Sustained release of drugs by devices such as dexamethasone implant placed in vitreous humor can reduce the frequency of intravitreal injections. The duration over which the device provides therapeutic drug exposure is a critical parameter and so models for predicting ocular pharmacokinetics after placing the device in vitreous humor are valuable. This study developed a model using parameters from literature to predict concentrations in aqueous humor, vitreous humor, retina and sclera-choroid after placing Ozurdex in vitreous humor and validated the model using data reported in literature for rabbits and Cynomolgus monkeys. The model is based on ordinary differential equations representing mass balances in vitreous humor, retina, aqueous humor and sclera-choroid. Additionally, a partial differential equation representing mass balance in the lens is included. The model can be simplified to yield explicit expressions for concentration in all tissues. The results are in reasonable agreement with concentrations reported in literature, particularly considering the in vivo data variability and lack of dependence on fitting parameters in the model. The simulation results suggest that the duration of therapeutic concentration in the retina is longer than the drug release duration from the implant because drug diffuses into the lens, creating a depot. The drug depot in the lens eventually releases the drug back into vitreous humor, which increases the total duration over which the concentrations are efficacious. The model can be applied to other sustained release devices placed in vitreous humor or elsewhere in the eye.

New insights on liposomal formulations based upon tear film lipids: A combined study of safety and ocular surface pharmacokinetics.

In vitro, ex vivo, and in vivo evaluation of ophthalmic ointments containing dexamethasone and tobramycin.

Ocular tolerance and tear film pharmacokinetics of 1% penciclovir cream in cats.

Luteolin attenuates experimental dry eye disease via dual modulation of macrophage JAK-STAT signaling and corneal epithelial MAPK pathways.

Therapeutic potential of phosphodiesterase inhibitor-loaded nanomicelles to treat endotoxin-induced anterior uveitis.

Drug delivery products based on poly(lactic-co-glycolic acid) (PLGA) are complex systems that may have significantly different drug release behavior under different release conditions, i.e., in different in vitro release tests (IVRTs) or in vivo. This must be appreciated when designing an IVRT for a given application. For example, when designing an IVRT for formulation development or bioequivalence testing, it is commonly desired that the IVRT is biorelevant to some extent, meaning that it imitates the relevant biological fluid/physiological environment ("compositional biorelevance") and by doing so simulates the in vivo release process ("mechanistic biorelevance"). Theoretically, biorelevance leads to "biopredictiveness," meaning that the IVRT predicts certain aspect(s) of in vivo performance. The objective of this study was to assess two IVRTs for dexamethasone/PLGA intravitreal implants according to a few selected aspects of biorelevance and biopredictiveness. These two IVRTs differed only in release medium composition: one used unbuffered isotonic saline, whereas the other used 12 mM phosphate-buffered saline (PBS) at pH 7.4. In the first part of this study, two different implant formulations were tested in these two IVRTs. The two implant formulations had the same composition and structure as each other but were manufactured using slightly different batches of PLGA. In the saline-based IVRT, the two formulations had similar in vitro release profiles, both lasting about 28 days; in the PBS-based IVRT, the two formulations had different release profiles, both lasting about 4 months. Next, these two implant formulations were injected into the left and right vitreous of 36 New Zealand White rabbits. In vivo drug release was measured directly by recovering implants at various timepoints and assaying their remaining drug content by high-pressure liquid chromatography (HPLC). Additionally, ocular pharmacokinetics were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The two implant formulations had similar in vivo release profiles and ocular pharmacokinetics as each other, and in vivo release lasted between 21 and 28 days; therefore, these in vivo results closely matched the saline-based IVRT. In the final part of this study, we endeavored to reconcile the saline-based IVRT's good prediction of in vivo release with the fact that the rabbit vitreous is buffered. This was investigated mechanistically by measuring the degradation of the implant's PLGA matrix during both in vitro and in vivo release. Matrix degradation was measured by recovering implant samples at various timepoints and measuring PLGA molecular weight by gel permeation chromatography. This was performed with one implant formulation in both IVRTs and in the vitreous of 4 rabbits. These measurements demonstrated that the PBS-based IVRT provided a better simulation of the implant's in vivo surface erosion, whereas the saline-based IVRT provided a better simulation of in vivo bulk erosion. Ultimately, we concluded that both IVRTs may provide value depending on the application: the saline-based IVRT may be preferred for predicting rabbit in vivo release, whereas the PBS-based IVRT may be preferred for a highly sensitive discriminatory test.

