Pseudotumor cerebri syndrome with different types of hormonal contraceptives in women of child-bearing age.

BACKGROUND AND PURPOSE: There is a lack of comparative safety data on the risk of pseudotumor cerebri syndrome (PTCS) associated with different hormonal contraceptives. We sought to quantify the risk of PTCS associated with eight different types of hormonal contraceptives compared with oral levonorgestrel. METHODS: We conducted a retrospective cohort study, with a case-control analysis of 4 871 504 women aged 15-45 years in the period 2008-2015, using IQVIA Ambulatory Electronic Medical Records data in the USA. Patients who used nine different contraceptive agents including intrauterine levonorgestrel, medroxyprogesterone injection, etonogestrel/ethinyl estradiol vaginal ring and combination oral contraceptives (COCs) that contained ethinyl estradiol and the progestins levonorgestrel, norgestimate, desogestrel, norethindrone and drospirenone, were included. Diagnosis of PTCS was defined using the first International Classification of Diseases, 9th or 10th revision, code for intracranial hypertension in patients who had also received an imaging code in the 30 days prior to the index date. RESULTS: A total of 3323 PTCS cases and 13 292 matched controls were identified. No increase in risk was found when analysing intrauterine levonorgestrel or COCs containing desogestrel, norethindrone, drospirenone, norgestimate or norgestrel versus COC levonorgestrel. The adjusted incidence rate ratio for etonogestrel/etonogestrel/ethinyl estradiol vaginal ring and medroxyprogesterone suspension compared with levonorgestrel COC was 4.45 [95% confidence interval (CI) 1.98-9.96] and 2.20 (95% CI 1.33-3.64), respectively. CONCLUSIONS: This study found an elevated risk for PTCS among users of etonogestrel vaginal ring and medroxyprogesterone suspension when compared with oral levonorgestrel. Future studies are needed to confirm these findings.

A comparison of the Muenster, SIOP Boston, Brock, Chang and CTCAEv4.03 ototoxicity grading scales applied to 3,799 audiograms of childhood cancer patients treated with platinum-based chemotherapy.

Childhood cancer patients treated with platinums often develop hearing loss and the degree is classified according to different scales globally. Our objective was to compare concordance between five well-known ototoxicity scales used for childhood cancer patients. Audiometric test results (n = 654) were evaluated longitudinally and graded according Brock, Chang, International Society of Pediatric Oncology (SIOP) Boston, Muenster scales and the U.S. National Cancer Institute Common Technology Criteria for Adverse Events (CTCAE) version 4.03. Adverse effects of grade 2, 3 and 4 are considered to reflect a degree of hearing loss sufficient to interfere with day-to-day communication (> = Chang grade 2a; > = Muenster grade 2b). We term this "deleterious hearing loss". A total number of 3,799 audiograms were evaluated. The prevalence of deleterious hearing loss according to the last available audiogram of each patient was 59.3% (388/654) according to Muenster, 48.2% (315/653) according to SIOP, 40.5% (265/652) according to Brock, 40.3% (263/652) according to Chang, and 57.5% (300/522) according to CTCAEv4.03. Overall concordance between the scales ranged from ĸ = 0.636 (Muenster vs. Chang) to ĸ = 0.975 (Brock vs. Chang). Muenster detected hearing loss the earliest in time, followed by Chang, SIOP and Brock. Generally good concordance between the scales was observed but there is still diversity in definitions of functional outcomes, such as differences in distribution levels of severity of hearing loss, and additional intermediate scales taking into account losses <40 dB as well. Regardless of the scale used, hearing function decreases over time and therefore, close monitoring of hearing function at baseline and with each cycle of platinum therapy should be conducted.

The influence of genetic variation on late toxicities in childhood cancer survivors: A review.

