Population Pharmacokinetic Analysis for Matuzumab (EMD 72000) – A Humanised EGFR-Targeted Monoclonal Antibody
Kuester, K(1), A. Kovar(2), B. Brockhaus(2), C. Kloft(1,3)
(1)Freie Universitaet Berlin, Institute of Pharmacy, Berlin, Germany; (2)Merck KGaA, Clin Pharmacokinetics&Pharmacology, Darmstadt, Germany; (3)Martin-Luther-Universitaet Halle-Wittenberg, Faculty of Pharmacy, Halle, Germany
Objectives: Matuzumab, a humanised monoclonal antibody (mAb), targets the epidermal growth factor receptor (EGFR) and has shown activity against EGFR-expressing tumours. A population pharmacokinetic (PK) model for matuzumab was developed using data from three phase I studies. The aim of the population analysis was to develop a PK model comprehensively characterising the pharmacokinetics of matuzumab.
Methods: 1265 serum concentration data from 90 subjects (multiple 1 h iv infusions with doses ranging from 400 to 2000mg, q1w-q3w) were fitted simultaneously. The analysis was performed using ADVAN6, TRANS1, TOL5 and the FOCE INTERACTION estimation method implemented in NONMEM.
Results: Serum concentration-time profiles were best described by a two compartment model. Within this model in addition to the linear clearance (CLL) a second elimination pathway as a non-linear process (Michaelis-Menten kinetics, CLNL) from the central compartment was included with the additional parameters Vmax and km. Implementation of CLNL from only the peripheral compartment or from both compartments did not result in an improvement in the model. Total clearance as the sum of CLL (15.4 mL/h) and CLNL (103 mL/h) was in the expected range for mAbs. Due to the non-linearity the half-lives ranged between 1.46 d and 10.8 d at concentrations of 0.02 and 1000 mg/L, respectively. The estimate of the central distribution volume of 3.79 L (V1) approximated serum volume. Peripheral distribution volume (V2) was estimated to be 1.86 L suggesting limited distribution throughout the body. Inter-individual variability could be established for CLL, V1, and V2 ranging from 18-35% CV. All parameters were generally estimated with good precision (RSE<35%, except the additive residual error component with 45%).
Conclusion: A basic structural population PK model including non-linear PK processes for matuzumab has successfully been developed describing the serum concentration-time profiles. Population parameters well corresponded to the known PK behaviour of mAbs. Refinement of the model includes the implementation of inter-occasion variability as random variation of different PK parameters between the different administrations within one subject.
As next steps, the influence of covariates and implementation of PD and in vitro data will be evaluated. The model developed could serve as a tool to guide selection of optimal dose regimens for matuzumab, a highly promising “targeted” cancer therapy.