Pharmacogenomics and adverse drug reactions: the case of statins

INTRODUCTION: The use of genomics to predict adverse drug reactions (ADRs) has been the subject of much research over the last decade. Concerns about the muscular safety of statins, a highly prescribed group of drugs, are partially related to their high exposure. Many studies have identified a variety of genetic markers related to statin-induced myopathy. However, only polymorphisms in the SLCO1B1 gene (which encodes the carrier responsible for the hepatic uptake of statins, which, in turn, contributes to the regulation of plasma levels of SLCO1B1) were strongly associated with statin-induced muscular adverse effects. These was found to be most prominent for simvastatin. The strength of these findings relies on the use of modern genetic approaches, such as well-designed, case-controlled and genome-wide association studies. Nevertheless, the clinical use of this information is far from known at present and needs to be evaluated. AREAS COVERED: The links between genetic polymorphisms (i.e., SLCO1B1 gene) and statin-induced muscle ADRs and the methodological issues involved in the establishment of such an association are explored. EXPERT OPINION: Despite there being a statin-gene association for myopathy, in the case of some statins the usefulness of this information still needs to be proven.     

Genetic marker of statin-induced rhabdomyolysis

This review summarizes genetic factors predisposed to statin-induced rhabdomyolysis. The first genetic risk factor of statin myopathy uncovered by genome-wide analysis of single nucleotide polymorphisms was the common variant of SLCO1B1 gene. Analysis of 30000 genetic markers in 85 patients with myopathy induced by high-dose simvastatin showed a strong association with 521T>C polymorphism of SLCO1B1. Another study also showed that this variant of SLCO1B1 has a significant association with myopathy in patients taking pravastatin or atorvastatin although the number of patients analyzed was limited. In addition to SLCO1B1, recent studies suggested that variants of genes encoding transporters (ABCG2 and ABCB1) and metabolic enzymes (CYP2C8 and UGT1A3) involved in the disposition of statins, and those involved in the metabolic muscle disease (glycogen storage disorders, carnitine palmitoyl-2 deficiency and myoadenylate deaminase deficiency) are also risk factors of statin-induced myopathy. These genetic factors may provide predisposition testing for statin-induced rhabdomyolysis.     

Individualized risk for statin-induced myopathy: current knowledge, emerging challenges and potential solutions

Skeletal muscle toxicity is the primary adverse effect of statins. In this review, we summarize current knowledge regarding the genetic and nongenetic determinants of risk for statin induced myopathy. Many genetic factors were initially identified through candidate gene association studies limited to pharmacokinetic (PK) targets. Through genome-wide association studies, it has become clear that SLCO1B1 is among the strongest PK predictors of myopathy risk. Genome-wide association studies have also expanded our understanding of pharmacodynamic candidate genes, including RYR2. It is anticipated that deep resequencing efforts will define new loci with rare variants that also contribute, and sophisticated computational approaches will be needed to characterize gene-gene and gene-environment interactions. Beyond environment, race is a critical covariate, and its influence is only partly explained by geographic differences in the frequency of known pharmacodynamic and PK variants. As such, admixture analyses will be essential for a full understanding of statin-induced myopathy.     

SLCO1B1 521 T>C和APOE基因多态性对阿托伐他汀调脂疗效及安全性的影响

目的 研究缺血性脑卒中伴血脂异常患者SLCO1B1 521 T>C和APOE基因多态性对阿托伐他汀临床疗效及安全性的影响。方法 收集上海市浦东新区公利医院2018年4月至2018年12月收治的缺血性脑卒中伴血脂异常的患者210例,测定纳入患者SLCO1B1 521 T>C和APOE基因多态性,给予阿托伐他汀20 mg/d口服进行降脂或调脂治疗,于治疗前和治疗后3个月测定其TC、TG、HDL-C、LDL-C水平来评价疗效,测定TBil、ALT、AST、CK水平,以及根据不良反应来评价安全性。结果 SLCO1B1 521 T>C的基因型分布为TT 79.05%,TC 19.05%,CC 1.90%;APOE基因的E2、E3、E4等位基因频率分别为14.28%、67.62%、18.10%,各基因型符合Hardy-Weinberg平衡定律。服药3个月后,APOE不同基因型患者TC、TG、LDL-C、HDL-C变化有显著性差异（P<0.01）。各项安全性指标未发现明显异常。SLCO1B1 521 T>C突变组肌痛发生率高于野生组,有显著性差异（P<0.01）。结论 APOE基因多态性影响阿托伐他汀的调脂疗效,患者SLCO1B1 521 T>C基因可能与阿托伐他汀肌痛不良反应相关。检测SLCO1B1和APOE基因分型有助于血脂个体化治疗,为药物治疗管理患者他汀类药物合理使用提供依据。     