INTRODUCTION: The variability in late toxicities among childhood cancer survivors (CCS) is only partially explained by treatment and baseline patient characteristics. Inter-individual variability in the association between treatment exposure and risk of late toxicity suggests that genetic variation possibly modifies this association. We reviewed the available literature on genetic susceptibility of late toxicity after childhood cancer treatment related to components of metabolic syndrome, bone mineral density, gonadal impairment and hearing impairment. METHODS: A systematic literature search was performed, using Embase, Cochrane Library, Google Scholar, MEDLINE, and Web of Science databases. Eligible publications included all English language reports of candidate gene studies and genome wide association studies (GWAS) that aimed to identify genetic risk factors associated with the four late toxicities, defined as toxicity present after end of treatment. RESULTS: Twenty-seven articles were identified, including 26 candidate gene studies: metabolic syndrome (n = 6); BMD (n = 6); gonadal impairment (n = 2); hearing impairment (n = 12) and one GWAS (metabolic syndrome). Eighty percent of the genetic studies on late toxicity after childhood cancer had relatively small sample sizes (n < 200), leading to insufficient power, and lacked adjustment for multiple comparisons. Only four (4/26 = 15%) candidate gene studies had their findings validated in independent replication cohorts as part of their own report. CONCLUSION: Genetic susceptibility associations are not consistent or not replicated and therefore, currently no evidence-based recommendations can be made for hearing impairment, gonadal impairment, bone mineral density impairment and metabolic syndrome in CCS. To advance knowledge related to genetic variation influencing late toxicities among CCS, future studies need adequate power, independent cohorts for replication, harmonization of disease outcomes and sample collections, and (international) collaboration.

The global spectrum of protein-coding pharmacogenomic diversity.

Differences in response to medications have a strong genetic component. By leveraging publically available data, the spectrum of such genomic variation can be investigated extensively. Pharmacogenomic variation was extracted from the 1000 Genomes Project Phase 3 data (2504 individuals, 26 global populations). A total of 12 084 genetic variants were found in 120 pharmacogenes, with the majority (90.0%) classified as rare variants (global minor allele frequency <0.5%), with 52.9% being singletons. Common variation clustered individuals into continental super-populations and 23 pharmacogenes contained highly differentiated variants (FST>0.5) for one or more super-population comparison. A median of three clinical variants (PharmGKB level 1A/B) was found per individual, and 55.4% of individuals carried loss-of-function variants, varying by super-population (East Asian 60.9%>African 60.1%>South Asian 60.3%>European 49.3%>Admixed 39.2%). Genome sequencing can therefore identify clinical pharmacogenomic variation, and future studies need to consider rare variation to understand the spectrum of genetic diversity contributing to drug response.

The pharmacogenetics of codeine pain relief in the postpartum period.

The objective of this study was to examine interindividual variability in codeine requirements and pain management by examining select genetic polymorphisms in the codeine pharmacological pathway. The study included a nested cohort of 98 women who were prescribed codeine following cesarean section. Participants were genotyped for select polymorphisms of the COMT, ABCB1, CYP2D6, UGT2B7 and OPRM1 genes and instructed to describe their level of pain using the visual analog scale (mm) 1 h following each dose of codeine. Analysis revealed that reported pain increases with maternal age (P=0.041). Asians required more codeine than Caucasians (P=0.048). Significant differences in mean dose consumption were seen among the genotypic groups of the OPRM1 A118G (P=0.001) and UGT2B7 C802T (P=0.015) variants. These variants were found to predict codeine consumption in the cohort overall (P=0.000) and among Caucasians (P=0.001). These findings will assist in customizing therapy to effectively manage postpartum pain.

Genetic markers of cisplatin-induced hearing loss in children.

This journal recently published a Commentary by Ratain and colleagues at the University of Chicago that criticizes our work on cisplatin-induced hearing loss in children. It is unfortunate that neither the authors nor the editors of Clinical Pharmacology & Therapeutics corresponded with us to provide an earlier opportunity to address these questions. Here we correct the authors' inaccuracies and provide additional analyses that further strengthen our published findings.

Pharmacogenomic diversity in Singaporean populations and Europeans.

