PK/PD modelling of an anti-FcRn mAb to optimise FIM design - translation from cyno to human
Rocio Lledo-Garcia (1), Grant Langdon (1,2), Ruth Oliver (1)
(1) UCB Pharma, Slough, UK, (2) ptxsolutions, UK
Objectives: UCB7665 is a mAb that aims at reducing levels of pathogenic IgG in autoimmune/alloimmune diseases by blocking FcRn receptor. Our objectives were: a) to develop a PK/PD model characterising the relationship between UCB7665 PK-IgG in cynomolgus monkeys (cynos); b) following its translation into humans, to optimise the FIM study design characterising the safety/tolerability at clinically relevant doses, and to prove the mechanism of action; and c) to update the model with FIM data and further understand cross-species differences.
Methods: Data from a PK/PD study in cynos was analysed by non-linear mixed-effects modelling. The model described by Lowe 2009 for drugs with target mediated disposition (TMDD) and an indirect effect model were used to describe PK and effects on IgG.
System and drug related parameters were translated from cyno to human using a combination of literature, in vivo and in vitro data. Uncertainty in the translation was included in the simulations of possible FIM scenarios. The model was updated with the FIM data.
Results: A two-compartment model with TMDD in the central compartment and an indirect-effect model where the free drug stimulates IgG catabolism characterised the PK-IgG relationship in cynos. Simulations from the cyno-to-human translated model were used to optimise the FIM design. A range of doses between a starting dose corresponding to MABEL (<10% IgG reduction) and a maximum dose providing a -70% mean change from baseline IgG, were chosen. Intermediate IV doses were predicted to provide a mean -32% and -52% change from baseline IgG. The observed FIM data shown mean (±SD) reductions on IgG of -15.06±3.95%, -36.04±5.98% and -47.6±3.16% (6-9 days post-dose) for the 3 first doses in the escalation. The alignment between predictions and observations increased at higher doses, as the system moved towards linearity. The model adequately described the human data. The linearly-related parameters where well translated by allometry, whereas some differences on the parameters driving the TMDD process were observed between human and cynos.
Conclusions: The PK/PD model allowed the combination of different sources of data to optimally inform the FIM design. It displayed alignment between human predictions and observations, and correctly characterised the non-linear and complex system in a simplified mathematical description.
References:
[1] Lowe P., Tannenbaum S., Wu K., Lloyd P. and Sims J. On Setting the First Dose in Man:Quantitating Biotherapeutic Drug-Target Binding through PK and PD models. Basic & Clinical Pharmacology & Toxicology (2009) 106: 195–209.