Wenyuan Xiong (1), Andrea Paoletti (2), Anna Bernhardt (3), Pascal Girard (1), Barbara Testa (2)
(1) Merck Serono S.A., Geneva (2) Merck Serono S.A., Ivrea (3) EMD Serono Inc., Billerica
Objectives: Identify the nonlinear animal PK of anti-LX, a fully human mAb directed against ligand X and predict the human exposure from the animal profiles, to support the dosing regimen selection in first-in-man (FIM) study.
Methods: PK and TK data from 48 mice and 21 monkeys were pooled and analyzed with population approach. In the model, PK parameters were scaled between species to human by allometric relationship to simulate human exposure and its variability. EC95 derived from mouse target occupany data was defined as the efficacy threshold. Dosing regimen of achieving at least 95% target occupancy in 70% of population was recommended as reference for the dose escalation in first in human trial.
Results: anti-LX demonstrated pronounced non-linear PK characteristics in mouse and monkey, which is speculated to be target-mediated clearance relevant. Nevertheless, limited PK samples impeded the development of a full mechanistic target-mediated drug disposition (TMDD) model. Two-compartment model with mixed linear and Michaelis-Menten elimination pathways, a simplification of TMDD model, characterized the PK profiles of anti-LX with good precision. Systematic inter-species variability of target affinity (Km) between mouse and monkey, random inter-individual variability of linear clearance, target density (Vm) and target affinity in monkey were identified. By assuming the same target affinity between human and monkey, human exposure was simulated with PK parameters of apparent volume of distribution, linear clearance and target density scaled up allometrically by the body weight with power factors of 1, 0.75 and 0.75, respectively. Time above target effective concentration in the predicted human profile is considered to be the key criteria to select the dose level for the human study. Simulation resutl suggested, a dose of 10mg/kg(90min infusion) administrated every other week could achieve a trough concentration above the efficacy threshold. Sensitivity analysis showed, deviating from the assumption of equivalent target affinity between monkeys and human has minor impact to the conclusion.
Conclusions: Two-compartment model with mixed elimination, a simplification of TMDD model, well described the PK profile of anti-LX both in mouse and monkey. Allometric scaled human simulation suggested that for maintaining a trough concentration of 50 µg/mL, a dose of 10 mg/kg (90min infusion) can be administered every other week. This supports the selection of the dose range and frequency to be tested in the FIM study, to maintain a minimum trough serum level for a PD response.
Reference: PAGE 21 () Abstr 2601 [www.page-meeting.org/?abstract=2601]
Poster: Oncology