Aurelia HM de Vries Schultink (1), Robert P Doornbos (2), Alexander BH Bakker (2), Setareh Shamsili (2), Mark Throsby (2), Jan H Schellens (1,3), Jos H Beijnen (1,3), Alwin DR Huitema (1)
(1) The Netherlands Cancer Institute, Amsterdam, the Netherlands, (2) Merus B.V., Utrecht, the Netherlands, (3) Utrecht University, Utrecht, the Netherlands
Objectives: MCLA-128 is a full length IgG1 bispecific monoclonal antibody (mAb) targeting receptor tyrosine kinases HER2 and HER3 to overcome HER3-mediated resistance to HER2 or EGFR targeted therapies. MAbs of the IgG1 subclass follow primarily linear clearance through cellular uptake followed by lysosomal degradation. The pharmacokinetics (PK) of mAbs are characterized by target mediated drug disposition, leading to saturation of the target and a co-existing nonlinear degradation. MCLA-128 was preclincally tested in cynomolgus monkeys to estimate PK parameters of MCLA-128 using a model based approach and to predict exposure to MCLA-128 in humans in order to support selection of first-in-human dose.
Methods: PK data was obtained from a single-dose toxicity study (n=6) and the first week of a repeated dose toxicity study (n=32) in cynomolgus monkeys. MCLA-128 was quantified in serum using a validated electrochemiluminescence immunoassay. PK parameters were estimated using NONMEM (v.7.3) and parameters were scaled to humans using allometric scaling. A two-compartment model with parallel linear and nonlinear elimination was tested. For model evaluation, parameter estimate plausibility, parameter precision, visual predictive checks and goodness of fit plots were examined. The safety margins for different proposed starting dose levels were obtained by dividing the AUC in cynomolgus monkeys at the NOAEL (no observed adverse effect level), which was found at the highest dose evaluated (100 mg/kg), by the predicted AUC in human.
Results: PK profiles were well described by a two-compartment model with parallel linear and nonlinear elimination pathways. Parameter estimates were scaled to 70 kg human. The estimated parameters were consistent with the general PK characteristics of therapeutic mAbs as expected based on the full length IgG1 format of MCLA-128 [1].
Proposed starting dose levels of 10 mg and 40 mg flat dose had associated safety margins of 6655 and 623, respectively.
Conclusions: MCLA-128 showed coexisting linear and nonlinear clearance pathways in cynomolgus monkeys. Based on calculated safety margins the proposed First-in-Human starting doses of 10 and 40 mg every three weeks have a large safety margin.
References:
[1] Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin. Pharmacokinet. 2010;49:633-59
Reference: PAGE 25 (2016) Abstr 5900 [www.page-meeting.org/?abstract=5900]
Poster: Drug/Disease modeling - Oncology