Role of genetic factors in statins side-effects

Statins are relevant drugs involved in the reduction of cardiovascular events both in primary and secondary prevention. Related muscular side-effects are the most common cause of withdrawal and statins discontinuation could induce a negative rebound effect in terms of vascular events. Among factors in association with statins side-effects the combination with other drugs and the female sex are established conditions. However recent data suggest a specific genetic influence in intolerance development, at least for some statins. Indeed a genome-wide study in patients treated with simvastatin found an impressive association between single-nucleotide polymorphisms (SNPs) located within SLCO1B1 gene on chromosome 12 and established myopathy. Furthermore, the association between the SLCO1B1*5 variant and side-effects was found also in patients treated with atorvastatin but not, apparently, with pravastatin and categorized as carriers of mild-myopathy. Recently a similar evidence has been suggested in type 2 diabetic patients treated mainly with simvastatin. However another relevant issue is that, apart from genetic influence in liver transporters influencing drug levels, the complexity of mechanisms involved in the muscular side effects of statins has been addressed by the evidence of other influencing pathways such as the variant within the COQ2 gene involved in Coenzyme Q(10) mild-asymptomatic deficiency and skeletal muscle drug transporters expression. In conclusion, the picture of putative pharmacogenetic modulation of statins safety is reaching a growing body of evidence for translation into clinical practice but more specific studies for each single statin, in different clinical settings, both from genome-wide or competitive candidate genes evaluation, are needed before describing a definitive class-risk profile.     

Association between statin-induced creatine kinase elevation and genetic polymorphisms in SLCO1B1, ABCB1 and ABCG2

Purpose

Treatment with statins requires close monitoring of serum creatine kinase (CK) levels to prevent myopathy, a common and potentially serious dose-dependent adverse effect of these drugs. We have investigated the correlation between elevated CK levels and polymorphisms in the genes encoding transporters involved in statin disposition.

Methods

Patients with and without statin-induced elevated serum CK levels were genotyped for polymorphisms in SLCO1B1 (SLCO1B1 A388G and SLCO1B1 T521C), ABCB1 (ABCB1 C1236T and ABCB1 C3435T) and ABCG2 (ABCG2 C421A).

Results

Patients carrying SLCO1B1 T521C or ABCB1 C1236T single nucleotide polymorphisms (SNPs) had an odds ratio (OR) for statin-induced elevated serum CK levels of 8.86 (p?<?0.01) and 4.67 (p?<?0.05), respectively, while patients carrying the SLCO1B1 A388G SNP had an OR of 0.24 (p?<?0.05). An arbitrary score based on genotype combination discriminated patients with and without CK elevation at a specificity of 97 % and a sensitivity of 39 %.

Conclusion

Genotyping of the SLCO1B1, ABCB1 and ABCG2 genes deserves consideration as a clinical approach to improve statin safety while concomitantly reducing the burden of blood tests for CK measurements.     

