Population pharmacokinetic data analysis of three phase I studies of matuzumab, a humanised anti-EGFR monoclonal antibody in clinical cancer development

Abstract

A population pharmacokinetic model based on data from three phase I studies was to be developed including a covariate analysis to describe the concentration -time profiles of matuzumab, a novel humanised monoclonal antibody. Matuzumab was administered as multiple 1 h i.v. infusions with 11 different dosing regimens ranging from 400 to 2000 mg, q1w -q3w. For analysis, 90 patients with 1256 serum concentration -time data were simultaneously fitted using the software NONMEMt. Data were best described using a two-compartment model with the parameters central (V 1 ) and peripheral distribution volume (V 2 ), intercompartmental (Q) and linear (CLL) clearance and an additional nonlinear elimination pathway (K m , V max ). Structural parameters were in agreement with immunoglobulin characteristics. In total, interindividual variability on V max , CLL, V 1 and V 2 and interoccasion variability on CLL was 22 -62% CV. A covariate analysis identified weight having an influence on V 1 ( þ 0.44% per kg) and CLL ( þ 0.87% per kg). All parameters were estimated with good precision (RSEo39%). A robust population pharmacokinetic model for matuzumab was developed, including a nonlinear pharmacokinetic process. In addition, relevant and plausible covariates were identified and incorporated into the model. When correlated to efficacy, this model could serve as a tool to guide dose selection for this 'targeted' cancer therapy.

Population pharmacokinetics of the humanised monoclonal antibody, HuHMFG1 (AS1402), derived from a phase I study on breast cancer

“…Rarely does a combined linear and non-linear process describe the elimination of antibodies (Kuester et al, 2008). Values of the final parameters were similar to those reported for other antibodies, with regard to CL from the central compartment and Q, V1 and V2 (Kovarik et al, 2001;Bruno et al, 2005;Ng et al, 2006;Dartois et al, 2007;Mould et al, 2007;Kuester et al, 2008;Lu et al, 2008). This indicates that the HuHMFG1 antibody, similar to other therapeutic antibodies, is mainly distributed in the serum.…”

“…In these models, the associated elimination is mainly linear (Kovarik et al, 2001;Bruno et al, 2005;Ng et al, 2006;Dartois et al, 2007) and less frequently non-linear (Mould et al, 1999(Mould et al, , 2007. Rarely does a combined linear and non-linear process describe the elimination of antibodies (Kuester et al, 2008). Values of the final parameters were similar to those reported for other antibodies, with regard to CL from the central compartment and Q, V1 and V2 (Kovarik et al, 2001;Bruno et al, 2005;Ng et al, 2006;Dartois et al, 2007;Mould et al, 2007;Kuester et al, 2008;Lu et al, 2008).…”

“…Lu et al (2008) also observed that AST could be linked to bevacizumab clearance, but found it unlikely that impaired hepatic enzymes would actually alter clearance. Moreover, some authors eliminate covariates because their importance was driven by few patients and simulations showed weak impact on PK parameters (Kuester et al, 2008). In our study, the link between AST and clearance was based on data from a significant number of patients, and simulations confirmed the impact of this covariate on HuHMFG1 clearance.…”

“…Interestingly, the hepatic enzyme AST was found to be significantly related to clearance of HuHMFG1. In contrast, in cases in which hepatic enzymes have been investigated as covariates in population PK modelling for other antibodies, they were found not to be significantly relevant (Kuester et al, 2008;Lu et al, 2008;Newsome and Ernstoff, 2008). Alanine aminotransferase has been found to be strongly linked to another covariate and then eliminated during the removal step of covariate study for trastuzumab (Bruno et al, 2005), and ALP was found to be significantly linked to the clearance of pertuzumab (Ng et al, 2006).…”

Population Pharmacokinetics of Therapeutic Monoclonal Antibodies: Examples and Estimation Method Performance Differences

“…CD25 Acute graft-versus-host disease 2C L mAbF19 (39) Mouse IgG FAP Colorectal cancer and soft tissue 2C L sarcoma Matuzumab (40) CDR-grafted mouse/human IgG1 EGFR Pancreatic and various cancers 2C NL+L (primarily colorectal) 6 CDR-grafted mouse/human IgG1 IgE Asthma, allergic rhinitis, and healthy TMDD atopic subjects Panitumumab (42) Human IgG2 EGFR Various solid tumors and colorectal, 2C NL+L non-small cell lung, and renal cancer Pertuzumab (43) CDR-grafted mouse/human IgG1 HER2 Breast cancer, ovarian cancer, and 2C L solid malignancies Rituximab (44) Chimeric mouse/human IgG1 CD20 Rheumatoid arthritis 2C L Sibrotuzumab (45) CDR-grafted mouse/human IgG1 FAP Colorectal and non-small cell lung 2C NL+L cancer Trastuzumab (46) CDR-grafted mouse/human IgG1 HER2 Breast cancer and solid tumors 2C L Ustekinumab (47) Human IgG1 BSV = between-subject variability; F = absolute bioavailability; Ka = absorption rate constant; NE = not estimated; %RSE = percent relative standard error. * 90% or ^ 95% bootstrap confidence interval.…”