PURPOSE. To develop pharmacokinetics models to describe the disposition of small lipophilic molecules in the cornea and retina after periocular (subconjunctival or posterior subconjunctival) administration. METHODS. Compartmental pharmacokinetics analysis was performed on the corneal and retinal data obtained after periocular administration of 3 mg of celecoxib (a selective COX-2 inhibitor) to Brown Norway (BN) rats. Berkeley Madonna, a differential and difference equation-based modeling software, was used for the pharmacokinetics modeling. The data were fit to different compartment models with first-order input and disposition, and the best fit was selected on the basis of coefficient of regression and Akaike information criteria (AIC). The models were validated by using the celecoxib data from a prior study in Sprague-Dawley (SD) rats. The corneal model was also fit to the corneal data for prednisolone at a dose of 2.61 mg in albino rabbits, and the model was validated at two other doses of prednisolone (0.261 and 26.1 mg) in these rabbits. Model simulations were performed with the finalized model to understand the effect of formulation on corneal and retinal pharmacokinetics after periocular administration. RESULTS. Celecoxib kinetics in the BN rat cornea can be described by a two-compartment (periocular space and cornea, with a dissolution step for periocular formulation) model, with parallel elimination from the cornea and the periocular space. The inclusion of a distribution compartment or a dissolution step for celecoxib suspension did not lead to an overall improvement in the corneal data fit compared with the two-compartment model. The more important parameter for enhanced fit and explaining the apparent lack of an increase phase in the corneal levels is the inclusion of the initial leak-back of the dose from the periocular space into the precorneal area. The predicted celecoxib concentrations from this model also showed very good correlation (r = 0.99) with the observed values in the SD rat corneas. Similar pharmacokinetics models explain drug delivery to the cornea in rat and rabbit animal models. Retinal pharmacokinetics after periocular drug administration can be explained with a four-compartment (periocular space, choroid-containing transfer compartment, retina, and distribution compartment) model with elimination from the periocular space, retina, and choroid compartment. Inclusion of a dissolution-release step before the drug is available for absorption or elimination better explains retinal tmax. Good fits were obtained in both the BN (r = 0.99) and SD (r = 0.99) rats for retinal celecoxib using the same model; however, the parameter estimates differed. CONCLUSIONS. Corneal and retinal pharmacokinetics of small lipophilic molecules after periocular administration can be described by compartment models. The modeling analysis shows that (1) leak-back from the site of administration most likely contributes to the apparent lack of an increase phase in corneal concentrations; (2) elimination via the conjunctival or periocular blood and lymphatic systems contributes significantly to drug clearance after periocular injection; (3) corneal pharmacokinetics of small lipophilic molecules can be explained by using similar models in rats and rabbits; and (4) although there are differences in some retinal pharmacokinetics parameters between the pigmented and nonpigmented rats, the physiological basis of these differences has yet to be ascertained.
Purpose
To determine whether combining measures of retinal structure and function predicts need for intervention for diabetic retinopathy (DR) better than either modality alone.
Methods
The study sample consisted of 279 diabetic patients who participated in an earlier cross-sectional study. Patients were excluded if they were previously treated for macular edema or proliferative DR or if they had other retinopathies. Medical records were reviewed for ocular interventions including vitrectomy, intravitreal injection, and laser treatment. Need for intervention was analyzed using Kaplan-Meier analyses and Cox proportional hazards. Baseline electroretinograms and fundus photographs were obtained. Two definitions of structural positive findings were as follows: 1. Early Treatment of Diabetic Retinopathy Study diabetic retinopathy severity scale (ETDRS-DR) severity ≥ level 53 (ETDRS-DR+) and 2. ETDRS-DR+ or clinically significant macular edema (VTDR+). A positive function finding corresponded to a RETeval DR Score >23.5 (RETeval+).
Results
For patients with VTDR+ the incidence of intervention was 19%, 31%, and 53% after 1, 2, and 3 years of follow-up. In these patients, intervention incidence increased to 34%, 54%, and 74% the subsequent 1, 2, and 3 years if function was above criterion (RETeval+), whereas RETeval− results reduced the risk to 3%, 4%, and 29%, respectively, reducing risk to similar levels seen for patients with VTDR− results at baseline.
Conclusions
Prediction of subsequent intervention was best when combining structural and functional information.