Ocular malignancies provide a unique therapeutic challenge because of their anatomical intricacy, limited accessibility, and vision-critical nature. Recent developments in radiopharmaceutical design have been paired with ultrasound-mediated medicine administration to create highly targeted, less invasive therapies for intraocular cancers. This research looks at the emerging topic of ultrasound-responsive radiopharmaceutical devices built specifically for ocular oncology. These methods enhance tumor selectivity, decrease off-target effects, and enable real-time imaging-guided therapy by utilizing targeted ultrasound to induce localized medication release or radiotherapeutic agent activation. Microbubble-assisted delivery, thermosensitive liposomes, and phase-transition nanodroplets carrying radionuclides have all been designed to optimize ocular pharmacokinetics and tissue penetration. Preclinical studies reveal promising results in increasing radiotherapeutic efficacy against retinoblastoma and uveal melanoma while sparing healthy ocular tissues.

PurposeABBV-RGX-314 is being developed for neovascular age-related macular degeneration (nAMD). Computational fluid dynamics (CFDs) modeling in the eye enables simulation of drug distribution incorporating geometry and substructures of the eye across species. Given the similarity between ranibizumab and ABBV-RGX-314 transgene product (TP), ranibizumab intraocular pharmacokinetic (PK) data from literature were used to simulate intraocular drug distribution of ABBV-RGX-314 TP. This investigation aims to use CFD modeling to estimate retinal TP level based on aqueous humor (AH) TP level following subretinal (SR) injection of ABBV-RGX-314 in patients with nAMD.MethodsOcular distribution of ranibizumab following a single intravitreal (IVT) injection was modeled in both monkey and human eyes independently. Following model validation, ABBV-RGX-314 TP distribution in human eyes was simulated following retinal transduction of ABBV-RGX-314.ResultsIterative simulations were performed to achieve similar AH ABBV-RGX-314 TP levels in patients with nAMD from phase I/IIa Study RGX-314-001. The CFD simulation estimated corresponding retinal TP concentrations of 1.86 to 5.50 µg/g at steady-state, which was assumed to be reached by 28 days and falls within the range of the estimated retinal ranibizumab trough retinal ranibizumab concentration (Ctrough; 0.718–5.37 µg/g) following monthly and every other month (EOM) dosing of 0.5 mg ranibizumab in patients with nAMD.ConclusionsThe current study results predict that the 2 pivotal trial ABBV-RGX-314 doses (6.4E10 and 1.3E11 genome copies/eye) are expected to achieve and maintain sufficient retinal ABBV-RGX-314 TP levels for the treatment of nAMD.Translational RelevanceCFD modeling effectively bridges limited human ocular PK data with rich preclinical data, supporting model-informed drug development (MIDD) for clinical dose selection.

