Chemical formula: C₄₃₁₈H₆₇₈₈N₁₁₆₄O₁₃₀₄S₃₂ Molecular mass: 115,000 g/mol
Vascular endothelial growth factor A and B (VEGF-A, VEGF-B), and placental growth factor (PlGF) are members of the VEGF family of angiogenic factors that can act as potent mitogenic, chemotactic, and vascular permeability factors for endothelial cells. VEGF-A acts via two receptor tyrosine kinases, VEGFR-1 and VEGFR-2, present on the surface of endothelial cells. PlGF and VEGF-B bind only to VEGFR-1, which is also present on the surface of leucocytes. Excessive activation of these receptors by VEGF-A can result in pathological neovascularisation and excessive vascular permeability. PlGF is also linked to pathological neovascularisation and recruitment of inflammatory cells into tumours.
Aflibercept, also known as VEGF TRAP in the scientific literature, is a recombinant fusion protein consisting of VEGF-binding portions from the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of the human IgG1. Aflibercept is produced by recombinant DNA technology in a Chinese hamster ovary (CHO) K-1 mammalian expression system. Aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, constituting an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa.
Aflibercept acts as a soluble decoy receptor that binds to VEGF-A, with higher affinity than its native receptors, as well as the related ligands PlGF and VEGF-B. By acting as a ligand trap, aflibercept prevents binding of endogenous ligands to their cognate receptors and thereby blocks receptor mediated signaling.
Aflibercept blocks the activation of VEGF receptors and the proliferation of endothelial cells, thereby inhibiting the growth of new vessels that supply tumours with oxygen and nutrients.
Aflibercept binds to human VEGF-A (equilibrium dissociation constant KD of 0.5 pM for VEGF-A 165 and 0.36 pM for VEGF-A121), to human PlGF (KD of 39 pM for PlGF-2), and to human VEGF-B (KD of 1.92 pM) to form a stable, inert complex which has no detectable biological activity.
Administration of aflibercept to mice bearing xenotransplant or allotransplant tumours inhibited the growth of various cancer types.
Aflibercept is administered directly into the vitreous to exert local effects in the eye.
Aflibercept is slowly absorbed from the eye into the systemic circulation after intravitreal administration and is predominately observed in the systemic circulation as an inactive, stable complex with VEGF; however only “free aflibercept” is able to bind endogenous VEGF.
In preclinical tumour models, biologically active doses of aflibercept correlated with those necessary to produce circulating concentrations of free aflibercept in excess of VEGF-bound aflibercept. Circulating concentrations of VEGF-bound aflibercept increase with the aflibercept dose until most available VEGF is bound. Further increases in the aflibercept dose resulted in dose-related increases in circulating free aflibercept concentrations but only small further increases in the VEGF-bound aflibercept concentration.
In patients, aflibercept is administered at the dose of 4 mg/kg intravenously every two weeks for which there is an excess of circulating free aflibercept compared to VEGF-bound aflibercept.
At the recommended dose regimen of 4 mg/kg every two weeks, concentration of free aflibercept were near steady-state levels by the second cycle of treatment with essentially no accumulation (accumulation ratio of 1.2 at steady-state compared to the first administration).
In a pharmacokinetic sub-study in 6 neovascular wet AMD patients with frequent sampling, maximum plasma concentrations of free aflibercept (systemic Cmax) were low, with a mean of approximately 0.02 microgram/ml (range 0 to 0.054) within 1 to 3 days after a 2 mg intravitreal injection, and were undetectable two weeks following dosage in almost all patients. Aflibercept does not accumulate in the plasma when administered intravitreally every 4 weeks.
The mean maximum plasma concentration of free aflibercept is approximately 50 to 500 times below the aflibercept concentration required to inhibit the biologic activity of systemic VEGF by 50% in animal models, in which blood pressure changes were observed after circulating levels of free aflibercept attained approximately 10 microgram/ml and returned to baseline when levels fell below approximately 1 microgram/ml. It is estimated that after intravitreal administration of 2 mg to patients, the mean maximum plasma concentration of free aflibercept is more than 100-fold lower than the concentration of aflibercept required to half-maximally bind systemic VEGF (2.91 microgram/ml) in a study of healthy volunteers. Therefore, systemic pharmacodynamic effects such as blood pressure changes are unlikely.
In pharmacokinetic sub-studies in patients with CRVO, BRVO, DME or myopic CNV mean Cmax of free aflibercept in plasma were similar with values in the range of 0.03 to 0.05 microgram/ml and individual values not exceeding 0.14 microgram/ml. Thereafter, plasma concentrations of free aflibercept declined to values below or close to the lower limit of quantitation generally within one week; undetectable concentrations were reached before the next administration after 4 weeks in all patients.
The volume of distribution of free aflibercept at steady-state is approximately 8 litres.
No metabolism studies have been conducted with aflibercept since it is a protein. Aflibercept is expected to degrade to small peptides and individual amino acids. Elimination Free aflibercept is primarily cleared by binding to endogenous VEGF to form a stable, inactive complex. As with other large proteins, both free and bound aflibercept, are expected to be cleared, more slowly, by other biological mechanisms, such as proteolytic catabolism.
At doses greater than 2 mg/kg, free aflibercept clearance was approximately 1.0L/day with a terminal half-life of 6 days.
High molecular weight proteins are not cleared by the renal route, therefore renal elimination of aflibercept is expected to be minimal.
Consistent with target-mediated drug disposition, free aflibercept exhibits a faster (non-linear) clearance at doses below 2 mg/kg, likely due to the high affinity binding of aflibercept to endogenous VEGF. Linear clearance observed in the dose range of 2 to 9 mg/kg is likely due to non saturable biological mechanisms of elimination such as protein catabolism.
