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Eltrombopag and serum of a different Hue.

To the Editor.--Eltrombopag (Promacta; 3'-{(2Z)-2-[1-(3,4-dimethylphenyl)-3-methyl-5-oxo-1,5-dihydro-4H-pyrazol-4-ylidene]hydrazino}-2'-hydroxy-3- biphenylcarboxylic acid-2aminoethanol [1:2]) is an oral thrombopoietin receptor agonist that is Food and Drug Administration (FDA) approved for the treatment of certain patient groups with chronic immune thrombocytopenia. (1) our institution is conducting a phase 1/2 clinical trial of eltrombopag for the treatment of acute myelogenous leukemia in elderly patients. (2) Doses in this study exceed the currently FDA-approved maximal dose of 75 mg daily. (2)

Gross inspection of sera from eltrombopag-treated patients (no signs of hepatotoxicity) treated with 200 or 300 mg of eltrombopag daily was remarkable for a deep brownish red coloration (Figure, A-C).

Because of the reported hepatotoxicity associated with this drug, liver function testing is routinely performed on patients while they are on eltrombopag therapy. We encountered 4 individuals receiving eltrombopag (200 or 300 mg daily) who had total bilirubin (Tbili; to convert total bilirubin concentration to micromoles per liter, multiply by 17.104) measurements of <0.1 mg/dL (diazo method, DxC 800 analyzer, Beckman Coulter, Brea, California) but discordant icteric indices (eg, index = 4, corresponding to 4.5-6.0 mg/dL). The unlikely nature of these results led us to investigate the possibility of an analytic interference specifically related to the drug.

Spiking experiments, the usual way to investigate a possible drug interference, demonstrated that eltrombopag at a concentration of 50 [micro]g/mL had no significant impact on the measured concentration of Tbili in a drug-free serum sample (Tbili, 4.6 mg/dL); however, a concentration of 200 [micro]g/ mL resulted in a Tbili of <0.1 mg/dL. A similar Tbili result (<0.1 mg/dL) was obtained at an eltrombopag concentration of 100 [micro]g/mL in a drug-free serum sample (initial Tbili, 0.25 mg/ dL). The spiked serum specimens exhibited a brownish red color similar to that observed with the eltrombopag-treated patient serum specimens. The mean peak plasma concentration of eltrombopag is reported to be ~10 1g/mL following typical FDA-approved dosing (up to 75 mg daily). (2) The 4-fold higher dosing in our clinical trial patients likely yields concentrations well above that observed with typical dosing, and concentrations exceeding 100 [micro]g/mL are possible assuming linear pharmacokinetic behavior; however, the drugs actual concentrations using a 200- or 300-mg daily dose are unknown.

The interference by eltrombopag is further complicated by the color of the drug (a diacid with carboxyl and phenolic functional groups), (3) which varies by solution pH and concentration--reddish brown at basic pH and yellow in acidic media (Figure, D-F). This pH-dependent change in color (and visible light absorbance), likened to a pH indicator dye, may have different effects in different assays. In the DxC Tbili assay, the pH of the sample following serial addition of the 2 assay reagents changes from 7.4 to 6.4. A direct bilirubin assay on the Beckman Coulter DxC that also uses the diazo method but does not have the associated changes in pH with reagent addition appears much less subject to interference by this drug (no observable interference at 100 [micro]g/mL).

This is the first description, to our knowledge, of an analytic interference produced by eltrombopag (or possibly its metabolites). The variability in color with changes in pH poses some unique challenges to the laboratory because the pH of serum may change following collection. Although this drug is not likely to be encountered frequently by clinical laboratories, it represents an important analytic interference that should be recognized and further explored because it may interfere in other spectrophotometric assays. At a pragmatic level, pretreatment and posttreatment bilirubin levels in these patients could be evaluated to provide an indication of what the background bilirubin level was in the affected samples during treatment, especially if there was no clinical evidence of hepatotoxicity and if other liver-related markers were unchanged.

Caption: Serum from patients treated with eltrombopag (A through C), eltrombopag in acidic (D) and basic conditions (E), and eltrombopag solution (200 [micro]g/mL) (F).

DAVID CARDAMONE, MS

MICHAEL C. MILONE, MD

LAUREL GLASER, MD

Department of Pathology & Laboratory Medicine, university of Pennsylvania Medical Center, Philadelphia, PA 19104

NOELLE V. FREY, MD

Department of Medicine, Perelman Center for Advanced Medicine, university of Pennsylvania Medical Center, Philadelphia, PA 19104

LARRY J. KRICKA, DPHIL

Department of Pathology & Laboratory Medicine, university of Pennsylvania Medical Center, Philadelphia, PA 19104

References

(1.) Zhang Y, Kolesar JM. Eltrombopag: an oral thrombopoietin receptor agonist for the treatment of idiopathic thrombocytopenic purpura. Clin Ther. 2011;33(11):1560-1576.

(2.) National Institutes of Health. Eltrombopag in elderly acute myelogenous leukemia (AML). ClinicalTrials.gov Web site. http://clinicaltrials.gov/ct2/ show/NCT01113502. Accessed April 10, 2013.

(3.) ChemAxon. Properties viewer: Eltrombopag. Chemicalize.org Web site. http://www.chemicalize.org/structure/#!mol=Eltrombopag. Accessed April 10, 2013.

The authors have no relevant financial interest in the products or companies described in this article.

doi: 10.5858/arpa.2012-0716-LE

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Author:Cardamone, David; Milone, Michael C.; Glaser, Laurel; Frey, Noelle V.; Kricka, Larry J.
Publication:Archives of Pathology & Laboratory Medicine
Article Type:Letter to the editor
Date:Sep 1, 2013
Words:838
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