SLCO1B1基因多态性与阿托伐他汀的安全性及有效性相关性分析

目的 研究高脂血症患者SLCO1B1基因多态性与阿托伐他汀安全性及有效性的相关性。方法 收集金华市人民医院2017年4月—2018年4月在门诊确诊为高脂血症患者的基本资料,测定纳入患者的SLCO1B1 c.388A>G和c.521T>C的基因多态性,定期随访受试者,并定期测定其甘油三酯、胆固醇、低密度脂蛋白胆固醇及肌酸激酶等相关实验室检查指标。结果 纳入患者SLCO1B1 c.388A>G和c.521T>C等位基因频率分别为72.8%和15.9%。随访期结束后不同基因型患者的血清血脂指标变化率无明显差异。SLCO1B1 c.521T>C基因多态性与阿托伐他汀的安全性有相关性（P=0.005）。结论 SLCO1B1c.388A>G基因多态性对阿托伐他汀降脂疗效及安全性无影响。SLCO1B1 c.521T>C基因多态性与阿托伐他汀的降脂疗效无相关性,但对其安全性有一定影响。     

血脂异常患者ApoE和SLCO1B1基因多态性与阿托伐他汀调脂治疗后血脂和肝功能的相关性

目的 研究血脂异常患者载脂蛋白（ApoE）、有机阴离子转运蛋白家族成员1B1（SLCO1B1）基因多态性与阿托伐他汀调脂治疗后血脂、肝功能的相关性。方法 选取2020年1月—2023年9月就诊于沧州市人民医院的128例高脂血症患者,阿托伐他汀治疗至少4周,检测ApoE、SLCO1B1基因和血脂、肝功能指标,分析其因型与调脂疗效、肝功能指标关系。结果 阿托伐他汀治疗后,ApoE基因表型E2组三酰甘油（TG）、高密度脂蛋白胆固醇（HDL-C）水平均较治疗前改善,E3组总胆固醇（TC）、HDL-C、低密度脂蛋白胆固醇（LDL-C）水平均较治疗前改善,E4组HDL-C水平均较治疗前改善,差异有统计学意义（P＜0.05）。治疗后,ApoE基因表型各组丙氨酸转氨酶（ALT）差异无统计学意义,仅E3组谷氨酰转移酶（GGT）差异有统计学意义（P＜0.05）。阿托伐他汀治疗后,SLCO1B1基因表型I型的TC、TG、HDL-C、LDL-C均较治疗前改善,Ⅱ型HDL-C较治疗前改善,差异有统计学意义（P＜0.05）。治疗后,SLCO1B1基因表型各组ALT、GGT差异无统计学意义。结论 临床使用阿托伐他汀时,可检测ApoE、SLCO1B1基因多态性评估降脂疗效,实现阿托伐他汀个体化用药。     

不同基因多态性对他汀类药物影响的研究进展

他汀类药物是目前临床应用最广泛的降脂药物,为心血管疾病的一级、二级预防的基石。他汀类药物为羟基-甲基戊二酰辅酶A还原酶抑制剂,可以显著降低血清总胆固醇、低密度脂蛋白胆固醇、三酰甘油水平,同时可轻度升高高密度脂蛋白胆固醇水平。目前研究的参与他汀类药物代谢的酶、转运蛋白、受体等基因多态性对他汀类药物安全性、不良反应有重要影响。阐述遗传因素载脂蛋白E、SLCO1B1、ATP结合盒转运蛋白B1、ABCG2、CYP、3-羟基-3-甲基戊二酰辅酶A还原酶基因等相关基因多态性对他汀类药物疗效和安全性的影响,为他汀类药物的个体化用药提供参考依据。     

