Advances in Drug Delivery to the Posterior Segment
Advances in Drug Delivery to the Posterior Segment
Most recently added to the market after FDA approval in September 2014 is the Iluvien injectable insert (fluocinolone acetonide; Alimera Sciences Inc., Alpharetta, Georgia, USA). Iluvien is indicated for the treatment of DME in patients who have demonstrated a lack of steroid-responsive intraocular pressure elevation. Recently, a multicentre, randomized, controlled trial compared a low and high-dose implant with sham treatment and demonstrated that the low-dose implants resulted in similar levels of significant visual improvement as the higher dose cohort with a lower rate of side effects. Among 953 patients, 28.7% (0.2 μg/day) and 27.8% (0.5 μg/day) achieved a gain of at least 15 letters in BCVA compared with 18.9% in the sham group (P = 0.018). Patients with DME for longer than 3 years at the onset of treatment experienced almost a doubling of treatment effect compared with sham groups in a preplanned subgroup analysis. Necessity for cataract surgery occurred in nearly all phakic patients, while only 4.8 and 8.1% of the low and high-dose groups, respectively, required glaucoma surgery after 3 years.
With multiple steroid-eluting devices on the market, several studies have now sought to investigate the differences among various therapeutic systems. Kiddee et al. compared the intraocular pressure elevation after injection of a 4 mg triamcinolone acetonide suspension, a 0.59 and 2.1 mg fluocinolone implant and a 0.35 and 0.7 mg dexamethasone implant. This meta-analysis showed that ocular hypertension developed after steroid injection in 32% of triamcinolone treated eyes, 66 and 79% in low and high-dose fluocinolone implanted eyes, and 11 and 15% of low and high-dose dexamethasone inserted eyes. Risk factors for developing steroid-responsive ocular hypertension were preexisting glaucoma or ocular hypertension, younger age and uveitis. This study concluded that the dexamethasone insert resulted in the lowest rate of ocular hypertension, whereas the fluocinolone implant conferred the highest risk of needing incisional glaucoma surgery.
An additional study sought to compare pharmacokinetics of the two fluocinolone acetonide delivery vehicles. Campochiaro et al. sampled aqueous steroid concentrations in two different prospective, interventional trial groups demonstrating that mean aqueous fluocinolone acetonide levels were comparable at 1 and 3-month intervals in the low (2.17 ng/ml) and high-dose (3.03 ng/ml) insert groups, but higher in the implant (6.12 ng/ml) group. This study also demonstrated steady-state trough levels remained stable up to 3 years in all groups.
In contrast to drug-impregnated devices that elute medication for a predetermined interval, drug-filled reservoirs with micropumps that have a capacity for minimally invasive refill have gained interest. The Replenish MicroPump (Replenish, Pasadena, California, USA) is a surgically implantable drug reservoir with a pump designed to release nanoliter doses at a programmed interval. Implanted into the eye similar to a glaucoma drainage device, the anterograde flow into the eye delivers continuous dosing while a readily accessible reservoir can be refilled via transconjunctival injection. Anterior and posterior platforms are in development for cannulation and targeting of both ocular segments.
Alternatively, the Port Delivery System (PDS, ForSight VISION4, Inc.) is a refillable drug delivery device that is in phase 1 and phase 2 trials for preliminary safety and efficacy for neovascular AMD and noninfectious uveitis (www.clinicaltrials.gov: NCT01186432 and NCT02125266).
Another promising approach to drug delivery has involved accessing the suprachoroidal space for the delivery of therapeutics. Delivering medication to this potential space has the proposed advantage of higher concentrations of medication to target tissues (retina, choroid) and lower concentration of medication to anterior segment structures. This benefit has been demonstrated in detailed anatomic studies of medication concentrations following suprachoroidal drug delivery.
Iluvien Injectable Insert
Most recently added to the market after FDA approval in September 2014 is the Iluvien injectable insert (fluocinolone acetonide; Alimera Sciences Inc., Alpharetta, Georgia, USA). Iluvien is indicated for the treatment of DME in patients who have demonstrated a lack of steroid-responsive intraocular pressure elevation. Recently, a multicentre, randomized, controlled trial compared a low and high-dose implant with sham treatment and demonstrated that the low-dose implants resulted in similar levels of significant visual improvement as the higher dose cohort with a lower rate of side effects. Among 953 patients, 28.7% (0.2 μg/day) and 27.8% (0.5 μg/day) achieved a gain of at least 15 letters in BCVA compared with 18.9% in the sham group (P = 0.018). Patients with DME for longer than 3 years at the onset of treatment experienced almost a doubling of treatment effect compared with sham groups in a preplanned subgroup analysis. Necessity for cataract surgery occurred in nearly all phakic patients, while only 4.8 and 8.1% of the low and high-dose groups, respectively, required glaucoma surgery after 3 years.
With multiple steroid-eluting devices on the market, several studies have now sought to investigate the differences among various therapeutic systems. Kiddee et al. compared the intraocular pressure elevation after injection of a 4 mg triamcinolone acetonide suspension, a 0.59 and 2.1 mg fluocinolone implant and a 0.35 and 0.7 mg dexamethasone implant. This meta-analysis showed that ocular hypertension developed after steroid injection in 32% of triamcinolone treated eyes, 66 and 79% in low and high-dose fluocinolone implanted eyes, and 11 and 15% of low and high-dose dexamethasone inserted eyes. Risk factors for developing steroid-responsive ocular hypertension were preexisting glaucoma or ocular hypertension, younger age and uveitis. This study concluded that the dexamethasone insert resulted in the lowest rate of ocular hypertension, whereas the fluocinolone implant conferred the highest risk of needing incisional glaucoma surgery.
An additional study sought to compare pharmacokinetics of the two fluocinolone acetonide delivery vehicles. Campochiaro et al. sampled aqueous steroid concentrations in two different prospective, interventional trial groups demonstrating that mean aqueous fluocinolone acetonide levels were comparable at 1 and 3-month intervals in the low (2.17 ng/ml) and high-dose (3.03 ng/ml) insert groups, but higher in the implant (6.12 ng/ml) group. This study also demonstrated steady-state trough levels remained stable up to 3 years in all groups.
Implantable Reservoirs
In contrast to drug-impregnated devices that elute medication for a predetermined interval, drug-filled reservoirs with micropumps that have a capacity for minimally invasive refill have gained interest. The Replenish MicroPump (Replenish, Pasadena, California, USA) is a surgically implantable drug reservoir with a pump designed to release nanoliter doses at a programmed interval. Implanted into the eye similar to a glaucoma drainage device, the anterograde flow into the eye delivers continuous dosing while a readily accessible reservoir can be refilled via transconjunctival injection. Anterior and posterior platforms are in development for cannulation and targeting of both ocular segments.
Alternatively, the Port Delivery System (PDS, ForSight VISION4, Inc.) is a refillable drug delivery device that is in phase 1 and phase 2 trials for preliminary safety and efficacy for neovascular AMD and noninfectious uveitis (www.clinicaltrials.gov: NCT01186432 and NCT02125266).
Suprachoroidal Drug Delivery
Another promising approach to drug delivery has involved accessing the suprachoroidal space for the delivery of therapeutics. Delivering medication to this potential space has the proposed advantage of higher concentrations of medication to target tissues (retina, choroid) and lower concentration of medication to anterior segment structures. This benefit has been demonstrated in detailed anatomic studies of medication concentrations following suprachoroidal drug delivery.
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