Neutralizing Antibody Formation with OnabotulinumtoxinA (BOTOX) Treatment from Global Registration Studies across Multiple Indications: A Meta-Analysis.

Though the formation of neutralizing antibodies (NAbs) during treatment with botulinum neurotoxin is rare, their presence may nonetheless affect the biological activity of botulinum toxin and negatively impact clinical response. The goal of this updated meta-analysis was to evaluate and characterize the rate of NAb formation using an expanded dataset composed of 33 prospective placebo-controlled and open-label clinical trials with nearly 30,000 longitudinal subject records prior to and following onabotulinumtoxinA treatment in 10 therapeutic and aesthetic indications. Total onabotulinumtoxinA doses per treatment ranged from 10 U to 600 U administered in ≤15 treatment cycles.

Impact of Modifying Abicipar Manufacturing Process in Patients with Neovascular Age-Related Macular Degeneration: MAPLE Study Results.

Purpose: To evaluate the impact of modifying the abicipar pegol (abicipar) manufacturing process on the safety and treatment effect of abicipar in patients with neovascular age-related macular degeneration (nAMD).

Methods: A new process for manufacturing abicipar was developed to reduce host cell impurities. In a prospective, Phase 2, multicenter, open-label, 28-week clinical trial, patients (n=123) with active nAMD received intravitreal injections of abicipar 2 mg at baseline (day 1) and weeks 4, 8, 16, and 24.

Effect of Anti-VEGF Therapy on the Disease Progression of Neovascular Age-Related Macular Degeneration: A Systematic Review and Model-Based Meta-Analysis.

Anti-vascular endothelial growth factor (VEGF) therapy is used to slow the disease progression of neovascular age-related macular degeneration. Due to the treatment burden of frequent intravitreal injections, anti-VEGFs are often used on treat and extend protocols rather than the labeled frequency. The current goal of anti-VEGF drug development is to minimize treatment burden by reducing the number of intravitreal injections.

Ocular Pharmacokinetics of Brimonidine Drug Delivery System in Monkeys and Translational Modeling for Selection of Dose and Frequency in Clinical Trials.

Brimonidine, a selective -adrenoceptor agonist, displays putative retinal cyto- and neuroprotective activity in vitro and in vivo. An intravitreal sustained-release brimonidine implant, Brimonidine Posterior Segment Drug Delivery System (brimonidine DDS), allowing targeted drug delivery to the retina has been developed for potential clinical application. This study evaluates the in vivo posterior segment pharmacokinetics of brimonidine DDS implant in the monkey eye and applies translational pharmacokinetic modeling to predict tissue exposure in the human eye.

Nonclinical Pharmacokinetic and Pharmacodynamic Assessment of Bimatoprost Following a Single Intracameral Injection of Sustained-Release Implants.

Purpose: To assess the pharmacokinetic (PK)/pharmacodynamic (PD) relationship following intracameral Bimatoprost sustained-release (SR) implants (8, 15, 30, and 60 µg) in dogs to determine the optimal investigative dose in humans.

Methods: Forty-four male normotensive beagle dogs were assigned to 1 of 8 groups receiving 8-, 15-, 30-, and 60-µg implants (PD assessment [n = 8/group, 4 groups]; PK assessment [n = 3/group, 4 groups]). Intraocular pressure (IOP) in PD animals and aqueous humor/blood concentrations of bimatoprost and its acid in PK animals were assessed.

Distribution of C-Latanoprost Following a Single Intracameral Administration Versus Repeated Topical Administration.

Purpose: To qualitatively evaluate the ocular and periocular distribution of C-latanoprost following a single intracameral administration or repeated topical ocular administration in beagle dogs and cynomolgus monkeys.

Methods: In the dog study, three animals received an intracameral dose of C-latanoprost bilaterally and were euthanized at 1, 2, and 4 h post dose; three control animals received topical C-latanoprost bilaterally once daily for 5 days and were euthanized at 1, 4, and 24 h post final dose. Sagittal 40-µm sections of eyes with surrounding tissues were collected and processed for autoradiography.

A Mechanistic and Translational Pharmacokinetic-Pharmacodynamic Model of Abicipar Pegol and Vascular Endothelial Growth Factor Inhibition.

Abicipar pegol (abicipar) is a novel DARPin therapeutic and highly potent vascular endothelial growth factor (VEGF) inhibitor intended for the treatment of neovascular age-related macular degeneration (nAMD). Here we develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for abicipar to guide dosing regimens in the clinic. The model incorporated abicipar-VEGF binding kinetics, VEGF expression levels, and VEGF turnover rates to describe the ocular and systemic PK data collected from the vitreous, aqueous humor (AH), choroid, retina, and serum of rabbits after a 1-mg abicipar intravitreal (IVT) dose.

Intracameral Sustained-Release Bimatoprost Implant Delivers Bimatoprost to Target Tissues with Reduced Drug Exposure to Off-Target Tissues.

Purpose: To explore the ocular distribution of bimatoprost after intracameral administration of a biodegradable sustained-release bimatoprost implant (Bimatoprost SR) versus repeated topical administration of bimatoprost 0.03% ophthalmic solution in dogs. Bimatoprost SR and topical bimatoprost 0.

Design and Conduct Considerations for First-in-Human Trials.

A milestone step in translational science to transform basic scientific discoveries into therapeutic applications is the advancement of a drug candidate from preclinical studies to initial human testing. First-in-human (FIH) trials serve as the link to advance new promising drug candidates and are conducted primarily to determine the safe dose range for further clinical development. Cross-functional collaboration is essential to ensure efficient and successful FIH trials.

Clinical Pharmacokinetics of Oxymetazoline Cream Following Topical Facial Administration for the Treatment of Erythema Associated With Rosacea.

Background: Oxymetazoline cream 1.0% is FDA-approved for the topical treatment of persistent facial erythema associated with rosacea in adults. This phase 2, multicenter, randomized, double-blind, parallel-group study assessed the pharmacokinetics, safety, and tolerability of oxymetazoline in patients with moderate to severe erythema associated with rosacea.

Ocular pharmacokinetics and tolerability of bimatoprost ophthalmic solutions administered once or twice daily in rabbits, and clinical dosing implications.

Purpose: Fixed-combination medications can benefit patients requiring multiple agents to lower their intraocular pressure (IOP), but combining agents with complementary mechanisms of action is challenging if their dosing frequency differs. This study compares in vivo pharmacokinetic and ocular tolerability of bimatoprost 0.01% ophthalmic solutions dosed once or twice daily.

Assessment of tear film osmolarity using the TearLab osmometer in normal dogs and dogs with keratoconjunctivitis sicca.

Objective: To evaluate repeatability and reproducibility of tear osmolarity measured using the TearLab osmometer in normal dogs and to assess its diagnostic potential in dogs with keratoconjunctivitis sicca (KCS).

Animals Studied: Beagle dogs; six normal and five with KCS.

Procedures: Tear osmolarity and Schirmer tear test-1 (STT-1) values were obtained at various times.

Multiple Natural and Experimental Inflammatory Rabbit Lacrimal Gland Phenotypes.

Purpose: To investigate lacrimal gland (LG) immunophysiological and immune-mediated inflammatory process (IMIP) phenotype diversity.

Methods: Ex vivo matured dendritic cells (mDC) were loaded with acinar cell microparticles (M). Peripheral blood lymphocytes (PBL) were activated in mixed cell reactions with mDC and injected directly into autologous, unilateral LG (1°ATD-LG) of two rabbit cohorts, one naïve, one immunized with a LG lysate membrane fraction (P).

Antibody-Drug Conjugate (ADC) Research in Ophthalmology--a Review.

Similar to cancer, many ocular proliferative disorders could be treated with a specific antibody conjugated to a toxin. Active targeting to inhibit epithelial and endothelial cell proliferation in the eye has been tested using antibody-drug conjugates (ADC) both pre-clinically and clinically. Achieving efficacious drug concentrations in the eye, in particular to treat back of the eye disorders is challenging, and the promise of targeted antibody mediated delivery holds great potential.

The biodisposition and hypertrichotic effects of bimatoprost in mouse skin.

Studies on bimatoprost were performed with two objectives: (i) to determine whether bimatoprost possesses hair growth-stimulating properties beyond eyelash hypertrichosis and (ii) to investigate the biodisposition of bimatoprost in skin for the first time. Bimatoprost, at the dose used clinically for eyelash growth (0.03%) and given once daily for 14 days, increased pelage hair growth in C57/black 6 mice.

Ocular penetration and anti-inflammatory activity of ketorolac 0.45% and bromfenac 0.09% against lipopolysaccharide-induced inflammation.

Purpose: Anti-inflammatory activity of topical nonsteroidal anti-inflammatory drugs is mediated by suppression of cyclooxygenase (COX) isoenzymes. This study compared ocular penetration and inflammation suppression of topical ketorolac 0.45% and bromfenac 0.

Ocular pharmacokinetics of 0.45% ketorolac tromethamine.

Purpose: A new carboxymethylcellulose (CMC)-containing ophthalmic formulation of 0.45% ketorolac, pH 6.8 (Acuvail(®)) was recently developed for treatment of inflammation and pain after cataract surgery.

Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant.

Purpose: To determine the pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone (DEX) intravitreal implant (Ozurdex; Allergan, Inc.).

Methods: Thirty-four male monkeys (Macaca fascicularis) received bilateral 0.

Ophthalmic drug delivery considerations at the cellular level: drug-metabolising enzymes and transporters.

Ophthalmic drugs typically achieve < 10% ocular bioavailability. A drug applied to the surface of the eye may cross ocular-blood barriers where it may encounter metabolising enzymes and cellular transporters before it distributes to the site of action. Characterisation of ocular enzyme systems and cellular transporters and their respective substrate selectivity have provided new insight into the roles these proteins may play in ocular drug delivery and distribution.

Disposition and biotransformation of the acetylenic retinoid tazarotene in humans.

Oral tazarotene, an acetylenic retinoid, is in clinical development for the treatment of psoriasis. The disposition and biotransformation of tazarotene were investigated in six healthy male volunteers, following a single oral administration of a 6 mg (100 microCi) dose of [14C]tazarotene, in a gelatin capsule. Blood levels of radioactivity peaked 2 h postdose and then rapidly declined.

Pharmacogenomic considerations in drug delivery.

Successful drug delivery will achieve an appropriate drug concentration at the target to elicit a desired level of response. The concentration of circulating free drug is dependent upon the pharmacokinetic processes of absorption, distribution, metabolism and elimination. The response usually results from interaction of a drug with a target protein.

Cytochrome P450 2C8 and flavin-containing monooxygenases are involved in the metabolism of tazarotenic acid in humans.

Upon oral administration, tazarotene is rapidly converted to tazarotenic acid by esterases. The main circulating agent, tazarotenic acid is subsequently oxidized to the inactive sulfoxide metabolite. Therefore, alterations in the metabolic clearance of tazarotenic acid may have significant effects on its systemic exposure.