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Abstract

Aim: This paper describes a case study of an antibody therapeutic targeting a membrane-bound receptor, also present in systemic circulation, as a soluble receptor. During phase I studies of astegolimab, nonlinear pharmacokinetics (PKs) were observed. We investigated the potential contribution of antidrug antibodies, target-mediated drug disposition and assay format. Materials & methods: A more target-tolerant assay was developed, and a subset of phase I samples were evaluated in both free and total PK assay formats. Results & conclusion: Our results demonstrate that there were two main contributors to PK nonlinearity: soluble target interference in the free PK assay, in addition to target-mediated drug disposition. Antidrug antibody status did not significantly impact PK.

Keywords:

  • free PK assay
  • non-linear PK
  • target-mediated drug disposition
  • total PK assay
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