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Dear all,

Thank you Yusuf for sharing with us. It is timely that Roche releases a memo on eltrombopag.

I work at a hospital pathology laboratory. I had the opportunity to investigate a case of eltrombopag interference - my patient was on a trial dose of eltrombopag 300 mg daily. The patient sample was brown-coloured. My publication is cited on the GOV.UK site (https://www.gov.uk/drug-safety-update/eltrombopag-revolade-reports-of-interference-with-bilirubin-and-creatinine-test-results) (Choy K, et al. Pathology 2016; 48: 754-756).

My comments on the Roche memo "No evidence of interference by Eltrombopag in Roche Clin. Chem. Tests":

1. Eltrombopag is a coloured drug and the colour changes with the solution pH (like a pH indicator dye). It is yellow in acidic media.

2. The mean peak plasma concentration of eltrombopag is reported to be about 10 ug/mL following typical FDA-approved dosing (up to 75 mg daily). Patients on trial dose (200 or 300 mg daily) (4-fold higher dosing) likely yields concentrations well above that observed with typical dosing, and concentrations exceeding 100 ug/mL are possible assuming linear pharmacokinetic behaviour (Cardamone D, et al. Arch Pathol Lab Med 2013; 137: 1175).

Before we conclude that there is NO interference, it may help to note we are referring to 'FDA-approved' doses or trial/higher doses. It may help to note if the patient sample is brown-coloured.

3. My patient sample was analysed on multiple instruments (see table). The patient was truly jaundiced; the radiometer ABL blood gas and Beckman AU total bilirubin measurements were likely correct. Other instruments such as Beckman DxC, Roche cobas, Abbott Architect appeared to have suffered negative interference.

Analyser	Total bilirubin (umol/L)	Creatinine (umol/L)
Radiometer ABL blood gas	100	47 (enzymatic)
Beckman AU	80	30 (kinetic Jaffe)
Ortho Vitros	Conj. 0 Unconj. 18	47 (enzymatic)
Siemens Advia	13	43 (kinetic Jaffe)
Abbott Architect	13	37 (kinetic Jaffe)
Roche cobas	9	49 (enzymatic)
Beckman DxC	<2	64 (kinetic Jaffe)
LC-MS/MS creatinine		56

Interestingly, my spike-in studies on 5 different instruments showed that Roche cobas and Abbott Architect total bilirubin assays were not affected at up to 900 ug/mL eltrombopag concentrations. My Roche findings are largely similar to Gouden and Zhao's (Ann Clin Biochem 2015; 53: 611-614).

Why the discordance between actual patient sample (my patient, n=1) and the spike-in studies? I wonder about eltrombopag metabolite interference. This needs to be investigated further with more of such coloured samples (patients on trial dose of eltrombopag).

4. While the Beckman Coulter DxC is affected by trial-dose eltrombopag, the Beckman Coulter AU is not affected. As I understand, the AU total bilirubin assay has two separate channels with identical pH reagents; therefore it 'cancels out' any pH-dependent colour change after addition of reagents. If Beckman Coulter AU is replacing DxC, then Beckman Coulter users have a robust total bilirubin assay resistant to interference.

I am happy to share my data with anyone or manufacturer.

Kind regards,

Kay Weng

On Wed, Oct 10, 2018 at 7:46 PM GRAY, Yusuf (UNIVERSITY HOSPITALS OF DERBY AND BURTON NHS FOUNDATION TRUST) <[log in to unmask]> wrote:

Received from Roche this morning.

Yusuf

Yusuf Gray

Biomedical Scientist Team Manager – Point of Care Technologies

Derbyshire Pathology

University Hospitals of Derby and Burton NHS Foundation Trust

Royal Derby Hospital

Telephone 01332 788537

Mobile 0737 938 0799

[log in to unmask]

www.uhdb.nhs.uk

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