Evgeny Metelkin (1), Tatiana Petukhova (1), Oleg Demin (1), Elena Shipaeva (2), Mikhail Samsonov (2), Anna Krotkova (2), Yan Lavrovsky (3)
(1) Institute for Systems Biology, Moscow, Russia, (2) JSC R-Pharm, Moscow, Russia, (3) R-Pharm Overseas, Inc., San Diego, USA
Objectives: RPH-104 (JSC R-Pharm) is a novel heterodimeric fusion protein, capable of inhibition of human IL-1 beta/IL-1F2 signaling pathway, for the treatment of autoimmune disorders associated with the overproduction of IL-1 beta cytokine (Behcet disease, FMF). The safety and PK of RPH-104 were assessed in studies on cynomolgus monkeys. The objective of this paper was to describe PK data in terms of population PK model and, in addition, to perform evaluation of immunogenic increase of elimination based on studies data in monkeys.
Methods: Based on PK monkeys data the population model was developed. Additional data of anti-drug antibody (ADA) production were used as categorical data (ADA-status) or as ADA levels in plasma to assess immunogenicity effect. The modeling and verification steps were performed in NONMEM V.7.3.0. FOCE method was used for estimations. Data processing and graphics were performed in R.
Results: Pharmacokinetics of RPH-104 in monkeys was described by 2-compartment model with linear elimination. Unexplained inter-individual variability was evaluated for parameters of central compartment volume and clearance. The parameter estimates of the model without effect of the immunogenicity were significantly biased. Implementation in model ADA production subject status in answer to RPH-104 therapy was allowed to decrease bias in parameter estimates. Model with effect of immunogenicity resulted in 5.5-fold increase of clearance following ADA response.
Conclusions: Population PK model of RPH-104 was developed. ADA production was describing as simple model with 5.5-fold increase of clearance following ADA response.
Reference: PAGE 25 (2016) Abstr 5961 [www.page-meeting.org/?abstract=5961]
Poster: Drug/Disease modeling - Other topics