Evaluation of the Relative Performance of Drug-Induced Skeletal Muscle Injury Biomarkers in Rats

Burch, Peter M.; Hall, Dianne; Walker, Edward A.; Bracken, William M.; Giovanelli, Richard; Goldstein, Richard A.; Higgs, Richard E.; King, Nicholas M.P.; Lane, Pamela; Sauer, John‐Michael; Michna, Laura; Muniappa, Nagaraja; Pritt, Michael L.; Vlasáková, Kateřina; Watson, David E.; Wescott, Debra; Zabka, Tanja S.; Glaab, Warren E.

doi:10.1093/toxsci/kfv328

Cited by 41 publications

(24 citation statements)

References 18 publications

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“…We observed a greater than 10‐fold increase in plasma‐circulating FABP3 protein levels following fenofibrate treatment and on first glance may suggest myocardial toxicity. However, circulating levels of FABP3 have also been correlated with skeletal muscle toxicity in rats following treatment with PPARα agonists (Burch et al, ; Pritt et al, ; Zhen et al, ). We observed a substantial increase in myosin light chain 3 (Myl3), a marker for cardiac and type‐I skeletal muscle (SKM).…”

Section: Discussionmentioning

confidence: 99%

Administration of Fenofibrate Markedly Elevates Fabp3 in Rat Liver and Plasma and Confounds Its Use as a Preclinical Biomarker of Cardiac and Muscle Toxicity

Kochansky

Lyman²,

Fauty

et al. 2018

Lipids

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Proteins involved in lipid homeostasis are often regulated through the nuclear peroxisome proliferator‐activated receptors (PPAR). PPARα is the target for the fibrate‐class of drugs. Fenofibrate has been approved for its lipid‐lowering effects in patients with hypercholesterolemia and hypertriglyceridemia. We were interested in understanding the expression of the energy transporters in energy‐utilizing tissues like liver, heart, muscle, and adipose tissues in rat with the hypothesis that the change in transporter expression would align with the known lipid‐lowering effects of PPARα agonists like fenofibrate. We found that several fatty‐acid transporter proteins had significantly altered levels following 8 days of fenofibrate dosing. The mRNA levels of the highly abundant Fatp2 and Fatp5 in rat liver increased approximately twofold and decreased fourfold, respectively. Several fatty‐acid‐binding proteins and acyl‐CoA‐binding proteins had a significant increase in mRNA abundance but not the major liver fatty‐acid‐binding protein, Fabp1. Of particular interest was the increased liver expression of Fabp3 also known as heart‐fatty acid binding protein (H‐FABP or FABP3). FABP3 has been proposed as a circulating clinical biomarker for cardiomyopathy and muscle toxicity, as well as a preclinical marker for PPARα‐induced muscle toxicity. Here, we show that fenofibrate induces liver mRNA levels of Fabp3 ~5000‐fold resulting in an approximately 50‐fold increase in FABP3 protein levels in the whole liver. This increased liver expression complicates the interpretation and potential use of FABP3 as a specific biomarker for PPARα‐induced muscle toxicities.

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Section: Discussionmentioning

confidence: 99%

Administration of Fenofibrate Markedly Elevates Fabp3 in Rat Liver and Plasma and Confounds Its Use as a Preclinical Biomarker of Cardiac and Muscle Toxicity

Kochansky

Lyman²,

Fauty

et al. 2018

Lipids

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“…A study that treated rats with drugs that are highly toxic to myocytes (carbamate acetylcholinesterase inhibitor; isoproterenol, a synthetic catecholamine), but not with statins, identified fatty acid binding protein 3 (FABP3) and myosin light chain 1 (MLC1) as biomarkers of skeletal muscle toxicity based on the specific tissue distribution of these proteins [ 55 , 56 ]. Burch et al [ 57 ] evaluated skeletal muscle troponin I (sTnI), myosin light chain 3 (MYL3 [S3]), CK isoform M (CKM), and FABP3 compared with CK in the monitoring of drug-induced skeletal muscle injury. sTnI, MYL3, CKM, and FABP3 all outperformed CK and/or added value for the diagnosis of drug-induced novel skeletal muscle injury (i.e., myocyte degeneration/necrosis) [ 57 ].…”

