Clinical pharmacology of intravitreal anti-VEGF drugs

Abstract

Clinical efficacy of intravitreal anti-VEGF drugs has been widely demonstrated in several angiogenesis-driven eye diseases including diabetic macular edema and the neovascular form of age-related macular degeneration. Pegaptanib, ranibizumab, and aflibercept have been approved for use in the eye, whereas bevacizumab is widely used by ophthalmologists to treat patients "off-label". These drugs are active in the nanomolar to picomolar range; however, caution is required when establishing the rank order of affinity and potency due to in vitro inter-experimental variation. Despite the small doses used for eye diseases and the intravitreal route of administration may limit systemic side effects, these drugs can penetrate into blood circulation and alter systemic VEGF with unknown clinical consequences, particularly in vulnerable groups of patients. Clinical pharmacokinetics of ocular anti-VEGF agents should therefore be taken into account when choosing the right drug for the individual patient. The gaps in current understanding that leave open important questions are as follows: (i) uncertainty about which drug should be given first, (ii) how long these drugs can be used safely, and (iii) the choice of the best pharmacological strategy after first-line treatment failure. The current review article, based on the information published in peer-reviewed published papers relevant to anti-VEGF treatments and available on the PubMed database, describes in detail the clinical pharmacology of this class of drugs to provide a sound pharmacological basis for their proper use in ophthalmology clinical practice.

Fig. 1

Mechanism of action of intravitreal antiangiogenic drugs. Angiogenic factors (e.g., VEGF) stimulate their specific receptors (e.g., VEGFR) activating the signaling cascade. Binding of intravitreal antiangiogenic drugs to their ligands (e.g., VEGF) form the drug–ligand complex (DL) preventing ligand/receptor interaction and keeping (or turning) the angiogenic switch off. Affinity is defined as the degree of attraction between drug and the target, and it is expressed by the dissociation constant, K_d (that is, the ratio between dissociation (K_off) and association (K_on) rates). K_d is the inverse of the affinity to the binding site (i.e., the lower the K_d, the higher the affinity). Potency is the amount of drug needed to produce the pharmacological effect. For these drugs, potency is expressed by the half maximal inhibitory concentration (IC₅₀), a measure of the effectiveness of a substance in inhibiting a specific biological function (the lower the IC₅₀, the higher the potency)

Fig. 2

Pharmacokinetic model for intravitreal antiangiogenic drugs. Intravitreally injected Fc-carrying molecules can penetrate into the systemic circulation by a FcRn-dependent transport. The presence of the Fc portion may also reduce systemic clearance thus prolonging drug exposure (see text for further details). Renal clearance may depend on the molecular size; in particular, the higher the molecular weight, the lower the drug clearance (e.g., pegylated molecules, full-length monoclonal antibodies). FcRn neonatal Fc receptor, BRB blood retinal barrier