the rs12081765, rs1532269, rs17301249 and rs7305646 genetic variants do not have a role as genetic predictors of TNFi treatment outcomes.

Confirmation of -174G/C interleukin-6 gene promoter polymorphism as a genetic marker predicting antitumor necrosis factor treatment outcome.

BACKGROUND: The IL-6 -174G/C genetic variant has recently been associated with the clinical response to etanercept therapy in rheumatoid arthritis (RA) patients. Considering previous results, the aim of our study was to validate the role of this polymorphism as a predictor of the antitumor necrosis factor (anti-TNF) treatment outcome in RA. MATERIALS AND METHODS: Our study population was composed of 199 Spanish patients with RA receiving anti-TNF therapy. The IL-6 -174G/C (rs1800795) genetic variant was genotyped using the TaqMan allelic discrimination technology. Patients were classified, according to the European League Against Rheumatism (EULAR) criteria, as responders (good and moderate response) and nonresponders at 6, 12, 18, and 24 months after the first infusion. RESULTS: The -174*G allele was significantly associated with a good or moderate EULAR response at 12 [P=0.015, odds ratio (OR)=2.93, 95% confidence interval (CI) 1.29-6.70], 18 (P=4.54E-03, OR=5.17, 95% CI 1.80-14.85), and 24 months (P=4.54E-03, OR=14.86, 95% CI 2.91-75.91). A meta-analysis combining these data with the results from a previous study confirmed this association (P=1.89E-02, OR=1.80, 95% CI 1.13-2.87, at 12 months). CONCLUSION: Our results support the role of the -174G/C IL-6 polymorphism as a genetic marker of responsiveness to anti-TNF therapy.

Detection of adverse drug reactions through the minimum basic data set.

OBJECTIVE: To analyze adverse drug reaction (ADR) detection using the Minimum Basic Data Set (MBDS) at hospital discharge and to compare the ADR reporting rate to the Pharmacovigilance Referral Centre with other similar hospitals that do not use this reporting system. Setting 650-bed University Hospital serving a population of 294,000 inhabitants in Spain. METHOD: A retrospective descriptive study was conducted between January 2006 and December 2007. All reports of ADRs gathered in MBDS (a tool that encodes all administrative and clinical information generated for each patient during a hospitalization episode) with International Classification Disease codes between E930 and E949.9 were analyzed to assess the appropriateness of their referral to the pharmacovigilance centre. Finally, we compared our reporting rate with other hospitals that do not use this system for ADR identification. MAIN OUTCOME MEASURE: The incidence of ADRs detected in hospitalized patients and the reporting rate (per thousand inhabitants) to the referral pharmacovigilance centre using the Yellow Card system. RESULTS: Out of 43,282 hospital discharges, 386 ADR were recorded (0.89% of hospitalized patients). The mean (+/-SD) age of patients with reported ADR was 61.9 years (+/-19.2), median age was 65 years, and 55.2% were female. The Department of Pharmacy reported 276 (71.5%) of ADR using the Yellow Card system. The most frequently reported drugs were anti-cancer agents (42.5%) and cardiovascular drugs (23.8%), with a high frequency of digitalis glycosides (18.4%). ADR were most frequently recorded by the Departments of Oncology (41.7%) and Internal Medicine (17.9%). CONCLUSION: The MBDS is a useful and accessible instrument to determine the incidence of ADR in a hospital, resulting in the notification of severe events that might otherwise not be reported. Its use also improves identification of the main drugs responsible for ADR and of the patient populations at greatest risk, facilitating the implementation of alert systems and the development of prevention and detection strategies.