Dilemma with Matrix Effect in Bioanalysis – Perspectives from Bioavailability/Bioequivalence Studies for Product Registration?

Sir:

In this age of triple quad mass spectrometric use (LC-MS/MS) for highly sensitive bioanalytical assays, the heightened awareness of challenges with matrix effects has led to careful planning and optimization of assay conditions during the initial method development and validation [1] [2] [3] [4] [5] [6] [7]. A closer look at the published literature suggests that researchers have numerous options to circumvent the challenges of matrix effects [4] [5] [6] [7]. It is needless to say that the evaluation of matrix effect has become an integral part of method validation and provides additional assurance on the quality of the pharmacokinetic characterization of the novel compounds under development.

Although evaluation of matrix effect is relevant, it should not in itself add further complexity for the bioanalyst. In other words, while it is important to confirm whether matrix effect exists or not, the existence of matrix effect should not discredit the assay and/or should not lead to expending additional resources to fix the problem unless it is warranted. There are numerous assays which have been published where matrix effects have been reported to be higher than 25%; however, these assays were found satisfactory for the quantitative determination of the selected compounds in the chosen matrix [8] [9] [10] [11].

My recent conversations with bioanalysts/researchers has suggested that there is a dilemma when it comes to evaluating matrix effects especially for assays that are newly developed to analyse pharmacokinetic (PK) samples for bioavailability/bioequivalence (BA/BE) studies. One school of thought advocates evaluation of matrix effect and suitable modification of the method to minimize matrix effect, if deemed necessary, prior to the application of the assay for a BA/BE study. The other school of thought questions the need of evaluation of matrix effect, let alone modification of the assay to overcome matrix effects. The reasoning for this is supported by the fact that the matrix remains the same between samples collected for reference and test formulations in a given individual and therefore, hypothetically the observed matrix effects (if any) would balance between the 2 sets of samples and hence, should have no bearing on the outcome of the BA/BE study.

The intent of this note is to provide some introspection and perspectives on this important ­subject matter. Several hypothetical cases are presented to reflect the on-going dilemma in the thinking of the younger researchers as it relates to dealing with matrix effect in assays to be used for PK sample analyses in BA/BE studies.

• References

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