Manoranjenni Chetty (1), Katherine Gill (1), Krishna Machavaram (1), Linzhong Li (1), Iain Gardner (1), Amin Rostami (1,2), Masoud Jamei (1)
(1) Simcyp (A Certara Company), Blades Enterprise Centre, Sheffield, UK (2) Manchester Pharmacy School, Manchester University, Manchester
Objectives: To identify covariates that impact significantly on the pharmacokinetic (PK) parameters of monoclonal antibodies (mAbs) in population pharmacokinetic (POPPK) studies and to evaluate whether current human physiologically based pharmacokinetic (PBPK) models account for the PK variability due to these covariates.
Methods: A literature review was conducted to retrieve POPPK studies on mAbs. Studies were evaluated to identify covariates tested and those that had a significant impact on the PK variability. Published human PBPK models for mAbs were evaluated for their potential ability to account for variability in PK, with special reference to the significant covariates identified by POPPK studies.
Results: 37 POPPK studies were evaluated. Cumulatively, 59 different covariates were tested and 17 were identified as significant covariates. Weight was found to be significant in 20 studies, with covariates such as serum albumin, antibodies to the mAb, body surface area, sex, concurrent medication, white blood cells, dose, smoking status, aspartate aminotransferase (AST), ethnicity, age, target concentration, formulation, route of administration and glomerular filtration rate reported to be significant in 6 studies or less. PBPK models have the potential to account for the variability due to the majority of these covariates but most of the current models do not focus on sources of variability. Weight, the major covariate identified in POPPK analyses, requires to be considered in PBPK models, although many mAbs are dosed according to the weight of the patient. Antibodies to the mAb were found to be significant in only 16% of the studies. However, this covariate could present some challenges for PBPK modelling.
Conclusions: Weight was the major significant covariate identified. PBPK models generally do not adequately incorporate variability due to the relevant covariates.
Reference: PAGE 24 (2015) Abstr 3680 [www.page-meeting.org/?abstract=3680]
Poster: Methodology - Covariate/Variability Models