Section: Methodsmentioning

confidence: 99%

Management of Statin Intolerance in 2018: Still More Questions Than Answers

Tóth

Patti

Giglio

et al. 2018

Am J Cardiovasc Drugs

143

111

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Statin therapy is generally well tolerated and very effective in the prevention and treatment of cardiovascular disease, regardless of cholesterol levels; however, it can be associated with various adverse events (myalgia, myopathy, rhabdomyolysis, and diabetes mellitus, among others). Patients frequently discontinue statin therapy without medical advice because of perceived side effects and consequently increase their risk for cardiovascular events. In patients with statin intolerance, it may be advisable to change the dose, switch to a different statin, or try an alternate-day regimen. If intolerance is associated with all statins—even at the lowest dose—non-statin drugs and certain nutraceuticals can be considered. This review focuses on the definition of statin intolerance and on the development of clinical and therapeutic strategies for its management, including emerging alternative therapies.

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“…The muscle injury panel (MIP) selected for evaluation included skeletal troponin I, myosin light chain, fatty acid-binding protein and creatine kinase measured by a mass assay. These markers were assessed in 34 rat studies and were shown to outperform AST and CK (enzymatic assay) individually and as a panel in terms of sensitivity and specificity and/or added value for the diagnosis of druginduced SKM injury defined as myocyte degeneration/ necrosis (Burch et al, 2016). Based on this data, the FDA and EMA issued Letters of Support (EMA, 2015;FDA, 2015) for the use of these markers in preclinical development and encouraged their use in early clinical trials in an exploratory context.…”

Section: Next Generation Biomarkers For Skeletal Muscle Degenerationmentioning

confidence: 99%

“…These preclinical and clinical evaluations provided support for a qualification submission which is currently in progress. This qualification, sponsored by the PSTC, will evaluate the marker's ability to monitor SKM degeneration/necrosis in conjunction with AST and CK enzymatic activity in early clinical trials and encourage the utilization of the MIP markers throughout drug development to improve patient safety in clinical trials (Burch et al, 2016). In support of the qualification effort, Pfizer has included the MIP markers on a number of clinical trials as exploratory biomarkers; however, the utility of the markers as SKM safety or efficacy end points to these therapeutic interventions has yet to be determined (Goldstein, 2017).…”

Section: Next Generation Biomarkers For Skeletal Muscle Degenerationmentioning

confidence: 99%

Safety biomarker applications in drug development

et al. 2019

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Biomarkers are invaluable drug development tools to assess and monitor safety in early clinical trials especially when exposure margins are limiting for promising therapeutics. Although progress has been made towards identifying and implementing translational safety biomarkers for a number of organ toxicities such as kidney and liver, significant biomarker gaps still exist to monitor toxicities for testis, pancreas, etc. Several precompetitive consortia [e.g., Predictive Safety Testing Consortia (PSTC), Innovative Medicines Initiative (IMI)] are working with industry, academia, government, patient advocacy groups and foundations with a goal to qualify biomarkers such that they can be used in preclinical studies and clinical trials to accelerate drug development. This manuscript discusses the complexities of novel biomarker discovery, validation and international regulatory qualifications intended for clinical trial applications and shares specific examples from Pfizer Research and Development. As safety biomarkers become widely accepted and qualified by the regulatory agencies, they will increasingly be implemented in early clinical trials, play a key role in decision making and facilitate the progression of promising therapeutics from preclinical through clinical development.

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Evaluation of the Relative Performance of Drug-Induced Skeletal Muscle Injury Biomarkers in Rats

Cited by 41 publications

References 18 publications

Administration of Fenofibrate Markedly Elevates Fabp3 in Rat Liver and Plasma and Confounds Its Use as a Preclinical Biomarker of Cardiac and Muscle Toxicity

Administration of Fenofibrate Markedly Elevates Fabp3 in Rat Liver and Plasma and Confounds Its Use as a Preclinical Biomarker of Cardiac and Muscle Toxicity

Management of Statin Intolerance in 2018: Still More Questions Than Answers

Safety biomarker applications in drug development

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