Differences in the frequency of pharmacogenomic variants may influence inter-population variability in drug efficacy and risk of adverse drug reactions (ADRs). We investigated the diversity of ∼ 4500 genetic variants in key drug-biotransformation and -response genes among three South East Asian populations compared with individuals of European ancestry. We compared rates of reported ADRs in these Asian populations to determine if the allelic differentiation corresponded to an excess of the associated ADR. We identified an excess of ADRs related to clopidogrel in Singaporean Chinese, consistent with a higher frequency of a known risk variant in CYP2C19 in that population. We also observed an excess of ADRs related to platinum compounds in Singaporean CHS, despite a very low frequency of known ADR risk variants, suggesting the presence of additional genetic and non-genetic risk factors. Our results point to substantial diversity at specific pharmacogenomic loci that may contribute to inter-population variability in drug response phenotypes.

The emerging era of pharmacogenomics: current successes, future potential, and challenges.

The vast range of genetic diversity contributes to a wonderful array of human traits and characteristics. Unfortunately, a consequence of this genetic diversity is large variability in drug response between people, meaning that no single medication is safe and effective in everyone. The debilitating and sometimes deadly consequences of adverse drug reactions (ADRs) are a major and unmet problem of modern medicine. Pharmacogenomics can uncover associations between genetic variation and drug safety and has the potential to predict ADRs in individual patients. Here we review pharmacogenomic successes leading to changes in clinical practice, as well as clinical areas probably to be impacted by pharmacogenomics in the near future. We also discuss some of the challenges, and potential solutions, that remain for the implementation of pharmacogenomic testing into clinical practice for the significant improvement of drug safety.

Higher frequency of genetic variants conferring increased risk for ADRs for commonly used drugs treating cancer, AIDS and tuberculosis in persons of African descent.

There is established clinical evidence for differences in drug response, cure rates and survival outcomes between different ethnic populations, but the causes are poorly understood. Differences in frequencies of functional genetic variants in key drug response and metabolism genes may significantly influence drug response differences in different populations. To assess this, we genotyped 1330 individuals of African (n=372) and European (n=958) descent for 4535 single-nucleotide polymorphisms in 350 key drug absorption, distribution, metabolism, elimination and toxicity genes. Important and remarkable differences in the distribution of genetic variants were observed between Africans and Europeans and among the African populations. These could translate into significant differences in drug efficacy and safety profiles, and also in the required dose to achieve the desired therapeutic effect in different populations. Our data points to the need for population-specific genetic variation in personalizing medicine and care.

Replication of TPMT and ABCC3 genetic variants highly associated with cisplatin-induced hearing loss in children.

Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. A serious complication of cisplatin treatment is permanent hearing loss. The aim of this study was to replicate previous genetic findings in an independent cohort of 155 pediatric patients. Associations were replicated for genetic variants in TPMT (rs12201199, P = 0.0013, odds ratio (OR) 6.1) and ABCC3 (rs1051640, P = 0.036, OR 1.8). A predictive model combining variants in TPMT, ABCC3, and COMT with clinical variables (patient age, vincristine treatment, germ-cell tumor, and cranial irradiation) significantly improved the prediction of hearing-loss development as compared with using clinical risk factors alone (area under the curve (AUC) 0.786 vs. 0.708, P = 0.00048). The novel combination of genetic and clinical factors predicted the risk of hearing loss with a sensitivity of 50.3% and a specificity of 92.7%. These findings provide evidence to support the importance of TPMT, COMT, and ABCC3 in the prediction of cisplatin-induced hearing loss in children.

HLA-A 31:01 and HLA-B 15:02 as genetic markers for carbamazepine hypersensitivity in children.

