Definition

A biomarker measured before or after an exposure to a medical product or an environmental agent to indicate the likelihood, presence, or extent of toxicity as an adverse effect.

Examples

• Hepatic aminotransferases and bilirubin may be used as safety biomarkers when evaluating potential hepatotoxicity (Senior 2014).
• Serum creatinine may be used as a safety biomarker when evaluating patients on drugs that affect kidney function to monitor for nephrotoxicity (Wasung et al. 2015).
• Serum potassium may be used as a safety biomarker when evaluating patients on diuretics (decreased levels), angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or aldosterone antagonists (increased levels) (James et al. 2014; Roush and Sica 2016).
• Urinary kidney biomarkers (Kim-1, Albumin, Total Protein, β2 Microglobulin, Urinary Clusterin, Urinary Trefoil Factor 3 and Urinary Cystatin C) may be used as safety biomarkers in animal studies for the detection of acute drug-induced nephrotoxicity, either tubular or glomerular with associated tubular involvement (U.S. Food and Drug Administration 2009, U.S. Food and Drug Administration 2010).
• Neutrophil count may be used as a safety biomarker when evaluating patients on cytotoxic chemotherapy to adjust dose, determine the need to interrupt therapy, or consider the use of growth factors (Rizzo et al. 2010; Smith et al. 2015).
• Corrected QT interval (QTc) may be used as a safety biomarker to assess the potential for drugs to induce torsades de pointes (International Conference for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 2015; U.S. Food and Drug Administration 2005).
• HLA-B*1502 allele may be used as a safety biomarker to screen patients prior to initiating carbamazepine treatment, as those with the allele are at increased risk of serious and fatal skin reactions. HLA-B*1502 allele is found almost exclusively in individuals with ancestry across broad areas of Asia. Patients testing positive for the allele should not be treated with carbamazepine unless the benefit clearly outweighs the risk (Chung et al. 2004).

Explanation

Medical interventions and environmental exposures may have undesirable, potentially harmful, or overtly toxic effects. Common to all safety biomarkers is the ability to detect or predict these adverse drug or exposure effects. In some cases, the toxicity is signaled by the detection of or change in a biomarker, allowing dose modification or treatment interruption before toxicity becomes severe, e.g., measuring granulocyte count while using clozapine or serum potassium while using a diuretic (see monitoring biomarker). In other cases the safety biomarker can indicate needed treatment, e.g., hypokalemia with a diuretic can indicate need for potassium supplementation, and hyperkalemia with an aldosterone antagonist can indicate need for dose adjustment or increase in loop diuretics. Periodic monitoring of such biomarkers is required for many drugs to ensure that their potential toxicity is detected and managed. Ideally, a safety biomarker would signal developing toxicity, e.g., drug induced organ injury, prior to clinical signs and before any irreversible damage occurs. Examples include monitoring creatinine phosphokinase for drugs that can cause muscle damage, serum creatinine for potentially nephrotoxic drugs, and transaminases for potentially hepatotoxic drugs. Sometimes effects on biomarkers indicate potential serious (even if rare) toxicity. Observation of even a few patients with elevated transaminases accompanied by elevated bilirubin predicts the occurrence of serious liver injury (i.e., “Hy’s Law”), an unacceptable risk for most drugs.

In addition, safety biomarkers can be used to identify patients for whom particular therapies should not be initiated because of significant safety risks. For example, deficiencies of metabolizing enzymes can identify individuals at risk for toxicity unless drug dose is decreased or identify patients who will not respond to a critical treatment because they cannot make the active metabolite (e.g., thiopurine methyltransferase (TPMT) genotype is used to identify patients who should not be given 6-mercaptopurine or azathioprine because severe toxicity due to high drug concentrations may occur; patients with HLA-B*5701 should not be given abacavir due to hypersensitivity reactions).

At a population level, biomarker measurements can identify persons affected by exposure to certain environmental agents, prompting public health policies or interventions to control or mitigate risk. For example, serum lead levels may be assessed to detect exposure to lead or urinary cotinine levels may be assessed to detect exposure to nicotine (i.e., cigarette smoke). Results from environmental safety biomarker assessments can initiate a search for the source of the exposure, followed by a public health intervention.

References

• Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, Wu JY, Chen YT. Medical genetics: a marker for Stevens-Johnson syndrome. Nature. 2004 Apr 1;428(6982):486. [PubMed: 15057820] [CrossRef]
• International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. E14 Implementation Working Group. ICH E14 guideline: the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. Questions and answers (R3). 10 December 2015. Accessed December 2016. http://www​.ich.org/fileadmin​/Public_Web_Site​/ICH_Products/Guidelines​/Efficacy/E14​/E14_Q_As_R3__Step4.pdf.
• James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC Jr, Svetkey LP, Taler SJ, Townsend RR, Wright JT Jr, Narva AS, Ortiz E. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5;311(5):507–20. [PubMed: 24352797] [CrossRef]
• Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, Bennett CL, Bohlius J, Evanchuk D, Goode MJ, Jakubowski AA, Regan DH, Somerfield MR., American Society of Clinical Oncology. American Society of Hematology. American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Clin Oncol. 2010 Nov 20;28(33):4996–5010. [PubMed: 20975064] [CrossRef]
• Roush GC, Sica DA. Diuretics for Hypertension: A Review and Update. Am J Hypertens. 2016 Oct;29(10):1130–7. [PubMed: 27048970] [CrossRef]
• Senior JR. Evolution of the Food and Drug Administration approach to liver safety assessment for new drugs: current status and challenges. Drug Saf. 2014 Nov;37 Suppl 1:S9–17. [PMC free article: PMC4212154] [PubMed: 25352324] [CrossRef]
• Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, Goldberg JM, Khatcheressian JL, Leighl NB, Perkins CL, Somlo G, Wade JL, Wozniak AJ, Armitage JO., American Society of Clinical Oncology. Recommendations for the Use of WBC Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015 Oct 1;33(28):3199–212. [PubMed: 26169616] [CrossRef]
• U.S. Food and Drug Administration. Review of Qualification Data for Biomarkers of Nephrotoxicity Submitted by the Predictive Safety Testing Consortium. January 16, 2009. Accessed October 2016. http://www​.fda.gov/downloads​/Drugs/DevelopmentApprovalProcess​/DrugDevelopmentToolsQualificationProgram/UCM382536.pdf.
• U.S. Food and Drug Administration. Review of Qualification Data for Biomarkers of Nephrotoxicity Submitted by the ILSI-HESI Nephrotoxicity Working Group. September 13, 2010. Accessed October 2016. http://www​.fda.gov/downloads​/Drugs/DevelopmentApprovalProcess​/DrugDevelopmentToolsQualificationProgram/UCM382527.pdf.
• U.S. Food and Drug Administration. Guidance for Industry: E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. October 2005. Accessed December 2016. http://www​.fda.gov/downloads​/Drugs/GuidanceComplianceRegulatoryInformation​/Guidances/ucm073153.pdf. [PubMed: 16237860]
• Wasung ME, Chawla LS, Madero M. Biomarkers of renal function, which and when? Clin Chim Acta. 2015 Jan 1;438:350–7. [PubMed: 25195004] [CrossRef]