A White Paper—Consensus and Recommendations of a Global Harmonization Team on Assessing the Impact of Immunogenicity on Pharmacokinetic Measurements

Abstract

Abstract. The Global Bioanalysis Consortium (GBC) set up an international team to explore the impact of immunogenicity on pharmacokinetic (PK) assessments. The intent of this paper is to define the field and propose best practices when developing PK assays for biotherapeutics. We focus on the impact of anti-drug antibodies (ADA) on the performance of PK assay leading to the impact on the reported drug concentration and exposure. The manuscript describes strategies to assess whether the observed change in the drug concentration is due to the ADA impact on drug clearance rates or is a consequence of ADA interference in the bioanalytical method applied to measure drug concentration. This paper provides the bioanalytical scientist guidance for developing ADA-tolerant PK methods. It is essential that the data generated in the PK, ADA, pharmacodynamic and efficacy/toxicity evaluations are viewed together. Therefore, the extent for the investigation of the PK sensitivity to the presence of ADA should be driven by the project needs and risk based.

Recommendations for the Assessment and Management of Pre-existing Drug-Reactive Antibodies During Biotherapeutic Development

“…ADA, as well as pre-existing antibodies, may not only interfere but also directly enhance drug clearance by forming immune complexes. In order to better understand the specific nature of the ADA impact, including pre-existing antibodies, on drug PK, an additional investigation may be required, as previously described (54,55).…”

“…Alternatively, a practical conservative approach using a pre-established subjective % inhibition cut point in a standard specificity inhibition assay can also eliminate pre-existing antibodypositive samples (54). Once positives are removed, the cut point should be calculated with an adequate quantity of remaining negative samples using standard approaches (i.e., 95th percentile) (29,55). The presence of pre-existing antibodies may necessitate a larger sample size during assay validation so that enough antibody-negative subjects will remain for statistical assessment of the cut point.…”

Utility of a Bayesian Mathematical Model to Predict the Impact of Immunogenicity on Pharmacokinetics of Therapeutic Proteins

“…A second component of the modeling exercise required the accurate measurement of PK and ADA levels during bioanalytical analysis (5,21). The influence of high levels of TP limit detection of ADA, and high levels of ADA interfere with accurate measurement of TP.…”

“…of ADA. Several factors can contribute to the inaccuracy of assessment of impact of ADA on PK of a therapeutic protein including (i) interference in the analytical measurement of TP due to excess ADA levels in a sample (4), (ii) presence of ADA in a sample which can either bind at the idiotypic region (complementarity determining region, CDR) or the framework (Fc) region (5) and interfere with accurate measurement of TP. The in-depth delineation of this interplay between ADA and PK interactions that can have a significant clinical impact is still evolving.…”

Detection of cynomolgus monkey anti-protein XYZ antibody using immunocapture-LC/MS

“…ADA can affect drug efficacy, biodistribution and drug clearance, and complicate interpretation of toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) data [3][4][5]. During drug development, immunogenicity is examined using a risk-based approach along with specific strategies for developing "fit-for-purpose" bioanalytical methods [6].…”