The occurrence of hypersensitivity reactions including rare but life-threatening Stevens-Johnson syndrome (SJS) and drug-induced hypersensitivity syndrome (HSS) limits the use of the anticonvulsant carbamazepine (CBZ). Human leukocyte antigen-B (HLA)-B 15:02 and HLA-A 31:01 have been identified as predictive genetic markers for CBZ hypersensitivity in Asian and European patients. To replicate these genetic associations in pediatric patients from North America with a diverse ethnic background, we investigated HLA-A 31:01 and HLA-B 15:02 in 42 children with CBZ hypersensitivity and 91 CBZ-tolerant children from across Canada. HLA-A 31:01 was significantly associated with CBZ-HSS (odds ratio (OR): 26.4, P = 0.0025) and maculopapular exanthema (MPE) (OR: 8.6, P = 0.0037) but not with CBZ-SJS. Conversely, HLA-B 15:02 was associated with CBZ-SJS (OR: 38.6, P = 0.002) but not HSS or MPE. This study is the first to demonstrate the association of HLA-A 31:01 with CBZ hypersensitivity in children, providing important replication of this association and highlighting the importance of HLA-A 31:01 as a predictive biomarker across various ancestries.

Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline-induced cardiotoxicity in children.

BACKGROUND: The use of anthracyclines as effective antineoplastic drugs is limited by the occurrence of cardiotoxicity. Multiple genetic variants predictive of anthracycline-induced cardiotoxicity (ACT) in children were recently identified. The current study was aimed to assess replication of these findings in an independent cohort of children. PROCEDURE: . Twenty-three variants were tested for association with ACT in an independent cohort of 218 patients. Predictive models including genetic and clinical risk factors were constructed in the original cohort and assessed in the current replication cohort. RESULTS: . We confirmed the association of rs17863783 in UGT1A6 and ACT in the replication cohort (P = 0.0062, odds ratio (OR) 7.98). Additional evidence for association of rs7853758 (P = 0.058, OR 0.46) and rs885004 (P = 0.058, OR 0.42) in SLC28A3 was found (combined P = 1.6 × 10(-5) and P = 3.0 × 10(-5), respectively). A previously constructed prediction model did not significantly improve risk prediction in the replication cohort over clinical factors alone. However, an improved prediction model constructed using replicated genetic variants as well as clinical factors discriminated significantly better between cases and controls than clinical factors alone in both original (AUC 0.77 vs. 0.68, P = 0.0031) and replication cohort (AUC 0.77 vs. 0.69, P = 0.060). CONCLUSIONS: . We validated genetic variants in two genes predictive of ACT in an independent cohort. A prediction model combining replicated genetic variants as well as clinical risk factors might be able to identify high- and low-risk patients who could benefit from alternative treatment options.

Prediction of codeine toxicity in infants and their mothers using a novel combination of maternal genetic markers.

Substantial variation exists in response to standard doses of codeine ranging from poor analgesia to life-threatening central nervous system (CNS) depression. We aimed to discover the genetic markers predictive of codeine toxicity by evaluating the associations between polymorphisms in cytochrome P450 2D6 (CYP2D6), UDP-glucuronosyltransferase 2B7 (UGT2B7), P-glycoprotein (ABCB1), mu-opioid receptor (OPRM1), and catechol O-methyltransferase (COMT) genes, which are involved in the codeine pathway, and the symptoms of CNS depression in 111 breastfeeding mothers using codeine and their infants. A genetic model combining the maternal risk genotypes in CYP2D6 and ABCB1 was significantly associated with the adverse outcomes in infants (odds ratio (OR) 2.68; 95% confidence interval (CI) 1.61-4.48; P(trend) = 0.0002) and their mothers (OR 2.74; 95% CI 1.55-4.84; P(trend) = 0.0005). A novel combination of the genetic and clinical factors predicted 87% of the infant and maternal CNS depression cases with a sensitivity of 80% and a specificity of 87%. Genetic markers can be used to improve the outcome of codeine therapy and are also probably important for other opioids sharing common biotransformation pathways.

Economic impact of a genetic test for cisplatin-induced ototoxicity.

