119: Impact of Inflammatory Diseases on the Pharmacokinetics of Therapeutic Proteins

Statement of Purpose: Therapeutic proteins are increasingly important in the treatment of immuno-inflammatory diseases. However, the impact of inflammation in these diseases on the pharmacokinetics (PK) of therapeutic proteins is not well understood, making it difficult to reliably predict the PK profile in patients based on data from healthy volunteers (HVs) in the early stages of drug development. The goal of this research is to evaluate the extent to which inflammation affects the PK of therapeutic proteins and to provide a level of guidance for the clinical pharmacology strategies in biological drug development.

Description of Methods & Materials: US Food & Drug Administration (FDA) Purple Book [updated as of January 25, 2023] was used to identify a list of approved therapeutic proteins indicated for the treatment of inflammatory diseases. These drugs were searched on FDA database and PubMed to extract literature that compared PK in patients and HVs. A separate PubMed search was conducted on February 3, 2023 to identify additional drugs still in development pipeline with relevant literature. PK parameter values in patients and HVs were extracted from identified clinical pharmacology reviews in FDA database and published literature in PubMed, and clearance (CL) ratios [𝐂𝐋(𝐏𝐚𝐭𝐢𝐞𝐧𝐭𝐬)/𝐂𝐋(𝐇𝐕𝐬)] were calculated to evaluate the PK difference between patients and HVs. Values that fell within the cut-off range of 0.8 to 1.25 were deemed to indicate similar PK in patients and HVs.

Data & Results: 85 therapeutic proteins including antibody-based drugs, Fc fusion proteins, and interferons were evaluated, of which 20 monoclonal antibodies and two fusion proteins were identified with literature comparing PK parameter values of patients and HVs. Based on the calculated CL ratios, 11 (50%) out of the 22 drugs showed difference in PK in presence of inflammatory diseases, whilst the remaining half did not exhibit marked PK difference between patients and HVs. Of the 11 drugs with PK difference, 10 (91%) had increased CL in patients than HVs, and only one showed lower CL in patients. After accounting for reported PK parameters of drugs in all examined diseases and dosages, 29 CL ratios were obtained with a mean of 1.24 (SD = 0.27, range = 0.75 to 1.76). CL of therapeutic proteins appears to change most dramatically in inflammatory bowel diseases (IBD). Interestingly, for certain given drugs, different inflammatory diseases had varying degrees of impact on CL.

Interpretation, Conclusion or Significance: Inflammation could impact the PK of therapeutic proteins by increasing the overall rate of clearance and resulting in lower exposure in patients. However, based on the current available data, the magnitude of the impact of inflammatory diseases on clearance has not exceeded a 2-fold range, with the most dramatic impact observed in IBD. Future investigations will seek to elucidate the underlying mechanisms responsible for such observation of PK difference between patients and HVs and probe the temporal correlation between alterations in drug clearance and changes in the degree of inflammation at different disease state.

Disclosures: