The in vivo release profile of the DEX implant in an animal eye was similar to the pharmacokinetics achieved with pulse administration of corticosteroids (high initial drug concentration, followed by a prolonged period of low concentration). These results are consistent with those in clinical studies supporting the use of the DEX implant for the extended management of posterior segment diseases.

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. The aim of this publication is to serve as a tutorial for conducting FIH trials for both small molecule and biological drug candidates with topics covering regulatory requirements, preclinical safety testing, study design considerations, safety monitoring, biomarker assessment, and global considerations. An emphasis is placed on FIH trial design considerations, including starting dose selection, study size and population, dose escalation scheme, and implementation of adaptive designs. In light of the recent revision of the European Medicines Agency (EMA) guideline on FIH trials to promote safety and mitigate risk, we also discuss new measures introduced in the guideline that impact FIH trial design.

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 0.03% previously were shown to have similar intraocular pressure-lowering effects in humans in a phase 1/2 clinical trial.Methods: Twenty-four beagle dogs received either once-daily topical bimatoprost 0.03% for 7 days or a bilateral intracameral administration of Bimatoprost SR (15 μg). At predetermined time points, ocular tissues were collected and concentrations of bimatoprost and bimatoprost acid were quantified using liquid chromatography–tandem mass spectrometry.Results: Bimatoprost SR administration enhanced delivery of study drug to a site of action [iris–ciliary body (ICB)] compared with topical bimatoprost (Cmax [bimatoprost+bimatoprost acid] = 18,200 and 4.13 ng/g, respectively). However, distribution of drug to tissues associated with prostaglandin analog (PGA)-related side effects (i.e., bulbar conjunctiva, eyelid margins, and periorbital fat) was limited following Bimatoprost SR administration (Cmax [bimatoprost+bimatoprost acid] = BLQ [beneath the limit of quantitation] to 0.354 ng/g) compared with topical dosing (Cmax [bimatoprost+bimatoprost acid] = 36.6–2,110 ng/g).Conclusions: Bimatoprost SR administration in dogs selectively delivered drug to the ICB with low or undetectable drug levels in ocular surface and extraocular tissues. Use of Bimatoprost SR for glaucoma treatment may reduce the incidence of adverse events typically associated with topical PGAs by targeting bimatoprost delivery to the key site of action of the PGA class and reducing exposure to off-target tissues.

Sulfogalactosylglycerolipid (SGG) is the major sulfoglycolipid of mammalian male germ cells. Like other sulfoglycolipids, SGG is believed to be involved in cell-cell/extracellular matrix adhesion. Specifically, we investigated whether sperm SGG played a role in sperm-egg interaction. Initially, we produced an affinity-purified, rabbit polyclonal immunoglobulin (Ig) G antibody that specifically recognized SGG (anti-SGG). Indirect immunofluorescence using anti-SGG IgG localized SGG to the convex and concave ridges and the postacrosome of the mouse sperm head. Pretreatment of sperm with anti-SGG IgG/Fab inhibited sperm-zona pellucida (ZP) binding in vitro in a concentration-dependent manner (to a maximum of 62%). This inhibition was observed at the level of primary binding. Sperm treated with anti-SGG IgG underwent the spontaneous and ZP-induced acrosome reaction at the same rate as control sperm treated with preimmune rabbit serum IgG. Fluorescently labeled SGG liposomes were shown to associate specifically with the egg ZP, whereas fluorescently labeled liposomes of galactosylglycerolipid (SGG's parental lipid) and phosphatidylserine (negatively charged like SGG) did not. Furthermore, coincubation of SGG liposomes with sperm and isolated ZP inhibited sperm-ZP binding in a concentration-dependent manner. These results strongly suggest an involvement of sperm SGG in direct binding to the ZP.