Population pharmacokinetic analysis from phase I and phase II studies of the humanized monovalent antibody, onartuzumab (MetMAb), in patients with advanced solid tumors

Abstract

Onartuzumab is a unique, humanized, monovalent (one-armed) monoclonal antibody (mAb) against the MET receptor. The intravenous (IV) pharmacokinetics (PK) of onartuzumab were investigated in a phase I study and a phase II study in recurrent non-small cell lung cancer (NSCLC) patients. The potential for drug-drug interaction (DDI) was assessed during co-administration of IV onartuzumab with oral erlotinib, by measuring the PK of both drugs. The concentration-time profiles of onartuzumab were adequately described using a two-compartment model with linear clearance (CL) at doses between 4 and 30 mg/kg. The estimates for CL, central compartment volume (V1 ), and median terminal half-life were 0.439 L/day, 2.77 L, and 13.4 days, respectively. Statistically significant covariates included creatinine clearance (CrCL) on clearance, weight and gender on V1 , and weight on peripheral compartment volume (V2 ), but the clinical relevance of these covariates needs to be further evaluated. The current analysis did not indicate obvious DDI between onartuzumab and erlotinib. MET diagnostic status did not impact the exposure of either agent. Despite the slightly faster clearance compared with typical bivalent mAbs, the PK of onartuzumab support dosing regimens of 15 mg/kg every 3 weeks or doses equivalent to achieve the target minimum tumoristatic concentration in patients.

Onartuzumab (MetMAb): Using Nonclinical Pharmacokinetic and Concentration–Effect Data to Support Clinical Development

“…15 mg/mL in 90% or more of patients (36,37). Importantly, this dose was well tolerated and resulted in statistically significant and clinically meaningful improvements in both progression-free survival and OS in the MET-positive subgroup (26).…”

“…Ninety-five percent of these patients achieved AUC observed at 30 mg/kg in mice after first dose. Therefore, 15 mg/kg Q3W was selected for testing in the phase II study (36,37).…”

Exposure–Response and Tumor Growth Inhibition Analyses of the Monovalent Anti-c-MET Antibody Onartuzumab (MetMAb) in the Second- and Third-Line Non-Small Cell Lung Cancer

“…The clinically relevant covariates tested included those related to demographics, laboratory tests, concomitant medications, and pathophysiological factors (Table I). Onartuzumab serum concentrations were determined at Genentech Inc. by a validated sandwich enzyme-linked immunosorbent assay described previously that was designed to measure free onartuzumab (16). The lower limit of quantification (LLOQ) was 0.2 μg/mL.…”

“…Serum concentration data were fit to the previously published population PK model (16) to obtain individual empirical Bayesian estimates of PK parameters (post hoc step using NONMEM (20)), which were subsequently used to derive the individual onartuzumab exposure (trough (Cmin) and peak (Cmax) concentration and area under the concentration time curve (AUC)) during the first dosing interval and at steady state (fifth dosing interval). AUC was calculated using the trapezoidal method.…”

“…Simulations based on a population pharmacokinetic (PK) model derived from phase I study OAM4224g and phase II study OAM4558g suggested that onartuzumab 15 mg/kg Q3W would achieve a target tumoristatic trough concentration of 15 μg/mL, which was derived from xenograft studies (16). However, OAM4224g showed that onartuzumab was tolerable up to 30 mg/kg (17), opening up the possibility of dose intensification.…”