Impact of Chronic Inflammatory Diseases on Clinical Pharmacokinetics of Antibody-Based Therapeutic Proteins.

Abstract

Antibody-based therapeutic proteins (TPs) emerged as a promising therapeutic modality for chronic inflammatory diseases. During clinical development, the impact of disease on pharmacokinetics (PK) should be carefully considered to reliably extrapolate PK from healthy volunteers (HVs) in early-phase studies to patients in later-phase studies. This paper aimed to provide an overview of the impact of chronic inflammatory diseases on the PK of antibody-based TPs. A literature search was conducted on Drugs@FDA and PubMed, yielding 30 TPs with author-drawn conclusions about PK differences between HVs and patients with inflammatory diseases. Nine out of 30 TPs suggested PK differences in patients with inflammatory diseases compared with HVs, and patients mostly appeared to have higher drug clearance or lower drug exposure compared with HVs. However, the remaining 21 TPs appeared to have no apparent PK differences between patients and HVs. Based on ratios of reported drug clearance in patients vs. HVs (N: 31 ratios for 22 TPs), the difference in TP clearance due to inflammatory diseases did not exceed twofold (mean clearance ratio: 1.23; standard deviation: 0.25), with the most noticeable difference (>50% higher clearance) observed in patients with inflammatory bowel diseases and rheumatoid arthritis. Covariate assessment in published population PK models of TPs revealed that higher baseline C-reactive proteins and lower baseline albumin levels tend to be correlated with higher TP clearance. Future investigation is necessary to further elucidate the mechanism behind the inflammatory disease-mediated PK differences.