Translational Relevance
This study demonstrates that clinical management of diabetic retinopathy is improved by adding electroretinography to fundus photographic information in assessing the risk of the need for intervention.
by
Guorong Li;
Chanyoung Lee;
Vibhuti Agrahari;
Ke Wang;
Iris Navarro;
Joseph M. Sherwood;
Karen Crews;
Sina Farsiu;
Pedro Gonzalez;
Cheng-Wen Lin;
Ashim K. Mitra;
Ross Ethier;
W. Daniel Stamer
Ocular corticosteroids are commonly used clinically. Unfortunately, their administration frequently leads to ocular hypertension, i.e., elevated intraocular pressure (IOP), which, in turn, can progress to a form of glaucoma known as steroid-induced glaucoma. The pathophysiology of this condition is poorly understood yet shares similarities with the most common form of glaucoma. Using nanotechnology, we created a mouse model of corticosteroid-induced ocular hypertension. This model functionally and morphologically resembles human ocular hypertension, having titratable, robust, and sustained IOPs caused by increased resistance to aqueous humor outflow. Using this model, we then interrogated the biomechanical properties of the trabecular meshwork (TM), including the inner wall of Schlemm’s canal (SC), tissues known to strongly influence IOP and to be altered in other forms of glaucoma. Specifically, using spectral domain optical coherence tomography, we observed that SC in corticosteroid-treated mice was more resistant to collapse at elevated IOPs, reflecting increased TM stiffness determined by inverse finite element modeling. Our noninvasive approach to monitoring TM stiffness in vivo is applicable to other forms of glaucoma and has significant potential to monitor TM function and thus positively affect the clinical care of glaucoma, the leading cause of irreversible blindness worldwide.
by
Timothy Olsen;
Roy B. Dyer;
Fukutaro Mano;
Jeffrey Boatright;
Micah A. Chrenek;
Daniel Paley;
Kathy Wabner;
Jenn Schmit;
Ju Byung Chae;
Jana T. Sellers;
Ravinder J. Singh;
Timothy S. Wiedmann
Purpose
To determine local ocular tissue levels of the bile acid, tauroursodeoxycholic acid (TUDCA), in the pig model using oral, intravenous (IV), intravitreal injection (IVitI) and low- and high-dose suprachoroidal, sustained-release implants (SCI-L or SCI-H).
Methods
Forty-six pigs (92 globes) were included in the study. TUDCA was delivered orally in 5 pigs, IV in 4, IVitI in 6, SCI-L in 17, and SCI-H in 14. Testing timeframes varied from the same day (within minutes) for IV; 1 to 6 days, oral; and 1 to 4 weeks, IVitI and SCI. Enucleated globes were dissected, specimens from specific tissues were separated, and TUDCA was extracted and quantified using mass spectrometry.
Results
The highest TUDCA tissue levels occurred after IV delivery in the macula (252 ± 238 nM) and peripheral retina (196 ± 171 nM). Macular choroid and peripheral choroid levels were also high (1032 ± 1269 and 1219 ± 1486 nM, respectively). For IVitI delivery, macular levels at day 6 were low (0.5 ± 0.5 nM), whereas peripheral choroid was higher (15.3 ± 16.7 nM). Neither the SCI-L nor SCI-H implants delivered meaningful macular doses (≤1 nM); however, peripheral retina and choroid levels were significantly higher. Bile acid isoforms were found in the serum specimens.
Conclusions
The highest TUDCA tissue levels in the pig model were obtained using IV delivery. Oral delivery was associated with reasonable tissue levels. Local delivery (IVitI and SCI) was able to achieve measurable local ocular tissue levels.
Translational Relevance
Diffusional kinetics from the suprachoroidal space follow the choroidal blood flow, away from the macula and toward the periphery.