安徽地区汉族心血管疾病患者SLCO1B1与ApoE基因多态性分布及其在他汀类药物临床个体化应用中的意义

目的:探讨脂质及药物代谢相关基因SLCO1B1和ApoE的基因多态性在安徽地区汉族心血管疾病患者中的分布,以评估他汀类药物个体化用药的效益/风险比。方法:利用PCR-荧光探针法技术检测2019年1月至2020年8月合肥市第二人民医院736例心血管疾病患者外周血基因组中SLCO1B1基因的rs2306283(388A>G)和rs4149056(521T>C)位点和ApoE基因的rs429358(388T>C)和rs7412(526C>T)位点的基因多态性分布特点,并与已报道的中国其他地区汉族心血管疾病患者的数据进行比较,分析不同地区间的基因型分布差异。结果:检测到安徽地区汉族心血管疾病患者中SLCO1B1基因型有6种,分别为*1a/*1a型(6.11%)、*1a/*1b型(29.08%)、*1b/*1b型(44.57%)、*1a/*15型(4.08%)、*1b/*15型(15.49%)、*15/*15型(0.68%),未检测到*1a/*5型、*5/*5型和*5/*15型;ApoE基因有6种表型,分别为E2/E2型(0.41%)、E2/E3型(11.96%)、E2/E4型(1.09%)、E3/E3型(67.66%)、E3/E4型(17.93%)、E4/E4型(0.95%)。两种基因的基因多态性频率分布满足Hardy-Weinberg遗传平衡,具有群体代表性。本研究人群中携带SLCO1B1正常肌病风险型的比例最高,约占79.76%;SLCO1B1中度肌病风险型和高度肌病风险型的人群比例较低,分别为19.57%和0.68%。ApoE大众类基因型比例最高,约占68.75%;ApoE保护类基因型及风险类基因型的人群比例分别为12.37%和18.88%。不同性别间SLCO1B1和ApoE基因表型患者差异无统计学意义。与华南地区心血管疾病患者相比,安徽地区ApoE基因多态性分布差异有统计学意义(P<0.05)。结论:安徽地区736例心血管疾病患者SLCO1B1和ApoE基因型分别以他汀药物剂量耐受性较高的正常肌病风险型和对他汀药物敏感的大众类基因型为主,服用他汀类药物诱发肌病的风险较低,降脂疗效较好;且两种基因的多态性分布均不受性别的影响,但ApoE基因多态性分布特征可能在地域上存在差异。因此,检测SLCO1B1和APOE基因多态性对于临床评估效益/风险比有重要的指导意义。     

Direct and Rapid Genotyping of SLCO1B1 388A>G and 521T>C in Human Blood Specimens Using the SmartAmp-2 Method

Organic anion-transporting polypeptide (OATP) 1B1, encoded by the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene, mediates the active uptake of various organic anions into hepatocytes and determines their hepatic clearances as the first step in the detoxification pathway. Previous reports indicated that alterations in its function by drug–drug interactions or genetic polymorphisms affect the pharmacokinetics of the substrate drugs. In the present study, we developed a method to genotype SLCO1B1 388A>G (rs2306283) and 521>C (rs4149056), which significantly affect the clinical pharmacokinetics and subsequent side effects such as myopathy caused by statins, OATP1B1 substrates in humans. We used a small aliquot of blood and the isothermal Smart Amplification Process version 2 (SmartAmp-2), which could complete the genotyping of 388A>G and 521T>C within 60 min. The genotypes of 101 genomic DNA samples and blood samples assessed by SmartAmp-2 matched perfectly to those determined previously by the conventional PCR-SSCP method. The SmartAmp-2 method enables the rapid identification of the 388A>G and 521T>C genotypes, saving time and effort in the genomic DNA preparation in clinical practice. This method will be useful for evaluating and predicting altered pharmacological and toxicological effects of substrate drugs caused by SLCO1B1 polymorphisms.     

ABCB1(2677T>G)和SLCO1B1(521T>C)基因多态性对阿托伐他汀降脂疗效的影响

目的：探讨新乡地区人群ABCB1（2677T>G）、SLCO1B1（521T>C）基因多态性分布及其与阿托伐他汀降脂疗效的相关性。方法：采用荧光原位杂交方法,检测120例血脂异常患者ABCB1（2677T>G）、SLCO1B1（521T>C）基因型分布;入选患者每晚服用阿托伐他汀20 mg,连续用药4周后,检测用药前后血脂水平,评价降脂疗效。结果：在新乡市中心医院的120例入选患者中,ABCB1（2677T>G）和SLCO1B1（521T>C）基因突变频率分别为70.5%和21.8%,该基因分布符合Hardy-Weinberg平衡。携带ABCB1 2677GG型患者对LDL-C的调节作用显著高于同一位点的其他基因型,而其他血脂指标未见相关性。SLCO1B1（521T>C）各基因型患者间血脂变化差异无统计学意义。结论：携带ABCB1 2677GG基因型的患者接受阿托伐他汀治疗时,降脂疗效较佳。     

Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake

The importance of membrane transporters for drug pharmacokinetics has been increasingly recognized during the last decade. Organic anion transporting polypeptide 1B1 (OATP1B1) is a genetically polymorphic influx transporter expressed on the sinusoidal membrane of human hepatocytes, and it mediates the hepatic uptake of many endogenous compounds and xenobiotics. Recent studies have demonstrated that OATP1B1 plays a major, clinically important role in the hepatic uptake of many drugs. A common single-nucleotide variation (coding DNA c.521T>C, protein p.V174A, rs4149056) in the SLCO1B1 gene encoding OATP1B1 decreases the transporting activity of OATP1B1, resulting in markedly increased plasma concentrations of, for example, many statins, particularly of active simvastatin acid. The variant thereby enhances the risk of statin-induced myopathy and decreases the therapeutic indexes of statins. However, the effect of the SLCO1B1 c.521T>C variant is different on different statins. The same variant also markedly affects the pharmacokinetics of several other drugs. Furthermore, certain SLCO1B1 variants associated with an enhanced clearance of methotrexate increase the risk of gastrointestinal toxicity by methotrexate in the treatment of children with acute lymphoblastic leukemia. Certain drugs (e.g., cyclosporine) potently inhibit OATP1B1, causing clinically significant drug interactions. Thus, OATP1B1 plays a major role in the hepatic uptake of drugs, and genetic variants and drug interactions affecting OATP1B1 activity are important determinants of individual drug responses. In this article, we review the current knowledge about the expression, function, substrate characteristics, and pharmacogenetics of OATP1B1 as well as its role in drug interactions, in parts comparing with those of other hepatocyte-expressed organic anion transporting polypeptides, OATP1B3 and OATP2B1.     

Association between genetic polymorphisms of SLCO1B1 and susceptibility to methimazole‐induced liver injury

Methimazole (MMI) has been used in the therapy of Grave's disease (GD) since 1954, and drug‐induced liver injury (DILI) is one of the most deleterious side effects. Genetic polymorphisms of drug‐metabolizing enzymes and drug transporters have been associated with drug‐induced hepatotoxicity in many cases. The aim of this study was to investigate genetic susceptibility of the drug‐metabolizing enzymes and drug transporters to the MMI‐DILI. A total of 44 GD patients with MMI‐DILI and 118 GD patients without MMI‐DILI development were included in the study. Thirty‐three single nucleotide polymorphisms (SNPs) in twenty candidate genes were genotyped. We found that rs12422149 of SLCO2B1, rs2032582_AT of ABCB1, rs2306283 of SLCO1B1 and rs4148323 of UGT1A1 exhibited a significant association with MMI‐DILI; however, no significant difference existed after Bonferroni correction. Haplotype analysis showed that the frequency of SLCO1B1*1a (388A521T) was significantly higher in MMI‐DILI cases than that in the control group (OR = 2.21, 95% CI = 1.11‐4.39, P = 0.023), while the frequency of SLCO1B1*1b (388G521T) was significantly higher in the control group (OR = 0.52, 95% CI = 0.29‐0.93, P = 0.028). These results suggested that genetic polymorphisms of SLCO1B1 were associated with susceptibility to MMI‐DILI. The genetic polymorphism of SLCO1B1 may be important predisposing factors for MMI‐induced hepatotoxicity.     