There was no effect of age on the pharmacokinetics of free aflibercept.
No effect of race was identified in the population analysis.
Gender was the most significant covariate for explaining the interindividual variability of free aflibercept clearance and volume with a 15.5% higher clearance and a 20.6% higher volume of distribution in males than in females. These differences do not affect exposure due to weight-based dosing and no dose modifications based on gender are required.
Weight had an effect on free aflibercept clearance and volume of distribution resulting with a 29% increase in aflibercept exposure in patients weighing ≥100 kg.
There have been no formal studies with aflibercept in patients with hepatic impairment. In a population pharmacokinetic analysis with data from 1,507 patients with various types of advanced malignancies receiving aflibercept with or without chemotherapy, 63 patients with mild hepatic impairment (total bilirubin >1.0 x – 1.5 x ULN and any AST) and 5 patients with moderate hepatic impairment (total bilirubin >1.5 x – 3 x ULN and any AST) were treated with aflibercept. In these mild and moderate hepatic impairment patients, there was no effect on clearance of aflibercept. There are no data available for patients with severe hepatic impairment (total bilirubin >3 x ULN and any AST).
There have been no formal studies with aflibercept in patients with renal impairment. A population pharmacokinetic analysis was conducted with data from 1,507 patients with various types of advanced malignancies receiving aflibercept with or without chemotherapy. This population included; 549 patients with mild renal impairment (CLCR between 50-80 ml/min), 96 patients with moderate renal impairment (CLCR between 30-50 ml/min), and 5 patients with severe renal impairment (CLCR <30 ml/min).
This population pharmacokinetic analysis revealed no clinically meaningful differences in clearance or systemic exposure (AUC) of free aflibercept in patients with moderate and mild renal impairment at the 4 mg/kg dose of aflibercept as compared to the overall population studied. No conclusion can be drawn for patients with severe renal impairment due to very limited data available. In the few patients with severe renal impairment, drug exposure was similar to that observed in patients with normal renal function.
Weekly/every two weeks intravenous administration of aflibercept to cynomolgus monkeys for up to 6 months resulted in changes in the bone (effects on growth plate and the axial and appendicular skeleton), nasal cavity, kidney, ovary, and adrenal gland. Most aflibercept-related findings were noted from the lowest dose tested corresponding to plasma exposures close to those in patients at the therapeutic dose. Most aflibercept-induced effects were reversible after a 5-month drug free period with the exception of skeletal and nasal cavity findings. Most findings were considered to be related to the pharmacological activity of aflibercept.
Aflibercept administration resulted in a delay in wound healing in rabbits. In full-thickness excisional and incisional skin wound models, aflibercept administration reduced fibrous response, neovascularisation, epidermal hyperplasia/re-epithelialisation, and tensile strength. Aflibercept increased blood pressure in normotensive rodents.
Effects in non-clinical studies on repeated dose toxicity were observed only at systemic exposures considered substantially in excess of the maximum human exposure after intravitreal administration at the intended clinical dose indicating little relevance to clinical use.
Erosions and ulcerations of the respiratory epithelium in nasal turbinates in monkeys treated with aflibercept intravitreally were observed at systemic exposures in excess of the maximum human exposure. The systemic exposure based on Cmax and AUC for free aflibercept were approximately 200- and 700-fold higher, respectively, when compared to corresponding values observed in humans after an intravitreal dose of 2 mg. At the No Observed Adverse Effect Level (NOAEL) of 0.5 mg/eye in monkeys the systemic exposure was 42- and 56-fold higher based on Cmax and AUC, respectively.
No studies have been conducted on the mutagenic or carcinogenic potential of aflibercept.
No specific studies with aflibercept have been conducted in animals to evaluate the effect on fertility.
However, results from a repeat dose toxicity study suggest there is a potential for aflibercept to impair reproductive function and fertility. In sexually mature female cynomolgus monkeys inhibition of ovarian function and follicular development was evidenced. These animals also lost normal menstrual cycling. In sexually mature male cynomolgus monkeys a decrease in sperm motility and an increase in incidence of morphological abnormalities of spermatozoa were observed. There was no margin of exposure to patients in relation to these effects. These effects were fully reversible within 8-18 weeks after the last injection.
Effects on male and female fertility were assessed as part of a 6-month study in monkeys with intravenous administration of aflibercept at doses ranging from 3 to 30 mg/kg. Absent or irregular menses associated with alterations in female reproductive hormone levels and changes in sperm morphology and motility were observed at all dose levels. Based on Cmax and AUC for free aflibercept observed at the 3 mg/kg intravenous dose, the systemic exposures were approximately 4,900-fold and 1,500-fold higher, respectively, than the exposure observed in humans after an intravitreal dose of 2 mg. All changes were reversible.
Aflibercept has been shown to be embryotoxic and teratogenic when administered intravenously to pregnant rabbits every 3 days during the organogenesis period (gestation days 6 to 18) at doses approximately 1 to 15 times the human dose of 4 mg/kg every 2 weeks. Observed effects included decreases in maternal body weights, an increased number of foetal resorptions, and an increased incidence of external, visceral, and skeletal foetal malformations.
An effect of aflibercept on intrauterine development was shown in embryo-foetal development studies in pregnant rabbits with intravenous (3 to 60 mg/kg) as well as subcutaneous (0.1 to 1 mg/kg) administration. The maternal NOAEL was at the dose of 3 mg/kg or 1 mg/kg, respectively. A developmental NOAEL was not identified. At the 0.1 mg/kg dose, the systemic exposures based on Cmax and cumulative AUC for free aflibercept were approximately 17- and 10-fold higher, respectively, when compared to corresponding values observed in humans after an intravitreal dose of 2 mg.
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