CHAPTER

10

Routes for drug delivery to the eye and retina: intravitreal injections and vitrectomy

Carsten H. Meyer, MD, Tim U. Krohne, MD, FEBO, Peter Charbel Issa, MD, FEBO, and Frank G. Holz, MD

INTRODUCTION

THE RATIONALE FOR INTRAVITREAL DRUG DELIVERY

Different approaches have been proposed to deliver drugs into the eye. One of the main challenges is to achieve therapeutic concentrations at the posterior pole. Systemic applications may lead to sufficient concentrations at the retina; however unwanted systemic side-effects are of concern, especially in the long term. Topical applications have the disadvantage that the active agent may not penetrate deep enough into the eye, limiting the therapeutic effect at the posterior pole. Periocular sub-Tenon injections may potentially minimize systemic side-effects, but the drug still has to penetrate the sclera and the blood–retinal barrier (BRB) to reach the intended target in the subretinal space. To overcome these limitations, numerous physicians have suggested intravitreal drug application to achieve locally therapeutic levels with prolonged effective concentrations1 (Figure 10.1).

HISTORY

Intravitreal drug administrations by single injections or during vitrectomy have become an efficient approach to deliver drugs in therapeutic levels. The advantage of this targeted drug delivery is an immediate and increased therapeutic effect at the intended tissue. Intravitreal injections were initially described by Ohm in 19112 to employ an intravitreal air bubble tamponading a retinal tear. Intravitreal application of antibiotics, e.g., sulfanilamide or penicillin, was studied in the early 1940s to treat endophthalmitis. Additional studies, evaluating the appropriate injection technique as well as its feasibility and safety, focused on the treatment of endophthalmitis, submacular hemorrhage, or cytomegalovirus (CMV) retinitis. Triamcinolone acetonide (TA) was the first intravitreally applied drug with widespread application. Most recently, repeated intravitreal injections of antiangiogenic agents like vascular endothelial growth factor (VEGF) inhibitors have become the first-line treatment for exudative age-related macular degeneration (AMD).

The development of additional novel pharmacotherapies has led to an increased use of intravitreal injections. With the recent widespread use of this technique, there has been an increased interest regarding the best approach and application technique.

KEY CONCEPTS AND FUNDAMENTAL POINTS IN RETINAL DRUG DELIVERY

The optimal technique for intravitreal injections is still under evaluation in an attempt to minimize complications and to optimize the “best practice” approach. Extensive clinical experience with intravitreal injection has provided clinicians with an outline of avoidable risks through empirical experience. At present several publications have evaluated the technique of intravitreal injection.3

Numerousnationalboardshavedefinedguidelinesonhowtoperform safe intravitreal injection reliably. The injection should be performed using a standard protocol. While some countries recommend that the injection be applied in an operating room, other countries perform the injection in a conventional examining office under sterile conditions.4

STRATEGIES AND IMPLICATIONS FOR RETINAL PHARMACOTHERAPY

PREOPERATIVE PREPARATION

There is now agreement regarding the perioperative management of patients with long-term anticoagulation while undergoing repeated intravitreal injections. A major concern associated with preoperative discontinuation of anticoagulation therapy is the increased risk of thromboembolic or cerebrovascular events.5

Previously surgeons discontinued any antiplatelet or anticoagulation therapy perioperatively and determined mild vitreous hemorrhages in less than 0.1%. The low incidence (3/500) convinced them to continue anticoagulation therapy throughout the period of numerous consecutive injections. They performed intravitreal injections with VEGF inhibitors under the currently prescribed anticoagulation therapy.6,7 During our initial consecutive 3000 injections, no vitreous hemorrhages occurred. Selected eyes received up to 20 consecutive injections. Nineteen percent of our patients were receiving aspirin or warfarin on a regular basis. We found no evidence to suggest that patients under­ going anticoagulation therapy may face persistent vision-threatening vitreal hemorrhages after intravitreal injections.

The Lucentis study trials observed a similar incidence of ocular hemorrhages in patients maintaining warfarin. In the MARINA trial there were a total of 60 warfarin-treated participants, receiving a mean of 22.0 (sd, 3.6) injections.8 No ocular bleeding was observed during the 1318 consecutive injections. The ANCHOR trial included 25 patients who maintained warfarin. Each patient received a mean of 21.4 (sd, 4.6) injections.9 The authors concluded that intraocular injections in warfarin-treated patients are unlikely to cause ocular hemorrhages.

Subretinal, vitreal, or subconjunctival hemorrhages (Figure 10.2) after intravitreal injections may relate to the procedure itself, the applied drug, as well as the anticoagulation status of the patient. Small-incision techniques can reduce the risks of hemorrhagic ocular events in the anticoagulated patient. Approximately 10% of all patients with exudative AMD receive warfarin anticoagulation due to concomitant medical conditions. These patients may undergo intravitreal injections without significant risk of hemorrhagic complications while maintaining their anticoagulation therapy.

PROPHYLAXIS OF ENDOPHTHALMITIS: LOCAL DISINFECTION AND TOPICAL ANTIBIOTIC THERAPY

It is mandatory to treat any active external infection, including significant blepharitis, before each intravitreal injection. It has been demonstrated in rabbits that 51 + 4 colony-forming units of Staphylococcus