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

Kuester K, Kovar A, Lüpfert C, Brockhaus B, Kloft C - Br. J. Cancer (2008)

Bottom Line: All parameters were estimated with good precision (RSE<39%).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacy, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.

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 NONMEM. Data were best described using a two-compartment model with the parameters central (V1) and peripheral distribution volume (V2), intercompartmental (Q) and linear (CLL) clearance and an additional nonlinear elimination pathway (Km, Vmax). Structural parameters were in agreement with immunoglobulin characteristics. In total, interindividual variability on Vmax, CLL, V1 and V2 and interoccasion variability on CLL was 22-62% CV. A covariate analysis identified weight having an influence on V1 (+0.44% per kg) and CLL (+0.87% per kg). All parameters were estimated with good precision (RSE<39%). 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.

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Semilogarithmic plot of the geometric mean and the standard deviation of the observed concentration–time profiles of the four weekly dose regimens (400, 800, 1200 and 1600 mg per week) after the first (left panel) and fourth (right panel) infusion. n=number of patients in the dose group. Last time point for 1600 mg dose group was after 1008 h and is not shown.
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fig1: Semilogarithmic plot of the geometric mean and the standard deviation of the observed concentration–time profiles of the four weekly dose regimens (400, 800, 1200 and 1600 mg per week) after the first (left panel) and fourth (right panel) infusion. n=number of patients in the dose group. Last time point for 1600 mg dose group was after 1008 h and is not shown.

Mentions: A total of 1256 serum concentrations from 0.258 to 1157 μg ml−1 were simultaneously analysed. The average number of concentrations per patient was 15 (range: 5–24). Serum concentration–time profiles were best described by a two-compartment model (e.g. ΔOFV>−300 compared with a one-compartment model, P<0.05). Within this model in addition to the linear clearance (CLL), a second elimination pathway as a nonlinear process (Michaelis–Menten kinetics, CLNL) from the central compartment was included with the additional parameters Vmax, the maximum elimination rate (mg h−1), and Km, the concentration (μg ml−1) with half-maximal elimination rate (ΔOFV>−100). A need to incorporate nonlinearity might also be concluded from the semilogarithmic plots in Figure 1, showing the geometric mean and the standard deviation of the observed concentration–time profiles of four weekly dose regimens of 400–1600 mg, after the first and fourth infusion. In the terminal phase, the slope of the curve was steeper at lower concentrations.


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

Kuester K, Kovar A, Lüpfert C, Brockhaus B, Kloft C - Br. J. Cancer (2008)

Semilogarithmic plot of the geometric mean and the standard deviation of the observed concentration–time profiles of the four weekly dose regimens (400, 800, 1200 and 1600 mg per week) after the first (left panel) and fourth (right panel) infusion. n=number of patients in the dose group. Last time point for 1600 mg dose group was after 1008 h and is not shown.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2266843&req=5

fig1: Semilogarithmic plot of the geometric mean and the standard deviation of the observed concentration–time profiles of the four weekly dose regimens (400, 800, 1200 and 1600 mg per week) after the first (left panel) and fourth (right panel) infusion. n=number of patients in the dose group. Last time point for 1600 mg dose group was after 1008 h and is not shown.
Mentions: A total of 1256 serum concentrations from 0.258 to 1157 μg ml−1 were simultaneously analysed. The average number of concentrations per patient was 15 (range: 5–24). Serum concentration–time profiles were best described by a two-compartment model (e.g. ΔOFV>−300 compared with a one-compartment model, P<0.05). Within this model in addition to the linear clearance (CLL), a second elimination pathway as a nonlinear process (Michaelis–Menten kinetics, CLNL) from the central compartment was included with the additional parameters Vmax, the maximum elimination rate (mg h−1), and Km, the concentration (μg ml−1) with half-maximal elimination rate (ΔOFV>−100). A need to incorporate nonlinearity might also be concluded from the semilogarithmic plots in Figure 1, showing the geometric mean and the standard deviation of the observed concentration–time profiles of four weekly dose regimens of 400–1600 mg, after the first and fourth infusion. In the terminal phase, the slope of the curve was steeper at lower concentrations.

Bottom Line: All parameters were estimated with good precision (RSE<39%).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Pharmacy, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.

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 NONMEM. Data were best described using a two-compartment model with the parameters central (V1) and peripheral distribution volume (V2), intercompartmental (Q) and linear (CLL) clearance and an additional nonlinear elimination pathway (Km, Vmax). Structural parameters were in agreement with immunoglobulin characteristics. In total, interindividual variability on Vmax, CLL, V1 and V2 and interoccasion variability on CLL was 22-62% CV. A covariate analysis identified weight having an influence on V1 (+0.44% per kg) and CLL (+0.87% per kg). All parameters were estimated with good precision (RSE<39%). 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.

Show MeSH