PurposeThe mechanistic target of rapamycin complex 1 (mTORC1) signaling has been reported to regulate lens-induced myopia (LIM) in guinea pigs. To address the challenge of delivering lipophilic mTORC1 inhibitors to the posterior eye segment, we developed a novel topical ophthalmic formulation of everolimus, a second-generation rapamycin derivative available only orally, and evaluated its antimyopic efficacy, ocular pharmacokinetics, and safety.MethodsVehicle formulations were optimized for delivering everolimus to the RPE–choroid complex. The efficacy of different concentrations of everolimus eye drops was tested in 3-week-old male pigmented guinea pigs that underwent LIM. We examined mTORC1 signaling activation, axial elongation, refractive changes, and fundus morphology. Pharmacokinetics was assessed in guinea pigs and New Zealand white rabbits. Ocular safety was evaluated through slit-lamp and fundus examinations, intraocular pressure measurements, and histologic analysis.ResultsThe optimized formulation of everolimus eye drops (0.001%, 0.01%, and 0.1% w/v) significantly attenuated axial elongation by 0.10 ± 0.03 mm (P = 0.054), 0.11 ± 0.02 mm (P = 0.001), and 0.14 ± 0.03 mm (P = 0.001), respectively. The everolimus eye drops also attenuated fundus tessellation, choroidal thinning, and mTORC1 activation. Peak everolimus concentrations in the RPE–choroid complex of guinea pigs ranged from 5.6 to 103 ng/g, with a Tmax of 1 hour. In rabbits, 0.005% to 0.01% everolimus eye drops achieved concentrations in the RPE–choroid complex comparable to the therapeutic levels in guinea pigs. No corneal, lenticular, retinal toxicity, or intraocular pressure alterations were observed.ConclusionsThis novel ophthalmic formulation effectively delivered everolimus to the posterior segment and inhibited myopia progression, supporting its clinical potential for myopia control.

Purpose: This study aims to evaluate the effects of brimonidine eye drops and intravitreal administration in guinea pigs with form-deprivation myopia (FDM) and to analyze the ocular pharmacokinetics and irritation. Methods: The experimental guinea pigs were randomized to the normal control, FDM, FDM brimonidine topical eye drops, and FDM intravitreal injection groups. The experiment period was 13 days. Changes in ocular refraction and axial length were monitored regularly. The ocular pharmacokinetics of brimonidine and its metabolite brimonidine-2,3-dione were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry. Ocular irritation was assessed by the Draize test, corneal fluorescein staining, and hematoxylin and eosin staining. Results: Two administration methods of brimonidine equally inhibited the increase in refraction and axial length in FDM guinea pigs (P < 0.05). Pharmacokinetic analysis revealed significant and sustained accumulation of brimonidine in the iris and choroid. Brimonidine was preferentially distributed to the cornea, conjunctiva, and sclera when administered topically, and preferentially to the retina and vitreous when administered intravitreally. The total area under the curve values for retinal and scleral tissues demonstrated that continuous topical administration was 1.95 times and 1.36 times that of intravitreal administration, respectively. The concentration of brimonidine-2,3-dione was significantly lower than that of brimonidine. Brimonidine topical eyedrops had less ocular irritation. Conclusions: At the drug concentrations in this study, both topical and intravitreal brimonidine achieved sufficient ocular exposure to exert similar myopia-suppressing effects. Continuous topical administration can maintain higher drug concentrations in the retinal and scleral tissues with less eye irritation.

Corneal sensory nerves play a pivotal role in supporting ocular surface integrity and immune defense mechanisms. Loss of this innervation has been associated with increased vulnerability to microbial invasion, yet the precise contribution of nerve depletion to bacterial adhesion on the cornea remains insufficiently characterized. Here, we present a reproducible and temporally controlled method for selective corneal sensory nerve suppression using bupivacaine, a long-acting sodium channel blocker. By combining subconjunctival and topical delivery routes, this dual-application strategy achieves robust, sustained denervation, allowing for precise investigation of how altered sensory input influences corneal epithelial susceptibility to bacterial colonization. Using this model, we investigate how sensory denervation influences microbial adhesion dynamics for Staphylococcus aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa three clinically relevant pathogens with distinct adhesion mechanisms. Standardized bacterial inoculation via the laboratory wipe blotting method ensures uniform deposition on the corneal surface, followed by quantitative assessment of bacterial adhesion. Bupivacaine-induced nerve depletion correlates with reduced corneal nerve density and increased bacterial adhesion, confirming a functional link between sensory depletion and microbial susceptibility. By simulating neuropathic conditions such as diabetic neuropathy and neurotrophic keratitis, this approach provides a novel framework for studying neuroimmune interactions in ocular infections. Beyond infection models, this subconjunctival injection strategy offers a versatile platform for investigating ocular drug pharmacokinetics, neuroprotective interventions, and immune modulation. Furthermore, it can be adapted for gene modification studies, including subconjunctival delivery of CRISPR/Cas constructs or viral vectors, broadening its applications in ophthalmic research and therapeutics.

