Population pharmacokinetic meta‐analysis of ramucirumab in cancer patients

Abstract

AimsRamucirumab 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.MethodsA 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.ResultsThe 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.ConclusionsThe 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.

Exposure-Response Analyses of Ramucirumab from Two Randomized, Phase III Trials of Second-line Treatment for Advanced Gastric or Gastroesophageal Junction Cancer

“…In that same analysis, although body weight did not meet the prespecified significance criteria for covariate selection, results did indicate a relationship between body weight and ramucirumab PK. Thus, although we were not able to identify patients who would be more likely to have higher or lower ramucirumab exposure, the previous PK meta-analysis confirmed the appropriateness of weight-based dosing (12). Likewise, biomarker analyses from the RAINBOW study have not identified a predictive biomarker for ramucirumab treatment, but did reveal several pharmacodynamic trends and potential markers for prognostic effects (15).…”

“…In a previous pooled popPK meta-analysis of 11 ramucirumab studies, the PK profile of ramucirumab was well characterized by a 2-compartment model with interpatient variability estimated on all parameters. However, the analysis did not identify any significant variables that accounted for the differences in ramucirumab exposure (12). In that same analysis, although body weight did not meet the prespecified significance criteria for covariate selection, results did indicate a relationship between body weight and ramucirumab PK.…”

“…Population PK (popPK) analyses were conducted as previously described, using a nonlinear mixed-effect modeling approach (12). Population PK-predicted minimum concentrations at steady-state [C min,ss ] were then determined for ramucirumabtreated patients using the developed model ( Supplementary Fig.…”

Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology

“…All covariates included in the final PopPK model for 23 mAbs, including the PK structural model, were summarized from the literature review (Table ) . The effect of covariates was evaluated specifically for the linear portion of CL for mAbs exhibiting linear or parallel linear and nonlinear CL.…”

Thyroid Dysfunction Related to the Antiangiogenic VEGFR2-Binding Monoclonal Antibody Ramucirumab: A Series of 14 Cases and a Descriptive Study

“…We excluded patients who had thyroid disease at the time of ramucirumab initiation. Clinical course and features and severity of thyroid dysfunction [serum thyroid-stimulating hormone (TSH) level >10 mU/L, which generally should be treated with levothyroxine (LT4) in patients with subclinical hypothyroidism] 15) were investigated as a case series. In addition, we performed a descriptive study of the change in TSH level over time during ramucirumab chemotherapy in patients with regularly confirmed thyroid function testing; patients' TSH levels were followed for up to 2 months after ramucirumab discontinuation because its elimination half-life is approximately two weeks.…”