Title:A Low Concentration of Tacrolimus/Semifluorinated Alkane (SFA) Eyedrop Suppresses Intraocular Inflammation in Experimental Models of Uveitis
VOLUME: 17 ISSUE: 3
Author(s):S. De Majumdar, M. Subinya, J. Korward, A. Pettigrew, D. Scherer and H. Xu*
Affiliation:The Wellcome-Wolfson Institute of Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, Formulation Development, Novaliq GmbH, Im Neuenheimer Feld 515, DE-69120 Heidelberg, Preclinical Development, Novaliq GmbH, Im Neuenheimer Feld 515, DE-69120 Heidelberg, Formulation Development, Novaliq GmbH, Im Neuenheimer Feld 515, DE-69120 Heidelberg, Formulation Development, Novaliq GmbH, Im Neuenheimer Feld 515, DE-69120 Heidelberg, The Wellcome-Wolfson Institute of Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, BT9 7BL, Belfast
Keywords:Tacrolimus, semifluorinated alkane, uveitis, intraocular inflammation, eyedrop, pharmacolinetic.
Abstract:Purpose: Corticosteroids remain the mainstay therapy for uveitis, a major
cause of blindness in the working age population. However, a substantial number of
patients cannot benefit from the therapy due to steroids resistance or intolerance.
Tacrolimus has been used to treat refractory uveitis through systemic administration. The
aim of this study was to evaluate the therapeutic potential of 0.03% tacrolimus eyedrop
in mouse models of uveitis.
Methods: 0.03% tacrolimus in perfluorobutylpentane (F4H5) (0.03% Tacrolimus/SFA)
was formulated using a previously published protocol. Tacrolimus suspended in PBS
(0.03% Tacrolimus/PBS) was used as a control. In addition, 0.1% dexamethasone (0.1%
DXM) was used as a standard therapy control. Endotoxin-induced uveitis (EIU) and
experimental autoimmune uveoretinitis (EAU) were induced in adult C57BL/6 mice using
protocols described previously. Mice were treated with eyedrops three times/day
immediately after EIU induction for 48 h or from day 14 to day 25 post-immunization (for
EAU). Clinical and histological examinations were conducted at the end of the
experiment. Pharmacokinetics study was conducted in mice with and without EIU. At
different times after eyedrop treatment, ocular tissues were collected for tacrolimus
measurement.
Results: The 0.03% Tacrolimus/SFA eyedrop treatment reduced the clinical scores and
histological scores of intraocular inflammation in both EIU and EAU to the levels similar
to 0.1% DXM eyedrop treatment. The 0.03% Tacrolimus/PBS did not show any
suppressive effect in EIU and EAU. Pharmacokinetic studies showed that 15 min after
topical administration of 0.03% Tacrolimus/SFA, low levels of tacrolimus were detected
in the retina (48 ng/g tissue) and vitreous (2.5 ng/ml) in normal mouse eyes, and the
levels were significantly higher in EIU eyes (102 ng/g tissue in the retina and 24 ng/ml in
the vitreous). Tacrolimus remained detectable in intraocular tissues of EIU eyes 6 h after
topical administration (68 ng/g retinal tissue, 10 ng/ml vitreous). Only background levels
of tacrolimus were detected in the retina (2-8 ng/g tissue) after 0.03% Tacrolimus/PBS
eyedrop administration.
Conclusion: 0.03% Tacrolimus/SFA eyedrop can penetrate ocular barrier and reach
intraocular tissue at therapeutic levels in mouse eyes, particularly under inflammatory
conditions. 0.03% Tacrolimus/SFA eyedrop may have therapeutic potentials for
inflammatory eye diseases including uveitis.