PurposeCorneal sensory innervation plays a crucial role in maintaining ocular surface integrity and immune homeostasis by regulating neuropeptide secretion in tear fluid. Sensory dysfunction disrupts tear production and neuropeptide signaling, increasing susceptibility to microbial infections. However, the mechanistic link between sensory nerve suppression, neuropeptide depletion, and bacterial adhesion remains incompletely understood. This study establishes a refined protocol for targeted corneal sensory nerve suppression using bupivacaine, a long-acting local anesthetic, and investigates the roles of substance P (SP) and calcitonin gene-related peptide (CGRP) in modulating tear production and bacterial adhesion.MethodMale and female C57BL/6J (wild-type) mice (6–8 weeks old) were used to establish a localized and sustained corneal nerve suppression model via subconjunctival bupivacaine injection combined with topical application every other day for 15 days. This approach ensured precise modulation of corneal sensory function. Using this model, we investigated how sensory denervation influences microbial adhesion dynamics for Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis, three clinically relevant pathogens with distinct adhesion mechanisms. Bacterial inoculation was standardized using the Kimwipe blotting method to achieve uniform deposition onto the corneal surface, followed by quantification of bacterial adhesion. Tear production was assessed using SMTube testing to evaluate nerve depletion-associated alterations. Enzyme-linked immunosorbent assay (ELISA) was used to quantify SP and CGRP levels in tear fluid, determining whether their depletion correlated with increased bacterial adhesion and altered tear production. To assess whether neuropeptide restoration mitigates bacterial adhesion, SP, CGRP, or phosphate-buffered saline (PBS; control) was administered via subconjunctival injection prior to bupivacaine treatment on day 14 and 15 during the experimental timeline. All assessments, including nerve depletion effects on tear production, bacterial adhesion, and neuropeptide loss, were conducted on day 15 post-bupivacaine treatment.ResultsTargeted corneal sensory denervation via combined subconjunctival and topical bupivacaine resulted in a ~ 50% reduction in corneal nerve density, achieving deeper and more localized nerve suppression compared to subconjunctival injection alone (P < 0.0001). This approach led to a 2.3-fold (~56.6%) reduction in tear production without inducing epithelial damage (P < 0.0001). This loss of sensory input led to a marked decrease in SP and CGRP levels in both the cornea and tear fluid, with the most pronounced reduction observed in the combined treatment group. Notably, neuropeptide depletion correlated with increased bacterial adhesion, with a ~ 1.18-fold increase for S. aureus and ~1.20-fold for P. aeruginosa, highlighting the critical role of corneal sensory nerves in modulating ocular surface immunity (P < 0.0001). Exogenous SP or CGRP supplementation restored neuropeptide levels and CGRP supplementation reversed bacterial adhesion, highlighting their critical function in maintaining antimicrobial defense.ConclusionThis study establishes a novel, controlled model of corneal sensory denervation, revealing a direct link between neuropeptide depletion, impaired tear production, and increased microbial adhesion. By simulating neuropathic conditions such as diabetic keratopathy and neurotrophic keratitis, this approach provides a valuable framework for investigating neuroimmune interactions in ocular infections. Beyond infection models, this subconjunctival injection strategy serves as a versatile platform for studying ocular drug pharmacokinetics, neuroprotective interventions, and immune modulation.

