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Clinical Chemistry 46: 1179-1183, 2000;
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(Clinical Chemistry. 2000;46:1179-1183.)
© 2000 American Association for Clinical Chemistry, Inc.

Technical Briefs

Validation of an Assay for Routine Monitoring of Sirolimus Using HPLC with Mass Spectrometric Detection

David W. Holt1,a, Terry Lee1, Kirsty Jones1 and Atholl Johnston2

1 St. George’s Hospital Medical School, London SW17 0RE, United Kingdom

2 St. Bartholomew’s & The Royal London School of Medicine & Dentistry, London EC1M 6BQ, United Kingdom
a address correspondence to this author at: Analytical Unit, St. George’s Hospital Medical School, London SW17 0RE, UK

Sirolimus (rapamycin, Rapamune®; Wyeth-Ayerst Research) is a potent immunosuppressive drug with a molecular mass of 913.6 Da (1). When licensed in the United States, measurement of circulating sirolimus concentrations was recommended for pediatric patients, for those with hepatic impairment, and for patients in whom potent inducers or inhibitors of the enzyme CYP3A4 are co-administered or in whom concomitantly administered cyclosporine dosing is markedly reduced or discontinued. Because 95% of the drug is sequestered within erythrocytes, whole blood has been recommended as the sample matrix (2).

In a series of concentration-controlled clinical trials, sirolimus was measured by HPLC with mass spectrometric (MS) detection (3) or HPLC with ultraviolet (UV) detection as a guide to dose adjustment (4)(5). For the double-blind pivotal phase III clinical studies, the drug was measured by an investigational microparticle enzyme immunoassay (Abbott Diagnostics) on the IMx® clinical analyzer (6). The immunoassay is not commercially available, and there is an acute need for an accurate, rapid, and simple chromatographic assay to manage patient care. Current clinical trials target predose (trough) whole-blood sirolimus concentrations within the approximate range 5–30 µg/L.

HPLC-UV assays for sirolimus have throughputs of only ~20–30 samples per day, and current sirolimus dosage regimes tend to achieve sirolimus trough concentrations close to the reported lower limits of quantification (LLOQ) of these assays, ~1–5 µg/L, despite the use of blood sample volumes in the range 1–2 mL (7)(8)(9). For most laboratories, the only feasible alternative to HPLC-UV currently available is HPLC-MS (10)(11), which has a shorter chromatographic run time (leading to a higher sample throughput), smaller sample volume, increased selectivity for sirolimus, and a lower LLOQ. With sample volumes of 0.5 or 1 mL, . . . [Full Text of this Article]


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The following articles in journals at HighWire Press have cited this article:


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 Clin. Chem.Home page
G. Khoschsorur
Simultaneous Measurement of Sirolimus and Everolimus in Whole Blood by HPLC with Ultraviolet Detection
Clin. Chem., September 1, 2005; 51(9): 1721 - 1724.
[Full Text] [PDF]

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 Clin. Chem.Home page
T. M. Annesley and L. Clayton
Simple Extraction Protocol for Analysis of Immunosuppressant Drugs in Whole Blood
Clin. Chem., October 1, 2004; 50(10): 1845 - 1848.
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B. G. Keevil, D. P. Tierney, D. P. Cooper, and M. R. Morris
Rapid Liquid Chromatography-Tandem Mass Spectrometry Method for Routine Analysis of Cyclosporin A Over an Extended Concentration Range
Clin. Chem., January 1, 2002; 48(1): 69 - 76.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Chem.Home page
D. C. French, M. Saltzgueber, D. R. Hicks, A. L. Cowper, and D. W. Holt
HPLC Assay with Ultraviolet Detection for Therapeutic Drug Monitoring of Sirolimus
Clin. Chem., July 1, 2001; 47(7): 1316 - 1319.
[Full Text] [PDF]


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