Cisplatin is a widely used chemotherapy drug in the treatment of pediatric solid tumors, but it is associated with significant rates of ototoxicity (medication-induced hearing loss). A genetic test has recently been developed that can help predict the likelihood that a cisplatin-treated pediatric patient will develop ototoxicity. This study estimates the potential economic impact of this test. Assuming that an alternative, non-preferred, medication to cisplatin exists that it is as efficacious as cisplatin but without the risk of hearing loss, and that the alternative treatment is no more expensive than current practice, we have estimated that administering this genetic test to every pediatric cancer patient for whom cisplatin is first-line therapy could potentially avoid an average of $71,168 in societal costs per tested patient. This translates into a potential present value savings of over $2.4 million annually in British Columbia and over $19.6 million in Canada.

Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin.

Statins reduce cardiovascular morbidity and mortality in appropriately selected patients. However, statin-associated myopathy is a significant risk associated with these agents. Recently, variation in the SLCO1B1 gene was reported to predict simvastatin-associated myopathy. The aim of this study was to replicate association of the rs4149056 variant in SLCO1B1 with severe statin-associated myopathy in a cohort of patients using a variety of statin medications and to investigate the association with specific statin types. We identified 25 cases of severe statin-associated myopathy and 84 controls matched for age, gender, statin type and dose. The rs4149056 variant in SLCO1B1 was not significantly associated with myopathy in this group as a whole. However, when subjects were stratified by statin type, the SLCO1B1 rs4149056 genotype was significantly associated with myopathy in patients who received simvastatin, but not in patients who received atorvastatin. Our findings provide further support for a role for SLCO1B1 genotype in simvastatin-associated myopathy, and suggest that this association may be stronger for simvastatin compared with atorvastatin.

Drug-induced heart failure.

PURPOSE: The published evidence on the role of various drugs and medication classes in causing or exacerbating heart failure (HF) is reviewed, with discussion of precautions and management strategies for use in clinical practice. SUMMARY: A literature search was conducted to identify reports of new-onset HF and exacerbations of HF associated with medication use published from 1960 to January 2011. A large body of evidence from controlled clinical trials has led to an improved understanding of well-established causes of drug-induced HF symptoms (e.g., thiazolidinediones, certain older chemotherapy agents) while implicating a wide range of other commonly used drugs and drug classes (e.g., tyrosine kinase inhibitors, biological response modifiers) as having causal or contributory roles. Among the various medications cited in cases of drug-induced HF, some have been linked to significantly increased risks of stroke, myocardial infarction, and death, particularly in patients with existing cardiovascular (CV) disorders or CV risk factors. In recent years, postmarketing and surveillance data have linked a number of newer medications--including the antiarrhythmic dronedarone, the antifungal itraconazole, and the anti-cancer drugs trastuzumab, lapatinib, and bevacizumab--to serious cardiac effects not reported during clinical trials. CONCLUSION: A variety of agents have been associated with drug-induced HF. Patients receiving agents that have been implicated in cases of new-onset HF or exacerbations of HF should be monitored for signs and symptoms of CV effects.

Phenotype standardization for immune-mediated drug-induced skin injury.

Advances in genetic research and molecular biology techniques have made it possible to begin to characterize the underlying genetic factors that predispose patients to serious forms of drug-induced skin injury (DISI). To facilitate research in this area, we have set out standardized phenotypic definitions for (i) Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), (ii) acute generalized exanthematous pustulosis (AGEP), and (iii) hypersensitivity syndrome (HSS; also known as drug reaction with eosinophilia and systemic symptoms (DRESS) and drug-induced hypersensitivity syndrome (DIHS)). A DISI Expert Working Group comprising participants with varied expertise reviewed and debated current terminology and diagnostic criteria for DISI and agreed on the minimum phenotypic criteria for selected forms of DISI (SJS/TEN, AGEP, and HSS). In addition, an algorithm has been developed to aid appropriate clinical categorization of patients with DISI. These standardized criteria will be important in facilitating adequate and accurate patient recruitment in order to advance research in pharmacogenomic, immunological, mechanistic, and epidemiological studies.