Pharmacokinetic and Pharmacodynamic Modeling of Antibody-Drug Conjugates

Antibody-drug conjugates (ADCs) have risen in prominence over the past 15 years, with numerous regulatory approvals in oncology. A complicating factor in the development of ADCs is the presence of numerous analytes with unique pharmacologic properties. Following administration, ADCs are present in the body as the intact ADC, unconjugated antibody, and liberated payload. Due to heterogeneity in conjugation and in vivo deconjugation rates, the drug-to-antibody ratio (DAR) changes with time. Each of these molecular species has unique pharmacokinetic (PK) and pharmacodynamic (PD) properties that should be understood and characterized. One approach that is frequently applied is the development of in silico mathematical models to characterize and predict the PK/PD of ADCs. In this review, we summarize key mechanisms controlling the PK/PD of ADCs. This provides context for a detailed discussion of the array of PK/PD models that have been applied for ADCs, ranging from empirical compartmental models all the way through system-level models, such as physiologically based pharmacokinetics (PBPK) and cell-level PK/PD models. We provide a critical discussion of the strengths, weaknesses, and utility of each of these model structures.