by
Asim V. Farooq;
Simona Degli Esposti;
Rakesh Popat;
Praneetha Thulasi;
Sagar Lonial;
Ajay Nooka;
Andrzej Jakubowiak;
Douglas Sborov;
Brian E. Zaugg;
Ashraf Z. Badros;
Bennie H. Jeng;
Natalie S. Callander;
Joanna Opalinska;
January Baron;
Trisha Piontek;
Julie Byrne;
Ira Gupta;
Kathryn Colby
The authors of the above mentioned article would like to highlight the following corrections, based upon recent changes to the FDA label and guidance on the use of belamaf. • Page 3: The second sentence under ‘‘Methods’’ should be ‘‘In brief, eligible patients with RRMM were randomized (1:1) to receive belamaf 2.5- or 3.4-mg/kg every 3 weeks by intravenous infusion over 30 min or longer on day 1 of each cycle.’’ • Page 5: Table 1, Grade 4, Recommended dose modification currently reads ‘‘Permanently discontinue treatment’’. This should be ‘‘Consider treatment discontinuation for a Grade 4 event. Based on a benefit:risk assessment, if continuing treatment with belamaf is being considered, treatment may be resumed at a reduced dose after the event has improved to Grade 1 or better event.’’ • Page 6: Table 2, BCVA change, event outcomes as of last follow-up reads ‘‘26/44 (48).’’ This should be ‘‘26/44 (59)’’. Subjective dry eye, first event outcomes reads ‘‘2/14 (31).’’ This should be ‘‘2/14 (14)’’. Blurred vision, event outcome as of last follow-up, not recovered reads ‘‘9/24 (37).’’ This should be ‘‘9/24 (38)’’. • Page 8, 2nd column, 1st paragraph reads ‘‘28% (25/95) of patients’’ this should read ‘‘28% (25/88) of patients’’. • Page 9, 2nd column, first paragraph reads ‘‘Cogan microscysts’’. This should be ‘‘microcysts’’. • Page 10: Fig. 4 legend, reads ‘‘In vivo confocal microscopic image from the same patient (d–f) demonstrating hyperreflective opacities within the corneal epithelium.’’ This should be ‘‘(c–f)’’. • Page 10, 2nd column, first paragraph, first sentence reads: ‘‘Following the first dose of belamaf 2.5 mg/kg, he presented on day 27 with MECs characterized as mild/patchy in the periphery/mid-periphery on slit lamp microscopy (Fig. 5a, b). IVCM of the involved areas revealed hyperreflective opacities (Fig. 5c).’’ This should read as ‘‘(Fig. 4a, b)’’ and ‘‘(Fig. 4c–f)’’, respectively. • Page 18: Under ‘‘Recommended Monitoring, Diagnosis, and Management Techniques’’ and ‘‘Diagnosis and Staging of MECs’’ the final sentence currently reads ‘‘The eye care professional should also determine if the decline in BCVA is related to belamaf-associated examination finding(s).’’ This should be ‘‘Determine the recommended dosage modification of belamaf based on the worst finding in the worst affected eye. Worst finding should be based on either a corneal examination finding or a change in visual acuity per the KVA scale.’’ • Page 18: Under ‘‘Recommended Monitoring, Diagnosis, and Management Techniques’’ and ‘‘Management’’ the sentence currently reads ‘‘Treatment should be permanently discontinued for a grade 4 event.’’ This should be ‘‘Consider treatment discontinuation for a grade 4 event. Based on a benefit: risk assessment, if continuing treatment with belamaf is being considered, treatment may be resumed at a reduced dose after the event has improved to grade 1 or better event.’’ The original article has been corrected.
PURPOSE. To compare the efficacy of microneedle-delivered suprachoroidal (SC) pazopanib to intravitreal (Ivit) delivery of pazopanib, bevacizumab, or a fusion protein hI-con1 versus vehicle controls on choroidal neovascularization (CNV) growth in a pig model. METHODS. Forty-one pigs were injected on the day of CNV induction (hI-con1 on postinduction day 14) with either 2.5 mg Ivit bevacizumab (n = 9), 1 mg Ivit pazopanib (n = 9), 300 Ivit μg hI-con1 (n = 4), or 1 mg SC pazopanib (n = 9), vs. 10 vehicle controls (3 SC + 7 Ivit = 10). Pigs were euthanized at week 2 (11), 3 (8), 4 (11), and 8 (11), and eyes were fixed for histology. The size of the CNV was determined from histology, and CNV height was the primary outcome measure. Immunostaining for cytotoxic T-cells was performed in the hI-con1 study. RESULTS. In 39 of 41 (95%) eyes, type 2 CNV lesions were identified. One CNV lesion was lost during dissection. One animal was euthanized due to surgical complications. For mean CNV size comparisons, Ivit pazopanib had smaller mean height measurements (90 ± 20 μm) versus controls (180 ± 20 μm; P = 0.009), and Ivit pazopanib had smaller maximum CNV height (173 ± 43 μm) compared to SC pazopanib (478 ± 105 μm; P = 0.018). The mean lesion size in hI-con1–treated animals trended smaller than in controls (P = 0.11). Immunostaining did not detect cytotoxic T-cells. CONCLUSIONS. Intravitreal pazopanib and to a lesser extent hI-con1 reduced the size of CNV lesions. The pig model has nearly a 100% rate of type 2 CNV induction and is a reliable preclinical model with pharmacodynamics similar to humans.