Vascular Endothelial Growth Factor (VEGF) Receptor 2 is the key mediator of VEGF induced angiogenesis. Ramucirumab is a human receptor-targeted antibody that specifically binds VEGF Receptor 2 and blocks binding of VEGF-A, VEGF-C, and VEGF-D. As a result, ramucirumab inhibits ligand stimulated activation of VEGF Receptor 2 and its downstream signalling components, including p44/p42 mitogen-activated protein kinases, neutralising ligand-induced proliferation and migration of human endothelial cells.
Following the dose regimen of 8 mg/kg every 2 weeks, the geometric means of ramucirumab Cmin prior to administration of the fourth and seventh dose of ramucirumab given as a single agent in advanced gastric cancer patients' serum were 49.5 μg/ml (range of 6.3-228 μg/ml) and 74.4 μg/ml (range of 13.8-234 μg/ml), respectively. In HCC patients' serum the geometric means of ramucirumab Cmin prior to administration of the second, fourth and seventh dose of ramucirumab were 23.5 μg/ml (range of 2.9-76.5 μg/ml), 44.1 μg/ml (range of 4.2-137 μg/ml) and 60.2 μg/ml (range of 18.3-123 μg/ml), respectively.
Following the dose regimen of 8 mg/kg ramucirumab every 2 weeks in combination with FOLFIRI, the geometric means of ramucirumab Cmin were 46.3 μg/ml (range of 7.7-119 μg/ml) and 65.1 μg/ml (range of 14.5-205 μg/ml) prior to administration of the third and fifth dose, respectively, in serum from patients with mCRC.
Following the dose regimen of 10 mg/kg ramucirumab every 3 weeks, the geometric means of ramucirumab Cmin were 28.3 μg/ml (range of 2.5-108 μg/ml) and 38.4 μg/ml (range of 3.1-128 μg/ml) prior to administration of the third and fifth dose, respectively of ramucirumab given in combination with docetaxel, in serum from patients with NSCLC.
Following the dose regimen of 10 mg/kg ramucirumab every 2 weeks, the geometric means of ramucirumab Cmin were 68.5 μg/ml (range of 20.3-142 μg/ml) and 85.7 μg/ml (range of 36.0-197 μg/ml) prior to administration of the fourth and seventh dose, respectively of ramucirumab given in combination with erlotinib, in serum from patients with NSCLC.
Ramucirumab is administered as an intravenous infusion. There have been no studies performed with other routes of administration.
Based on population pharmacokinetic approach (PopPK), the mean (% coefficient of variation [CV%]) volume of distribution at steady state for ramucirumab was 5.4L (15%).
The metabolism of ramucirumab has not been studied. Antibodies are principally cleared by catabolism.
Based on PopPK, the mean (CV%) clearance of ramucirumab was 0.015 L/hour (30%) and the mean half-life was 14 days (20%).
There was no clear deviation from dose proportionality in pharmacokinetics of ramucirumab from 6 mg/kg to 20 mg/kg. An accumulation ratio of 1.5 was observed for ramucirumab when dosed every 2 weeks. Based on simulations using the PopPK model, steady state would be attained by the sixth dose.
Based on PopPK, there was no difference in ramucirumab exposure in patients ≥65 years of age compared to patients <65 years old.
No formal studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of ramucirumab. Based on PopPK, ramucirumab exposure was similar in patients with mild renal impairment (creatinine clearance [CrCl] ≥60 to <90 ml/min), moderate renal impairment (CrCl ≥30 to <60 ml/min) or severe renal impairment (CrCl 15 to 29 ml/min) as compared to patients with normal renal function (CrCl ≥90 ml/min).
No formal studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of ramucirumab. Based on PopPK, ramucirumab exposure in patients with mild hepatic impairment (total bilirubin >1.0-1.5 upper limit of normal (ULN) and any AST or total bilirubin ≤1.0 ULN and AST >ULN) or moderate hepatic impairment (total bilirubin >1.5-3.0 ULN and any AST) was similar to patients with normal hepatic function (total bilirubin and AST ≤ ULN). Ramucirumab has not been studied in patients with severe hepatic impairment (total bilirubin >3.0 ULN and any AST).
Based on PopPK, the following covariates were found to have no impact on ramucirumab disposition: age, sex, race, albumin levels. These and other factors investigated had <20% effect on ramucirumab disposition. Body weight is considered a significant co-variate of ramucirumab pharmacokinetics supporting the dosing based on body weight.
Exposure-response analyses indicated that efficacy was correlated with ramucirumab exposure across pivotal studies. Efficacy, as measured by improvements in OS, was associated with increasing ramucirumab exposure range produced by 8 mg/kg ramucirumab given every 2 weeks and by 10 mg/kg ramucirumab given every 3 weeks. An improvement in PFS was also associated with increasing ramucirumab exposure for advanced gastric cancer, NSCLC with disease progression after platinum-based chemotherapy and mCRC.
In the REACH-2 study for HCC, a relevant exposure-efficacy association was observed for ramucirumab which showed that only patients with above-median exposure experienced an improvement in OS, compared to placebo, and these exposure-efficacy relationships remained after attempts to adjust for other prognostic factors. A treatment effect on PFS was observed for all exposure levels produced by 8 mg/kg ramucirumab given every 2 weeks. No such relation was observed in the RELAY study for NSCLC with 10 mg/kg ramucirumab plus erlotinib given every 2 weeks.
In RAINBOW, the incidences of Grade ≥3 hypertension, neutropenia, and leukopenia were increased with higher ramucirumab exposure.
In RAISE, the incidence of Grade ≥3 neutropenia was increased with higher ramucirumab exposure.
In RELAY, no exposure-safety relationship was identified for the selected safety endpoints, including Grade ≥3 hypertension, diarrhoea, proteinuria and dermatitis acneiform.
In REVEL, the incidences of Grade ≥3 febrile neutropenia and hypertension were increased with higher ramucirumab exposure.
In the pooled data from REACH-2 and REACH (patients with alpha fetoprotein ≥400 ng/ml), the incidences of Grade ≥3 hypertension was increased with higher ramucirumab exposure.
No animal studies have been performed to test ramucirumab for potential of carcinogenicity or genotoxicity.
The target organs identified in repeated dose cynomolgus monkey toxicity studies were kidney (glomerulonephritis), bone (thickening and abnormal endochondral ossification of the epiphyseal growth plate) and female reproductive organs (decreased weight of ovaries and uterus). A minimal grade of inflammation and/or mononuclear cell infiltration was seen in several organs.
Reproductive toxicity studies with ramucirumab have not been performed, however, animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryo-foetal development, and postnatal development. Based on ramucirumab’s mechanism of action, it is likely that in animals, ramucirumab will inhibit angiogenesis and result in adverse effects on fertility (ovulation), placental development, developing foetuses and postnatal development.
A single dose of ramucirumab did not impair wound healing in monkeys using a full-thickness incisional model.
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