Abstract
Intravitreal administration of anti-vascular endothelial growth factor (VEGF) antibodies has become the standard treatment for Age-Related Macular Degeneration; however, the knowledge of their pharmacokinetics is limited. A comprehensive review of the preclinical and clinical pharmacokinetic data that were obtained in different studies with intravitreal bevacizumab, ranibizumab, and aflibercept has been conducted. Moreover, the factors that can influence the vitreous pharmacokinetics of these drugs, as well as the methods that were used in the studies for analytical determination, have been exposed. These anti-VEGF drugs present different charge and molecular weights, which play an important role in vitreous distribution and elimination. The pharmacokinetic parameters that were collected differ depending on the species that were involved in the studies and on physiological and pathological conditions, such as vitrectomy and lensectomy. Knowledge of the intravitreal pharmacokinetics of the anti-VEGF drugs that were used in clinical practice is of vital importance.
Highlights
Age-Related Macular Degeneration (AMD) is the leading cause of irreversible visual impairment among individuals over the age of 65 years all around the world
A population approach of non-linear pharmacokinetic modelling that is based on serum samples that were collected from patients with AMD enrolled in five clinical trials, receiving from 0.3 to 2 mg per eye of single or multiple intravitreal ranibizumab estimated a vitreous half-life of nine days [22]
Bevacizumab vitreous half-life has been estimated at 4.32 days, following a 1.25 mg/0.05 mL unilateral intravitreal injection in rabbit eyes, with concentrations that remain above 10 μg/mL for 30 days [41]
Summary
Age-Related Macular Degeneration (AMD) is the leading cause of irreversible visual impairment among individuals over the age of 65 years all around the world (between 30 and 50 million people). Several treatments for neovascular AMD have been widely studied, such as laser photocoagulation and photodynamic eye therapy with verteporfin, but nowadays the standard treatment consists of intravitreal injections of inhibitors of vascular endothelial growth factor (anti-VEGF). Most clinical pharmacokinetics studies rely on indirect blood measurements, which have been mainly restricted to pivotal studies, which have not been studied in the great majority of post-authorisation trials [21,22] For these reasons, the information that is available in this field is very limited. Ranibizumab is a fragment of a monoclonal antibody that does not contain the Fc region (heavy chains) and w2.i1t.hRaanffiibiznu2im.t1ya.bRfaonrib2ia.z1ul.lmRsaaubnibbitzyumpaebs of VEGF-A (Table 1) It has been approved for the treatment of neovascular AMDRanbibaiszeumdaoRbaninsitabhifzreuagRmrmeaansebiunbitsilzotausffmaroaamgfbmotinwseonacotflrocanfglaimlnmaeinonctntiabolocfltdaorynmiataohllnaston(dctiAloboeonNsdanlyCoatnthHtcaiotbOnodtdoaRyeinstahntnhaoetddFcocMnersteaAgniinooRtnthcI(oNehnFetEcaavir)nye,gtwhioehnFe(chrreeeagv0iyo.n5(mheagvwy as administeredcohof annienosav) aamsncduocowlnahfriatntihhAenoMaslvy)ffDaaisncorchbifdeutaayngwlsiaenfeirioosmdtvr)hAoaaMaesnnlflcndfDustihnuwloaebibtriabytrtyshAesfepsoMadeuerfsrlfoDativsonnllfbioisttVnafyhusEtegbfewoGtdryroeiFpmosa-cunelAllsliptns(sohuTirfceobaoaVftbrlyveEtltwpesreGuei1oamFsl)tl.-csoAIlefti(onAnV(hfTiaNcEttawassGCblbolFiHtern-ceiAO1lani)lnvR.(saTiIicpt(aasAaphnbulaNrdltoesarCMvi1blaeH)elA.daseOIRnct(fAoRIhuaNraNpaitsEptnhCyb)rde,HoetwMevwrOnehARadieattRrpmfaheoIpnNer0rdngot.E5htMva)e,eiAdtwnrRefhsoaIeNrtrometEhfe0)e,n1.5tw1reh.a3etrmelee0nt.5tters in the ANCHmOgRwatsraidamlmiangniwsdtearse7adm.d2ogmnlwienaatimstteeaordrnemstdhiilonynnisrtaeteghrmieemdoneMontnholAaybsmrReorgIvniNmitnhegAlnyimrotebrpgsirieaomrvlve,einnmagoesbnimsctesoprivrnmoinvgpiesmiuamaerlpneartdsocuvintietomyviewstnuhitatsehliagnccaouvininstsyutoarwfloiatlchuggitaryionwusiotphfsga[i1n0s ,o1f 1]. D[2a3ta–2fr5o].m [23,24,25]
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