Gene therapies are emerging as a new treatment modality. Due to their novelty, general pharmacological properties have yet to be established. For example, the translation from animal models to humans for first-in-human dose selection and the dose-exposure relationship remain poorly characterized. A mechanistic and quantitative framework would improve preclinical program design, enable more robust first-in-human dose predictions, and support more rigorous dose adjustments during clinical development. This study establishes a semimechanistic mathematical model for aflibercept expression and pharmacokinetics (PK) following intravitreal (IVT) ADVM-022 administration in monkeys and humans, drawing on the preclinical and clinical data presently available. ADVM-022 is an AAV2.7m8-based viral vector that delivers the gene encoding aflibercept, an antivascular endothelial growth factor (VEGF) fusion protein. It was developed as a gene therapy for treating wet age-related macular degeneration (wAMD) and is administered through a single IVT injection. The proposed model incorporates established ocular PK for intravitreally administered proteins, along with an expression component that links AAV dose to aflibercept production. Based on pooled PK data from monkey studies, the model suggests that transduction occurs not only in the retina but also in other ocular tissues bordering the vitreous, contributing to the observed intraocular aflibercept levels. Increasing doses within the lower range of preclinical studies (3 × 1010-2 × 1013 vg/eye) lead to increased transduction and expression, plateauing at upper limits of approximately 12.7 μg/day·cm3 for the retina, and 0.785 μg/day for extra-retinal tissues at higher doses. Assuming similar transduction efficiency between humans and monkeys, with adjustments for anatomical differences, the model provided predictions of ocular aflibercept concentrations that aligned with observations from the two dose groups in the phase 1 OPTIC clinical trial, supporting the utility of this approach.

Purpose: Perfluorohexyloctane ophthalmical solution (PFHO) forms an anti-evaporative layer at the air-tear interface and is indicated for treatment of the signs and symptoms of dry eye disease (DED). This study evaluated the ocular pharmacokinetics and biodistribution of PFHO in rabbits. Methods: Radiolabeled PFHO was administered to female Dutch Belted rabbits as single (35 µL to each eye) or multiple (twice daily for 5 days) topical ocular doses. Animals were euthanized at designated timepoints. Tears (antemortem), ocular tissues, and blood were collected for pharmacokinetic analysis; heads and carcasses were collected for autoradiographic analysis. Concentrations were measured using liquid scintillation counting. Results: After multiple doses, maximum concentration (Cmax) and area under the concentration-time curve were highest in tears (2330 µg/g, 3720 µg•h/g) and Meibomian glands (222 µg/g, 1440 µg•h/g), followed by other anterior tissues (cornea, 27.6 µg/g, 463 µg•h/g; palpebral conjunctiva, 14.0 µg/g, 136 µg•h/g). PFHO was measurable in tears for 8 h and in Meibomian glands for ≥24 h. Distribution to the posterior ocular segment was minimal, and plasma concentrations were low (single-dose Cmax, 0.97 µg/g; multiple-dose Cmax, 3.2 µg/g). In non-ocular tissues, PFHO was confined primarily to nasal tissues and gastrointestinal tract contents; exposure to other systemic tissues was negligible. Conclusions: Exposure of PFHO was highest in tears, consistent with its anti-evaporative mode of action, followed by the Meibomian glands. PFHO exposure was very low in posterior ocular tissues and negligible in systemic circulation, consistent with the clinical safety profile.