Influence of Drug Transporter Polymorphisms on Pravastatin Pharmacokinetics in Humans

The role of drug transporters in pravastatin disposition is underlined by the fact that pravastatin does not undergo significant cytochrome P-450 (CYP)-mediated biotransformation. The organic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1, and multidrug resistance-associated protein 2 [MRP2 (ABCC2)], are thought to be the major transporters involved in the pharmacokinetics of pravastatin in humans. Other transporters that may play a role include OATP2B1, organic anion transporter 3 (OAT3), bile salt export pump (BSEP), and the breast cancer resistance protein (BCRP). OATP1B1 and MRP2 mediate the hepatic uptake and biliary excretion of pravastatin, respectively. The SLCO1B1 and ABCC2 polymorphisms probably contribute to the high interindividual variability in pravastatin disposition. Recent small studies have characterized the impact of the SLCO1B1 polymorphism on pravastatin in humans, and especially the c.521T>C single-nucleotide polymorphism (SNP) seems to be an important determinant of pravastatin pharmacokinetics. Pravastatin plasma concentrations may be up to 100% higher in subjects carrying the c.521C variant, as found in the *5, *15, *16, and *17 haplotypes, reflecting diminished OATP1B1-mediated uptake into the major site of pravastatin elimination, the liver. The SLCO1B1 polymorphism seems to have a similar impact on the pharmacokinetics of single- and multiple-dose pravastatin. Overall, 2–5% of individuals in various populations may be expected to show markedly elevated plasma pravastatin concentrations due to the SLCO1B1 polymorphism. Of note, the impact of the SLCO1B1 polymorphism on statins may be dependent on ethnicity. Although individuals with a diminished hepatic uptake of pravastatin might be expected to show reduced cholesterol-lowering efficacy due to lower intracellular pravastatin concentrations, there is preliminary evidence to suggest that the SLCO1B1 polymorphism is not a major determinant of non-response to pravastatin. The possible consequences of drug transporter polymorphisms, especially the SLCO1B1 and ABCC2 polymorphisms, for the lipid-lowering efficacy and tolerability of pravastatin in various ethnic groups warrant further study.     

Genetic polymorphisms of SLCO1B1 for drug pharmacokinetics and its clinical implications

Various drug transporters are selectively expressed in single or multiple tissues, such as the intestine, liver and kidney, where these transporters play various roles in drug absorption, distribution and excretion. Genetic polymorphisms in drug transporters as well as drug-metabolizing enzymes are associated with interindividual differences in drug disposition, efficacy and toxicity. Organic anion transporting polypeptide 1B1 (OATP1B1, gene SLCO1B1) is expressed on the basolateral membrane of hepatocytes and can facilitate hepatic uptake of certain clinically relevant drugs such as statins except for fluvastatin, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, antidiabetic drug (repaglinide) and anticancer drugs (SN-38 and methotrexate). Some single nucleotide polymorphisms or haplotypes of the SLCO1B1 gene have been identified and demonstrated to have functional significance for transporter activity. For examples, the SLCO1B1*15 haplotype (or 521T>C genotype) results in decreased uptake activity of SN-38 from systemic circulation, leading to increased plasma concentration of SN-38 and an enhanced risk of neutropenia. This review focuses on the impact of genetic polymorphisms of the SLCO1B1 gene on transport activity, and implications for the clinical efficacy and toxicity of clinically useful drugs.     

Tolerability of statins is not linked to CYP450 polymorphisms, but reduced CYP2D6 metabolism improves cholesteraemic response to simvastatin and fluvastatin.

Statin therapy, although generally well tolerated, leads not infrequently to significant subjective and at times objective adverse effects (AEs), mainly of a muscular nature. The genetic background of these AEs is not clear and possibly side effects and lipid lowering efficacy may be linked. Aim of the study was a detailed evaluation of CYP450 and apolipoprotein E gene polymorphisms in two large series of age-sex matched patients with and without muscular side effects to statins. In a Clinical Institution specialised in lipid-lipoprotein disorders, 50 statin treated patients were selected, with subjective or objective statin-associated myopathy, evaluated using standardized forms. These were sex and age matched with 50 statin-treated patients from the same Clinic, without any subjective or objective complaints. DNA samples for the evaluation of CYP450 genetic polymorphisms and apo E genotypes were collected in order to assess correlations with both genetic polymorphisms and AEs, as well as with therapeutic efficacy. None of the assessed CYP450 polymorphisms appeared to be related to an increased incidence of AEs. The CYP2D6 *1/*4 and *4/4* poor metabolizer (PM) status was associated to a higher efficacy of statins metabolized by this system and, in addition, the apo E2 genotype was, in this series, linked to increased HDL-C levels after therapy. Patients with statin associated myopathy are not characterized by significantly different genotypes for the CYP450s responsible for statin metabolism. On the other hand, CYP2D6 PM status is associated to an increased efficacy of statins metabolized by this system.     

