Tolerability and pharmacokinetics of intravitreal sirolimus.
OBJECTIVE
To evaluate the pharmacokinetics (PK) and tolerability of a proprietary sirolimus depot-forming ocular formulation in rabbits and humans after a single intravitreal (i.v.t.) injection.


METHODS
New Zealand White (NZW) rabbits were intravitreally injected in both eyes with an injectable formulation in 5 (3 PK and 2 tolerability) studies. The rabbits received up to approximately 220 μg sirolimus per eye. At the desired timing post-injection, the animals were euthanized; both eyes were enucleated, frozen, and dissected to separate sclera, retina/choroid, and vitreous humor (VH). Whole blood (WB) samples were obtained at each time point before euthanasia. In clinical trials, patients received an i.v.t. injection of approximately 352 μg sirolimus. Sirolimus concentrations in ocular tissues and WB samples were measured using liquid chromatography/tandem mass spectrometry (LC/MS/MS). In both single- and repeat-dose tolerability studies, systemic and ocular adverse effects were evaluated.


RESULTS
After i.v.t. administration, sirolimus formed a depot in the VH. During dissolution, concentrations in VH were dose related and exhibited continuous release from the depot. This was characterized by a gradient of sirolimus concentration in the order of VH > retina/choroid > sclera > WB, and the concentrations were maintained for approximately 2 months after the i.v.t. injection. After repeat dosing (132 μg), no drug accumulation was seen in the ocular tissue or systemically. In clinical studies, the highest blood levels were <2 ng/mL at day 2, and half-time (t(1/2)) was 8-9 days. There was no accumulation at day 30 after the i.v.t. injection (up to 352 μg). Safety studies conducted on rabbits indicated good local tolerability. Sirolimus-related effects were limited to minor incipient cataract findings and mild lenticular changes. In the clinical studies where sirolimus was intravitreally administered up to 352 μg, injections were well tolerated.


CONCLUSIONS
Sustained i.v.t. delivery was achieved in a dose-dependent fashion after the i.v.t. injection of a proprietary sirolimus depot-forming ocular formulation. Across the tolerability and safety studies, no significant findings were observed for systemic and ocular tolerability. The human WB levels were well below the daily trough systemic blood level range required for systemic immunosuppression. An i.v.t. injection of sirolimus has a PK and safety profile that is favorable for treating inflammatory conditions of the eye, such as non-infectious uveitis, and warrants further investigation in humans.
Pharmaceutical and Preclinical Development Department, Santen Incorporated, Emeryville, California 94608, USA. smudumba@santeninc.com
Sri
S
Mudumba
Padma
P
Bezwada
Hitomi
H
Takanaga
Kazuhiro
K
Hosoi
Takashi
T
Tsuboi
Kenji
K
Ueda
Kouichi
K
Kawazu
Yusuf
Y
Ali
Joel
J
Naor
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002853:Chromatography, Liquid; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D058449:Intravitreal Injections; D008268:Macular Degeneration / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011817:Rabbits; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics* / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D014018:Tissue Distribution; D014822:Vitreous Body / Q000378:metabolism
D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; D020123:Sirolimus