Review
Surrogate matrix: opportunities and challenges for tissue sample analysis
Often there is limited availability of matching tissue matrix and/or the analyte may occur endogenously in the target tissue. Surrogate matrix provides an option for quantitation of drug, metabolite(s) and biomarker(s) in these circumstances. However, the use of a surrogate matrix also presents challenges. This paper summarizes and discusses the challenges of selecting a proper surrogate, validating the suitability of the surrogate and establishing a surrogate tissue method using the fit-for-purpose approach. This paper also systematically reviews the current practices for evaluating key parameters of a surrogate tissue assay, including sensitivity, specificity, selectivity, interference, precision, accuracy, recovery, matrix effects and stability. Considerations and suggestions are provided for dealing with such challenges during method establishment and tissue sample analysis.
Modern drug discovery and development can benefit from more information gener- ated from in vivo PK/TK studies as early as possible to make critical decisions,
reduce
cost in early stage and manage risk during the development. Quantitation of test com- pounds and metabolites in target tissue pro- vides important information and has become common practice, especially in the discovery stage. Measurements such as the ratio of the concentrations of an analyte in brain versus plasma, are used as a screening tool for select- ing CNS drug entity at many organizations. Generally, the use of calibration standards in authentic matrix, in other words, the same tissue as the sample (matching tissue) is preferred for accurate quantitation of drug in tissue. However, in some cases, using a substi- tute matrix is more suitable or more practical. This substitute is called surrogate matrix. A suitable surrogate matrix ‘is used to pre- pare calibration standards that is devoid of the target analyte and suitably depicts the behaviors of the biological sample matrix’ [1]. Using surrogate matrix for tissue analysis
offers new opportunities for quantitation, which are not possible otherwise. Driving factors for using surrogate matrix approaches
10.4155/bio.15.161 © 2015 Future Science Ltd
include the lack of blank authentic tissue, the need for better
limit of quantitation
for endogenous analytes, and the desire for higher
sample analysis efficiencies. Surro-
gate matrix approaches allow quantitation of analyte even when the matching matrix is limited in quantity or unavailable. There are many reasons why the blank matching tissue may be in short supply. For example, the amount of matching tissue may be insuf- ficient for the analysis of neonatal mouse tissues. The matching tissue may be impos- sible to obtain, such as may be the case for the analysis of clinical biopsy samples. In other cases it may be not worth the effort and costs required to collect the matching tissue such as for fast turnaround screening studies during the early drug discovery. Using sur- rogate matrix for tissue analysis can reduce the LLOQ when the analyte is endogenous in tissue and the desired LLOQ can only be achieved using analyte free matrix. Using surrogate for tissue analysis saves money and time as illustrated in Table 1 while generally yielding comparable quality data. The sav- ings can be significant when the same sur- rogate matrix is used for the analysis of many types of tissue and a large number of samples.
Bioanalysis (2015) 7(18), 2419–2433 ISSN 1757-6180
Stacy Ho*,1
& Hong Gao2 1Drug Metabolism & Pharmacokinetics,
Disposition, Safety & Animal Research (DSAR), Sanofi, 153 Second Avenue,
Waltham, MA 02451, USA 2
Drug Metabolism & Pharmacokinetics,
Vertex Pharmaceuticals Inc., 50 Northern Avenue, Boston, MA 02210, USA *Author for correspondence: Tel.: +1 781 434 3485 Fax: +1 781 466 3789
stacy.ho@sanofi.com
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