PurposeImproving our understanding of the ocular pharmacokinetics and pharmacodynamics of anti-vascular endothelial growth factor (VEGF) therapies, such as ranibizumab, is essential to enhance treatment strategies for a range of retinal diseases, and will help inform the development of novel anti-VEGF drug candidates.MethodsIn this study, we examine a two-compartment pharmacokinetic/pharmacodynamic model of an intravitreal ranibizumab injection to understand its impact on ocular VEGF suppression. We use Bayesian inference to infer the model parameters from aqueous humor data extracted from healthy cynomolgus macaques. We leverage this approach to explore various sources of uncertainty in the data, offering practical recommendations for minimizing avoidable uncertainty.ResultsThe model provides a robust description of ranibizumab pharmacokinetics and pharmacodynamics, identifying the recovery region of the aqueous humor VEGF concentration–time profile as critical for the precise estimation of parameters. Our results advocate focusing on this region in future studies for optimal data collection. We consider standard data correction techniques to reduce the data uncertainty introduced by the lower limit of quantification, identifying the most preferable technique for this model and data. Using a Bayesian approach we obtain an inferred mean posterior distribution of 1459 ± 98 pM for the ranibizumab dissociation constant, a pharmacodynamic parameter with notable variability across the literature.ConclusionsThis study extends our understanding of the ocular pharmacokinetics and pharmacodynamics of ranibizumab and provides theoretical insights for enhanced data collection schemes to be considered for clinical trials and in the development of novel anti-VEGF therapies.

The corneal permeability of an eye drop is crucial in drug delivery into the eye, but our understanding of drug migration through the cornea and drug distribution within the anterior chamber still requires improvement. To this end, we developed an electrochemical method using boron-doped diamond (BDD) to monitor real-time changes in the drug concentration in the anterior chamber. A needle-shaped BDD microelectrode, with a respective length and tip diameter of ∼200 and ∼40 μm, was used in the in vivo detection of brimonidine tartrate (BRM), which is a widely used antiglaucoma drug. We inserted the tip of the electrode into the right cornea of an anesthetized mouse. BRM was then administered to the right eye, resulting in the successful real-time monitoring of the changes in current. The recorded current reflected the combined reduction of BRM and dissolved oxygen within the anterior chamber. Based on the subtraction of the contribution of the oxygen, the BRM-specific reduction current increased immediately after administration, corresponding to 4.1 μM. Validation via liquid chromatography-tandem mass spectrometry confirmed the accuracy of this approach. Notably, the pharmacological effect of BRM, i.e., a reduced intraocular pressure, was observed 30 min after administration, lagging behind drug migration. These findings may provide valuable insights into the ocular pharmacokinetics of novel drugs and facilitate the development of more effective therapeutic approaches.

ObjectiveThe present study aims to evaluate the ocular pharmacokinetics of intravitreal conbercept after retinal scatter laser photocoagulation.MethodsThirty male Chinchilla rabbits (60 eyes) were used in this study. The control and photocoagulated animals received single bilateral intravitreal injections of conbercept, and the ocular tissues were collected and quantified for drug concentration using ELISA. Statistical analysis was then performed to compare the pharmacokinetic parameters between the control and photocoagulated eyes.ResultsThe conbercept concentrations were higher in the control rabbits than the photocoagulated rabbits and reached peak values in all ocular tissues 1 d after intravitreal dosing. The terminal t1/2 values in the vitreous humor (4.36 d), aqueous humor (4.19 d), retina (3.94 d), and choroid-RPE (3.84 d) of the control eyes were longer than those in the photocoagulated eyes (3.82 d, 3.69 d, 3.65 d, and 3.58 d, respectively). Conbercept exposure assessed using AUC0-t was lower in the photocoagulated rabbits than control animals in all four ocular matrices (p < 0.01). The clearance and volume of distribution were greater in the photocoagulated eyes than the control eyes, while the mean residence times were shorter in all four matrices.ConclusionRetinal scatter laser photocoagulation shortly before single intravitreal injection of conbercept enabled higher drug clearance and shorter half-life values, resulting in lower exposure in the ocular tissues compared to non-photocoagulated conditions. The distinct ocular pharmacokinetics of intravitreal conbercept observed in a rabbit model through retinal scatter laser photocoagulation is expected to enlighten further studies on investigating the optimal order of the combination of photocoagulation and anti-VEGF agents.

Nanoemulsion-based pseudopolyrotaxane hydrogel for enhanced corneal bioavailability and treatment of corneal inflammation.

Sustained release of RNA nanoparticles from reservoir implant for ocular delivery.