Drug Discovery Today Volume 24, Number 1 January 2019 PERSPECTIVE feature Drug-Induced Rhabdomyolysis Atlas (DIRA) for idiosyncratic adverse drug reaction management 1 1 1 2,3 4 5 2 Zhining Wen , Yu Liang , Yingyi Hao , Brian Delavan , Ruili Huang , Mike Mikailov , Weida Tong , 1 2 Menglong Li , [email protected] and Zhichao Liu , [email protected] Drug-induced rhabdomyolysis (DIR) is an idiosyncratic and fatal adverse drug reaction (ADR) characterized in severe muscle injuries accompanied by multiple-organ failure. Limited knowledge regarding the pathophysiology of rhabdomyolysis is the main obstacle to developing early biomarkers and prevention strategies. Given the lack of a centralized data resource to curate, organize, and standardize widespread DIR information, here we present a Drug-Induced Rhabdomyolysis Atlas (DIRA) PERSPECTIVE that provides DIR-related information, including: a classification scheme for DIR based on drug labeling information; postmarketing surveillance data of DIR; and DIR drug property information. To elucidate Features the utility of DIRA, we used precision dosing, concomitant use of DIR drugs, and predictive modeling development to exemplify strategies for idiosyncratic ADR (IADR) management. Introduction changes to cholesterol-lowering statin drugs diagnosis [10,11]. However, the lack of an agreed Rhabdomyolysis is a serious syndrome caused have been made because of drug-induced liver detection level of those clinical parameters by a direct or indirect injury to skeletal muscle, injury (DILI) and DIR (www.fda.gov/Drugs/ limits their diagnostic performance [11]. The which can lead to severe complications, such as DrugSafety/ucm293101.htm). major divergence in diagnostic criteria is related acute renal failure [1]. As one of the major forms Drugs in certain therapeutic categories ap- to the time muscle injury onset and the strength of rhabdomyolysis, DIR is idiosyncratic in nature pear to more likely to cause rhabdomyolysis. For of clinical parameters. For example, the serum and, thus, difficult to study [2–4]. The incidence example, statins, also known as HMG-CoA re- CK value typically increased from 2 to 12 h after of DIR is approximately 1 in 100,000. However, ductase inhibitors, are used to lower cholesterol the onset of injury, peaking between 24 h and the real incidence could be significantly higher, and treat cardiovascular disease; however, 72 h, and declining in 7–10 days [12]. There- given the wide exclusive and combined use of statin-induced rhabdomyolysis has been widely fore, the time of diagnosis is key to accurately drugs [5]. Serious regulatory decisions have reported [8,9]. Currently, serum creatine kinase measuring the severity of muscle injury. Fur- been made, including labeling changes or even (CK) and serum and urine myoglobin serve as thermore, CK levels vary among individuals. a market withdrawal, because of DIR. For ex- clinical biomarkers for rhabdomyolysis diagno- Generally, a CK level five times that of the normal ample, cerivastatin was withdrawn from US sis. Other strategies, such as magnetic reso- value is considered as a standard diagnostic market because of 52 deaths attributed to nance imaging (MRI) image, prothrombin time criterion for rhabdomyolysis diagnosis. Howev- rhabdomyolysis and resulting kidney failure (PT), and activated partial thromboplastin time er, higher CK values (i.e., ten times that of the [6,7]. In addition, important safety labeling (aPTT), might be also useful for rhabdomyolysis normal value) have been suggested as a cut-off 1359-6446/Published by Elsevier Ltd. https://doi.org/10.1016/j.drudis.2018.06.006 www.drugdiscoverytoday.com 9 PERSPECTIVE Drug Discovery Today Volume 24, Number 1 January 2019 Boxed warning or withdrawal Most-DIR concern Category: fatal or life threating Drug 4 Keywords: fatal; death; capillary leak syndrome; acute liver labeling failure; renal impairment Category: concomitant use 3 Keywords: concurrently; drug interactions; concomitant use Full-text search with concomitantly; contraindicated keyword ‘rhabdomyolysis’ Moderate-DIR concern Category: overdose 2 Keywords: overdose; dose modifications Drug Category: postmarketing experience labeling Less-DIR concern 1 Keywords: postmarketing surveillance; postmarketing experience No muscular injury-related ADR information mentioned in No-DIR concern 0 whole drug labeling Drug Discovery Today FIGURE 1 Classification scheme for drug-induced rhabdomyolysis (DIR) potential based on US Food and Drug Administration (FDA)-approved drug labeling. The FDA- approved drug labeling containing the keyword ‘rhabdomyolysis’ was extracted. Then, for each drug labeling, the severity score was assigned based on predefined keywords based on a priori knowledge. Finally, DIR