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Ocular Pharmacokinetics of a Topical Ophthalmic Nanomicellar Solution of Cyclosporine (Cequa®) for Dry Eye Disease

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Abstract

Cequa®, a unique and first-in-class preservative free cyclosporine-A (CsA) nanomicellar topical formulation was recently approved by US FDA for treatment of dry eye disease or keratoconjuntivitis sicca (KCS). Being highly hydrophobic, CsA is currently available as an oil based emulsion, which has its own shortcomings. Developing an aqueous and clear formulation of CsA is imperative yet a challenging need in the quest for a safe and better drug product. In this regard, a novel, clear, aqueous nanomicellar solution of CsA was developed which has the potential to deliver therapeutic concentrations of CsA with minimal discomfort to patients. Highly promising pre-clinical results of Cequa® (OTX-101), has led to its advancement to the clinical trials. Phase III clinical trials have demonstrated that OTX-101 is highly effective, safe, and has a rapid onset of action in treating KCS. This review presents a comprehensive insight on formulation development, preclinical and clinical pharmacokinetic results of Cequa®. Additionally, the translational development of Cequa® from the laboratory benchtop to patient bedside has been discussed.

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Abbreviations

APCs:

Antigen presenting cells

AUC:

Area under curve

BSS:

Balanced salt solution

CaN:

Calcineurin

CAPIR:

Circulation, accumulation, penetration, internalization and release

CMC:

Critical micelle concentration

CsA:

Cyclosporine

FK:

Filamentary keratitis

ICAM-1:

Intercellular adhesion molecule 1

IC:

Impression cytology

IL-2:

Interleukin 2

IOP:

Intraocular pressure

KCS:

Keratoconjunctivitis sicca

LFU:

Lacrimal functional unit

MGD:

Meibomian gland dysfunction

MMP-9:

Matrix metallopeptidase 9

MPTP:

Mitochondrial permeability transition pore

NF-ATc:

Cytoplasmic component of nuclear factor of activated T cells

NF-ATn:

Nuclear component of nuclear factor of activated T cells

PEG:

Polyethylene glycol

PK:

Pharmacokinetics

VCAM-1:

Vascular cell adhesion molecule-1

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Acknowledgements and Disclosures

The authors would like to acknowledge the contributions of Dr. Kishore Cholkar and Dr. Brian C. Gilger for the pharmacokinetic portions of the pre-clinical studies. The authors also acknowledge Joseph Tauber (Tauber Eye Centre), Sidney L. Weiss (Auven Therapeutics), William Kramer (Kramer consulting LLC) and Poonam Velagaleti (I-novion, Inc.) for their contributions in the various phases of the clinical studies. Authors also acknowledge Ocular Technologies Sarl (now wholly owned subsidiary of Sun Pharmaceutical Industries) and Sun Pharmaceutical Industries for sponsoring, conducting, monitoring and analyzing the clinical studies.

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Authors and Affiliations

  1. Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri, 2464 Charlotte Street, Kansas City, MO, 64108, USA

    Abhirup Mandal, Vrinda Gote, Dhananjay Pal & Ashim K. Mitra

  2. Sun Pharmaceutical Industries Ltd., Sun Ophthalmics Inc., 2 Independence Way, Princeton, NJ, 08540, USA

    Abayomi Ogundele

  3. Department of Ophthalmology, School of Medicine, University of Missouri, Kansas City, MO, USA

    Ashim K. Mitra

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  1. Abhirup Mandal
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Mandal, A., Gote, V., Pal, D. et al. Ocular Pharmacokinetics of a Topical Ophthalmic Nanomicellar Solution of Cyclosporine (Cequa®) for Dry Eye Disease. Pharm Res 36, 36 (2019). https://doi.org/10.1007/s11095-018-2556-5

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