Setting a Safe Starting Dose for a First-in-Man trial of a Monoclonal Antibody Based on Population PK-PD Predictions
L. Alifrangis (1), P. André (2), R.V. Overgaard (1), C. Sola (2), A. Tisserant (2), N. Wagtmann (1), F. Romagne (2), S.H. Ingwersen (1).
(1) Novo Nordisk A/S, Copenhagen, Denmark; (2) Innate Pharma, Marseille, France.
Objectives: The disastrous outcome of a recent phase 1 trial with a monoclonal antibody (mAb) (1) has highlighted the need for improved methods for determining safe starting doses for First-in-Man trials. Here, we used a population Pharmacokinetic (PK)-Pharmacodynamic (PD) model to predict a safe starting dose for the First-in-Man trial of a human IgG4 mAb specific for inhibitory Killer cell Ig-like Receptors (KIR) expressed on human NK cells. By blocking the interactions of KIR with its HLA-C ligands on target cells, the anti-KIR mAb (designated 1-7F9) facilitates NK-mediated killing of cancer cells.
Methods: An in vivo PK-PD model was established in a transgenic mouse strain expressing the human KIR. Using NONMEM V and population methods, a sequential approach was applied, first modelling PK followed by PD. Receptor occupancy was used as a measure of PD. The structural PD parameters of the mouse PK/PD model were combined with predicted PK parameters of IgG's in humans to devise a PK/PD model predicting the relationship between dose, resulting plasma concentration profile and KIR-receptor occupancy profile in humans.
Results: The PK of Anti-KIR(1-7F9) after i.v. administration in the transgenic as well as wild-type B6 mice was modelled by a 2-compartment model, combined with a 3rd saturable distribution compartment. The presence of the KIR antigen did not affect clearance or distribution of the Anti-KIR mAb. In vivo, the dissociation constant (Kd) changed from an initial 0.004 ug/ml to 0.1 ug/ml over time. Kd showed a good in vitro - in vivo correlation for the transgenic mice as well as a good interspecies correlation in vitro for KIR-transgenic mice vs humans. Based on the PK-PD model, a 0.3 ug/kg dose given to humans was predicted to result in 61% receptor saturation as the peak value with a rapid decay of saturation at later time points. Hence, this was suggested as the starting dose for the first phase 1 trial.
Conclusions: Using a combination of population PK-PD methods and in vitro-in vivo comparisons, a cautious starting dose based on all available scientific information has been suggested. The PK-PD model indicated that a surprisingly low dose of the Anti-KIR mAb may result in substantial receptor occupancy.
Reference:
[1] Suntharalingam, G et al.(2006). N Engl J Med 355:1018-1028.
