Abstract 92P
Background
Monoclonal antibody (mAb) development requires comprehensive preclinical and clinical analyses, particularly to determine the maximum recommended starting dose (MRSD), through pharmacokinetic (PK) profiling. The FDA and EMA provide guidelines for establishing first-in-human doses, with the FDA recommending the no observed adverse effect level (NOAEL) approach. This method, despite limitations, is commonly used for mAbs. It involves scaling factors to convert animal NOAEL doses into human equivalent doses (HED), although these factors were originally developed for conventional drugs, not mAbs.
Methods
In this study, we utilized PK datasets from preclinical single-dose studies in rodents and non-human primates (NHP) to determine theoretical human PK profiles using NOAEL scaling factors. Key PK parameters were calculated, including maximum concentration (Cmax), area under the curve from initial time to last concentration (AUClast), area under the curve extrapolated to infinity (AUCinf), clearance, volume of distribution, and half-lives. The calculated profiles were then compared to actual PK data from the TROIKA-1 (trastuzumab biosimilar, NCT03776240) and SAMSON-1 (bevacizumab biosimilar, NCT03390673) trials, enabling us to identify new, potentially more accurate interspecies conversion factors.
Results
Our analysis revealed estimated interspecies conversion ratios of 1.42 (95% CI: 0.56–2.27) from mice to humans, 0.79 (95% CI: 0.63–0.95) from rats to humans, and 0.88 (95% CI: 0.45–1.31) from NHP to humans. These proposed factors may provide more accurate HED estimation for mAbs in preclinical models. Additionally, we calculated conversion factors for rodents to NHP, obtaining values of 2.19 (95% CI: 2.05–2.33) from mice to NHP and 1.21 (95% CI: 1.18–1.23) from rats to NHP, which may support further mAb development stages.
Conclusions
While the NOAEL method is standard in drug development, it may benefit from refinement when applied to mAbs. Our proposed interspecies conversion factors—1.42 from mice to humans, 0.79 from rats to humans, and 0.88 from NHP to humans—could enhance HED estimation for mAbs.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
J. Kim, S. Pradhan, L. Jaison, L.S. Park: Financial Interests, Personal, Full or part-time Employment: Prestige Biopharma Limited. X. Pivot: Financial Interests, Personal, Advisory Role, Consults with honorarium: Prestige Biopharma Limited. All other authors have declared no conflicts of interest.