Stefan Roepcke, Glennda Smithson, Josh Yuan, Nele Plock, Gezim Lahu, Lin Zhao
Takeda Pharmaceuticals International
Objectives: We are studying a fully human, cell-depleting monoclonal antibody, which targets a pleiotropic transmembrane protein that is expressed on various white blood cells and up-regulated on activated lymphocytes. The antibody also binds the target and specifically depletes lymphocytes in cynomolgus monkeys and was therefore studied in several toxicology and pharmacology studies in this species. The objective of this work was to build PK-PD models based on the pooled PK and PD (changes in blood cell counts) data with the intention to gain mechanistic insights and to allow predictions of PK and PD effects in healthy human volunteers.
Methods and Results: We pooled PK and T, B, and NK cell count data (based on flow cytometric analyses) of 8 studies in healthy cynomolgus monkeys (dose range 0.03 – 100 mg/kg) and developed population PK and PK-PD models for each of the cell types. Similar to other therapeutic antibodies, the PK follows a linear 2-CMT model with a component for target-mediated drug disposition that describes non-linear elimination observed at concentrations below 0.5 µg/mL [1]. In 13-weeks toxicology studies anti-drug antibody (ADA) levels were found to increase in the majority of animals but to affect PK only above a certain threshold titer. Complete NK cell depletion was achieved with an IV dose of 0.3 mg/kg. This was adequately described with a simple turnover model (EC50=34.8 µg/mL on depletion rate). Intermediate effects on T cell counts were described with a direct response (EC50=9.43 µg/mL) and on B cell counts with a model with 4 transit compartments (EC50=19.3 µg/mL on depletion rate). Our analyses substantiate the observation that each of the measured lymphocyte subsets is cleared by the antibody at different rates and required different time spans to replete the blood compartment. In addition, we identified noticeable effects of frequent blood draws on the drop of lymphocyte counts in monkeys. The PK and PK-PD models were used to simulate PK and cell depletion profiles in monkeys and in humans after applying a straight-forward scaling approach for monoclonal antibodies. These simulations yielded predictions of exposures and effects for the ongoing First in Human clinical trial.
Conclusion: The model-based analysis of monkey PK and PD data of our cell depleting antibody provides opportunities to deepen the quantitative understanding of the pharmacology of the drug and to simulate scenarios in preparation of clinical trials.
References:
[1] Leonid Gibiansky, Ekaterina Gibiansky, Tarundeep Kakkar. Approximations of the target-mediated drug disposition model and identifiability of model parameters. Journal of Pharmacokinetics and Pharmacodynamics, 2008, Volume 35, Number 5, Page 573
Reference: PAGE 25 () Abstr 5957 [www.page-meeting.org/?abstract=5957]
Poster: Drug/Disease modeling - Other topics