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

Abstract

Purpose: We characterized the pharmacokinetics of onartuzumab (MetMAb) in animals and determined a concentration-effect relationship in tumor-bearing mice to enable estimation of clinical pharmacokinetics and target doses.Experimental Design: A tumor growth inhibition model was used to estimate tumoristatic concentrations (TSC) in mice. Human pharmacokinetic parameters were projected from pharmacokinetics in cynomolgus monkeys by the species-invariant time method. Monte Carlo simulations predicted the percentage of patients achieving steady-state trough serum concentrations (C trough ss ) !TSC for every 3-week (Q3W) dosing.Results: Onartuzumab clearance (CL) in the linear dose range was 21.1 and 12.2 mL/d/kg in mice and cynomolgus monkeys with elimination half-life at 6.10 and 3.37 days, respectively. The estimated TSC in KP4 pancreatic xenograft tumor-bearing mice was 15 mg/mL. Projected CL for humans in the linear dose range was 5.74 to 9.36 mL/d/kg with scaling exponents of CL at 0.75 to 0.9. Monte Carlo simulations projected a Q3W dose of 10 to 30 mg/kg to achieve C trough ss of 15 mg/mL in 95% or more of patients.Conclusions: Onartuzumab pharmacokinetics differed from typical bivalent glycosylated monoclonal antibodies with approximately 2-times faster CL in the linear dose range. Despite this higher CL, xenograft efficacy data supported dose flexibility with Q1W to Q3W dose regimens in the clinical setting with a TSC of 15 mg/mL as the C trough ss target. The projected human efficacious dose of 10 to 30 mg/kg Q3W should achieve the target TSC of 15 mg/mL. These data show effective pharmacokinetic/pharmacodynamic modeling to project doses to be tested in the clinic.

Nonclinical Evaluation of the Serum Pharmacodynamic Biomarkers HGF and Shed MET following Dosing with the Anti-MET Monovalent Monoclonal Antibody Onartuzumab

“…2Â/week) or vehicle (excipient buffer) for 1 month after which terminal serum levels of onartuzumab, sMET, and HGF were determined. Onartuzumab serum concentrations were within the expected range (29), with an average terminal serum level of 130 mg/mL (range 94-153 mg/mL). In contrast to the effect of onartuzumab on sMET accumulation in the conditioned media from treated BxPC-3 cells, serum levels of human sMET from BxPC-3 tumor-bearing mice were elevated to an average of 49 ng/mL, range 11 to 214 ng/mL, whereas mice receiving vehicle had undetectable (<4.8 ng/mL) levels of serum human sMET (Fig.…”

“…MET is naturally cleaved at the cell surface in an HGFindependent manner (28,29), by ADAM10/17 (30,31), resulting in the release of a large fragment of the extracellular domain (ECD), hereafter referred to as shed MET (sMET). Soluble MET-specific protein fragments of approximately 135 kDa have been measured in serum of healthy individuals, cancer patients, and in supernatants of MET-expressing cells (32)(33)(34).…”

Phase I Dose-Escalation Study of Onartuzumab as a Single Agent and in Combination with Bevacizumab in Patients with Advanced Solid Malignancies

“…This integrated analysis was based on the determined relationship between onartuzumab exposure in preclinical KP4 athymic xenograft mouse studies and the resulting antitumor activity in this model, and predicted human pharmacokinetics (15). The KP4 model was selected for this analysis, but other similar models, such as H596 and U87, had similar antitumor activity at comparable onartuzumab doses.…”

“…There was no MTD identified, the maximum administered dose was 30 mg/kg, and the RP2D, based on preclinical pharmacokinetic/pharmacodynamic modeling (15), was determined to be 15 mg/kg; a total of 13 patients were treated at this dose level in the dose-expansion phase.…”

CCR 20th Anniversary Commentary: Determining a Pharmacokinetic/Pharmacodynamic Relationship for Sunitinib—A Look Back

“…The pharmacokinetic properties of therapeutic antibodies are less flexible in practice, but an understanding of whether peak concentrations, total exposure, or time above an active trough concentration determine efficacy can contribute to the identification of doses and regimens predicted to be sufficient to maintain efficacy (12). With complex biologies (e.g., immunomodulatory molecules; ref.…”