gms | German Medical Science

Introduction: Nimotuzumab (Theralocâ) is a humanized antibody (mAb) that recognizes an epitope located in the extracellular domain of the human EGFR. In previous clinical phase I trials in pts with head and neck as well as nasopharyngeal cancer, nimotuzumab significantly improved the effects of simultaneous radiotherapy. In addition, efficacy was demonstrated in a first phase II study in children with recurrence/resistant brain cancer (high malignant glioma) utilizing nimotuzumab as monotherapy.

Purpose: This study was designed to evaluate the pharmacokinetics of nimotuzumab in pts with locally advanced or metastatic PC and refractory or relapsed after first line treatment. The primary objective for PK analyses was the determination of the area under the serum concentration versus time curve (AUC) from end of first infusion (time point: 0 h) up to 168h (AUC0-168h) and the elimination half-life (t1/2) and the maximum serum concentration (Cmax) concentration. Secondary objectives were the determination of (a) the trough nimotuzumab serum levels before subsequent infusions of the antibody, (b) the possible accumulation, (c) the anti-idiotypic response.

Methods: Blood samples were collected prior to first dose, at the end of a 30 min-infusion, 3h, 6h, 48h, as well as before the second dose at time point 168h. Nimotuzumab was measured by the use of a cellular ELISA and pharmacokinetic calculations were done using the program Kineticaâ.

Results: Currently, blood samples from 9 pts were analyzed at dose levels 200 mg (n=5 pts), 400 mg (n=3 pts) and 600 mg (n=1). After a single dose of 200 mg, the mean value of Cmax was calculated to 141 ± 33 µg/ml (mean ± SEM, n = 5). The t1/2 was calculated to 45 h (n = 4), volume of distribution to 1.46 ± 0.3 l (n = 5), respectively. The total clearance was determined to 23 ± 6 ml/h (n = 4). The trough values after 168 h were 6.2 ± 6.3 µg/ml (n = 5). These values changed with doubling the dose to 400 mg. As a consequence, terminal half life increased about 3fold to about 120 h, whereas total clearance was reduced to 9 ml/h for the 400 mg application (n = 3).

Conclusions: These preliminary analyses give indication for a non linear pharmacokinetic of the new monoclonal antibody nimotuzumab. Thus, AUC and terminal half life increased with dose, while increasing plasma concentrations of the antibody led to a decrease in clearance between the doses.