Purpose: Antibody- drug conjugates (ADCs) are a novel class of therapeutic agents that deliver potentcy totoxic drug molecules (payload) to their targets while reducing systemic exposure. ADCs may be composed of heterogeneous mixtures of conjugates with variations in both drug-to-antibody ratio (DAR) and conjugation sites, or homogenous compositions with a controlled DAR and specificsites of conjugation. To understand the complex disposition mechanisms of ADCs, acomprehensive PBPK model was developed in GastroPlus (SimulationsPlus,Inc.) to simulate the disposition of unconjugated antibody and payload, as well as conjugates with different DARs after ADC administration.
Methods: The previously developed whole-body PBPK model for unconjugated monoclonal antibodies (mAbs) in GastroPlus was expanded to include mechanisms related to ADC’s deconjugation and the production of payload. Similar to unconjugated mAbs, the mechanisms related to the absorption and disposition of ADCs include convective transport, lymph flow, fluid phase endocytosis, pH-dependent FcRn binding, FcRn recycling, endogenous IgG, and target-mediated drug disposition. The cytotoxic payload attached to the antibody can be released and distributed in the body when ADC clearance occurs, both through nonspecific and target-specific mechanisms. Also, higher DAR conjugates may be converted to lower DAR conjugates via the deconjugation of the payload molecule from the antibody in vascular and interstitial spaces (Figure 1). All of these mechanisms are incorporated in each tissue compartment (Figure 2) of the wholebody PBPK model. The released payload is cleared through metabolism or renal excretion.
AAPS (American Association of Pharmaceutical Scientists) Annual Meeting, November 13-17, 2016, Denver, CO
By Haiying Zhou, Michael B. Bolger, Viera Lukacova