concerns were determined based on the severity scores (i.e., most-DIR concern: Boxed warning or withdrawal drugs, and drugs with severity score 4; Moderate-DIR concern: drugs with severity score 2 and 3; Less-DIR concerns: drugs with severity score 1; and No-DIR concern: drugs with severity score 0). Features for younger patients [13]. Furthermore, few ef- application: the DIRA (www.ADRatlas.com/DIRA). [14,15], a DIR classification scheme was devel- fective biomarkers exist for the early detection The utility of DIRA is exemplified below based on oped based on drug labeling information PERSPECTIVE of DIR in the preclinical setting. DIR is currently key aspects of idiosyncratic ADR (IADR) man- (Fig. 1). Details of the proposed DIR classification detected based mainly on clinical observations agement, including precision dosing, concomi- scheme are described below. and postmarketing surveillance data from co- tant use of drugs, and predictive model hort studies, controlled population studies, and development. DIR-related labeling extraction spontaneous reporting systems. Unfortunately, To extract DIR-related drug labeling, we applied few case reports of DIR are available; those that Drug-induced rhabdomyolysis the following steps: (i) human drug labeling ‘ ’ are available are scattered throughout the lit- classification containing the keyword rhabdomyolysis [16]; erature, electronic medical records, and phar- It is challenging to develop a reproducible (ii) drug labeling with a single active ingredient; macovigilance databases, delaying any progress procedure to assess rhabdomyolysis risk for (iii) only drugs administered via the oral or in the development of early prevention and drugs. To annotate drugs for their DIR potential, parenteral route; and (iv) latest version of drug predictive models. major attributes, including seriousness, causali- labeling. Consequently, a 172-drug list was A classification scheme of the potential of a ty, severity, and expectedness, should be taken generated for further DIR classification. The drug to cause rhabdomyolysis in humans is im- into consideration. However, no centralized re- details of the labeling curation process are perative to facilitate community efforts to de- source comprising all the relevant information described in the Supplementary information velop early prediction strategies and to identify for DIR has existed previously. Drug labeling is a online. effective DIR diagnostic biomarkers. Here, we compilation of information about a drug prod- report a DIR classification scheme that was de- uct necessary for its safe and effective use, Distribution of DIR information across veloped based on drug labeling information. In written primarily for the healthcare practitioner, labeling sections addition, postmarketing DIR surveillance data approved by the FDA, and regulated by law ADR information described in different labeling from the US Food and Drug Administration (FDA) (www.accessdata.fda.gov/scripts/cdrh/cfdocs/ sections represents different levels of ADR seri- Spontaneous Adverse Events Reporting System cfCFR/CFRSearch.cfm?fr=201.57). Drug labeling ousness. For example, the Boxed Warning (BW) (FAERS) were extracted to represent DIR incidence contains consistent and up-to-date drug safety section is used to concisely summarize certain information. Moreover, drug properties, such as information and has been well established as contraindications or serious warnings, particularly chemical structures, therapeutic categories, and one of most stable resources to annotate ADR those that can lead to death or serious injury daily doses, were also curated. All information was risk for drugs. Inspired by the Liver Toxicity according to the Code of Federal Regulations centralized and managed under a web-based Knowledge Base (LTKB) project led by the FDA (21CFR201.57, www.accessdata.fda.gov/scripts/ 10 www.drugdiscoverytoday.com Drug Discovery Today Volume 24, Number 1 January 2019 PERSPECTIVE TABLE 1 Severity levels of DIR based on descriptions in drug labeling Severity DIR category Keywords Example description in drug labeling score 4 Fatal or life threating Fatal; death; capillary leak These serious adverse reactions include death, convulsions, cerebral syndrome; acute liver failure; hemorrhage, coma, paralysis, arachnoiditis, acute renal failure, cardiac renal impairment arrest, seizures, rhabdomyolysis, hyperthermia, and brain edema 3 Drug interaction induced Concurrently; drug As with other macrolides, clarithromycin has been reported to increase interactions; concomitant concentrations of HMG-CoA reductase inhibitors (e.g., lovastatin and use concomitantly; simvastatin). Rare reports of rhabdomyolysis have been reported in contraindicated patients taking these drugs