Population pharmacokinetic meta-analysis of ramucirumab in cancer patients

Abstract

Aims: Ramucirumab is a human IgG1 monoclonal antibody that specifically binds vascular endothelial growth factor receptor-2 (VEGFR-2) and blocks binding of VEGF-A, VEGF-C and VEGF-D. The objective of the analysis was to characterize the clinical pharmacology profile of ramucirumab using a population pharmacokinetic approach. Methods: A total of 1639 patients with 6427 serum concentrations from 11 Phase 1b, 2 and 3 clinical trials in patients with various cancer indications were included in the analysis. Ramucirumab was administered as an intravenous infusion over 1 h at 8 mg kg−1 every 2 weeks or 10 mg kg−1 every 3 weeks. A series of pharmacostatistical models were developed to describe the concentration data. The best model was used to evaluate patient factors for their effect on ramucirumab pharmacokinetics. Results: The pharmacokinetics of ramucirumab were well characterized by a two-compartment model. Mean population estimates of clearance, volume of distribution and half-life for a typical 68-kg patient were 0.0148 l h−1, 5.30 l and 13.4 days, respectively. A modest relationship was observed between body weight and ramucirumab disposition; clearance and central compartment volume increased with body weight. No other patient characteristics were shown to influence the disposition of ramucirumab in this patient population. Conclusions: The final model adequately described the concentration–time profile of ramucirumab in patients with a range of cancer indications. The model confirmed that a weight-normalized dosing regimen is appropriate for ramucirumab therapy. Dose adjustment was not required for patients with mild to moderate renal impairment or mild hepatic impairment.