Inosine triphosphate pyrophosphatase 94C> A polymorphism: clinical implications for patients with systemic lupus erythematosus treated with azathioprine

Importance of the field: Azathioprine (AZA) has immunosuppressive property and has been widely used in organ transplantation and in several autoimmune diseases including systemic lupus erythematosus. The use of AZA is limited by the occurrence of adverse drug reactions (ADRs) leading to treatment discontinuation. Under AZA therapy, inosine triphosphate pyrophosphatase (ITPA) deficiency presumably leads to accumulation of unusual thioinosine metabolites with the potential for ADRs. Japanese patients require lower doses of AZA compared with Caucasian patients to achieve the same concentration of active metabolites. This ethnic difference in part is probably due to genetic polymorphisms of ITPA.

Areas covered in this review: Relationships between ITPA genotype and enzyme activity, and efficacy and toxicity of AZA in both Caucasian and Asian populations are reviewed.

Take home message: Clinical studies using a dose of <?1.5 mg/kg/day in various autoimmune diseases have shown no association between ITPA genotype and ADRs. In studies using higher doses, ITPA deficiency appears to increase the risk for AZA toxicity. Genotyping of ITPA may be useful to achieve dose optimization. It is important to maintain the dose of AZA <?1.5 mg/kg/day for Asian patients with ITPA 94A allele, with careful monitoring of the therapeutic efficacy.     

Statin-induced myopathies

Statins are considered to be safe, well tolerated and the most efficient drugs for the treatment of hypercholesterolemia, one of the main risk factor for atherosclerosis, and therefore they are frequently prescribed medications. The most severe adverse effect of statins is myotoxicity, in the form of myopathy, myalgia, myositis or rhabdomyolysis. Clinical trials commonly define statin toxicity as myalgia or muscle weakness with creatine kinase (CK) levels greater than 10 times the normal upper limit. Rhabdomyolysis is the most severe adverse effect of statins, which may result in acute renal failure, disseminated intravascular coagulation and death. The exact pathophysiology of statin-induced myopathy is not fully known. Multiple pathophysiological mechanisms may contribute to statin myotoxicity. This review focuses on a number of them. The prevention of statin-related myopathy involves using the lowest statin dose required to achieve therapeutic goals and avoiding polytherapy with drugs known to increase systemic exposure and myopathy risk. Currently, the only effective treatment of statin-induced myopathy is the discontinuation of statin use in patients affected by muscle aches, pains and elevated CK levels.     

Preventable statin adverse reactions and therapy discontinuation. What can we learn from the spontaneous reporting system?

Background: Statin treatment is often associated with poor adherence, which may be due to the onset of adverse drug reactions (ADRs). We investigated on potential risk factors related to preventable cases of statin-induced ADRs and to the discontinuation of statin therapy.

Methods: We performed a study using the database of Italian spontaneous reporting. The target population for the preventability assessment was all patients with suspected statin-induced ADRs deriving from Campania Region (a territory of Southern Italy) between 2012 and 2017. Additionally, a local sentinel surveillance site involving General Practitioners was selected to countercheck in routine clinical practice the role of ADRs for statin discontinuation.

Results: In total, 34 of 655 (5.19%) regional cases were preventable and among detected risk factors 90.0% was related to healthcare professionals’ practices and 10.0% to patient behaviour. In 81.4% (533/655) of cases, statin therapy was discontinued due to ADRs, mainly classified as not serious and associated with a positive prognosis. These results were also confirmed in the active sentinel site.

Conclusions: Our findings suggest an inappropriate use of statins among the identified preventable cases and a potential inappropriate statin discontinuation due to ADRs. These factors may be useful for targeting interventions to improve statin adherence.