Rationale for Fixed Dosing of Pertuzumab in Cancer Patients Based on Population Pharmacokinetic Analysis

Abstract

A population PK model was developed for pertuzumab, the first monoclonal IgG1 antibody in a new class of agents known as HER dimerization inhibitors. In addition, our analyses demonstrate the feasibility of administering pertuzumab using a fixed dose in women with ovarian and breast cancers.

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

“…This indicates that CL seems to remain stable independently of the patient's weight. A similar conclusion was drawn by Ng et al (2006) who observed that weight and body surface area were significant covariates, but had a weak impact on patient sample concentrations. Therefore, one could consider recommending a fixed-dose instead of a weight-based dosing regimen for HuHMFG1.…”

“…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 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). In this study, when only AST was retained during the removal step, ALP and GGT were also found to be linked to the clearance of HuHMFG1 during the first step of covariate study.…”

“…Indeed, a structural two-compartmental model is commonly reported to describe the behaviour of antibodies. 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).…”

“…We choose to leave AST as a covariate to ensure future investigation into a potentially relevant finding, even if we cannot exclude the fact that the link is due to random chance, as the physiological implication of liver metabolism in IgG clearance is not obvious. A similar strategy was chosen by Ng et al (2006), which considered ALP as the covariate of pertuzumab clearance. Data obtained from further studies with HuHMFG1 are required to confirm whether AST is indeed a covariate.…”