A Model‐Based Approach to Quantify the Time‐Course of Anti‐Drug Antibodies for Therapeutic Proteins

Abstract

 The use of therapeutic proteins has increased dramatically for a wide range of diseases. The immunogenicity is an important factor because the formation of ADAs can cause adverse events and/or diminished efficacy. However, few studies directly quantified the time profiles of ADA levels. WHAT QUESTION DID THIS STUDY ADDRESS? The study was aimed to quantitatively describe the time course of ADA titers in response to the treatment of therapeutic proteins and to explore the relationship between titers and incidence of ADA from a longitudinal perspective. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The results from our research showed that the ADA incidence and titer are associated longitudinally. It could take about 16-24 weeks to reach steady state for incidence of ADA after chronic treatment. HOW MIGHT THIS CHANGE CLINICAL PHARMA COLOGY OR TRANSLATIONAL SCIENCE?  Quantification of the time profiles of ADAs is helpful for trial design to evaluate immunogenicity and investigate its impact for therapeutic proteins.

Physiologically‐Based Pharmacokinetic Modeling vs. Allometric Scaling for the Prediction of Infliximab Pharmacokinetics in Pediatric Patients

“…The immunogenic response is a modeling challenge because ADA assays often do not quantify concentrations, only titers of ADA molecules. 42 As a first step toward quantifying the response, the ADA-negative PK data for infliximab available in literature combined with the parameterization of the time course of ADA formation in humans by Ren et al 36 have enabled the first mechanistic representation of the immunogenic response to a therapeutic drug product. Figure S2 displays the simulated profile of mean ADA formation following first dose administration in a typical population of adults with inflammatory bowel disease.…”

“…In the absence of additional data, the zero order molar synthesis rates of IgM and IgG were assumed equal (). The typical ADA profile featured an initial period of IgM synthesis, a lag phase, and finally a sustained IgG response . The group noted differences in IgG degradation rates between healthy and autoimmune individuals, which were implemented in the model .…”

“…The typical ADA profile featured an initial period of IgM synthesis, a lag phase, and finally a sustained IgG response . The group noted differences in IgG degradation rates between healthy and autoimmune individuals, which were implemented in the model . Mechanistically, binding of infliximab to IgM or IgG caused the formation of a complex, which was eliminated from the system by a first order degradation rate ().…”

“…34 ADA molecules (IgM and IgG) bind to infliximab to form a complex, neutralizing its therapeutic potential and eventually resulting in degradation. In the PBPK model, ADA molecules (IgM and IgG) were synthesized, released, and contained within the plasma of venous and arterial blood, similar to the assumptions made by Chen et al 35 Mean ADA synthesis and degradation rates in the adult population were parameterized according to Ren et al, 36 who quantified the typical immune response after first-dose exposure to four therapeutic proteins with a PopPK modeling approach. In the absence of additional data, the zero order molar synthesis rates of IgM and IgG were assumed equal (k IgM syn = k IgG syn ).…”

Impact of Switching on Pharmacokinetics of Therapeutic Biologics and Interchangeability Assessment—A Simulation Study

“…For the simulations, the lag time (t lag ) to ADA production was set to a literature value of 4 weeks. [4][5][6] The production rate of ADA (P ADA ) was assumed to be a saturable function of the time (Equation 5) rather than the accumulated biologic dose, as the literature reported that the amount of ADA was relatively independent on the accumulated drug exposure. 2 ADA subsequently enters the central compartment (ADA C ) after going through 5 transit compartments (ADA T1 to ADA T5 ) with a same transit rate constant of K T (Equations 6-10).…”