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Hans van der Heiden, Thierry Amar, Willem Frans Lichtenauer; Plasma and ocular pharmacokinetic study comparing 3 µL micro-drop to typical 40 µL drop volume of timolol 0.5% in pigmented rabbits.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):453.
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Systemic exposure of timolol can induce serious side effects and lead to reduced compliance in glaucoma patients. A reduction of the eye-drop volume and thus the amount of medication delivered to the eye could lead to a serious reduction of the systemic exposure. This pharmacokinetic study investigated the level of timolol in the aqueous humor and plasma in pigmented rabbits after administration of a 0.5% timolol eye-drop of 3 µL versus a regular eye-drop of 40 µL. The purpose was to study whether a micro-drop of timolol leads to reduced systemic exposure and will yet create quantifiable timolol levels in the eye.
Thirty (30) pigmented HY79b rabbits were randomly divided into 5 groups of 3 animals corresponding to 5 time-points (0.5, 1, 2, 4, and 8 hours). A single dose of 0.5% timolol was instilled onto the cornea of both eyes in a volume of either 40 µL or 3 µL. Plasma was sampled at all time-points; as well as aqueous humor from both eyes. The timolol content was determined by RRLC-MS/MS.
The exposure of the aqueous humor, as determined by the area under the curve (AUC), was 328 versus 1091 ng/mL/24 h with 3 µL 0.5% timolol versus the 40 µL 0.5% timolol instillation. In plasma, timolol levels were in the ng/mL range, peaked at 0.5 h after instillation and dropped below the LLOQ after 8 h. The peak level of timolol in plasma was 0.8 ng/mL after 3 µL 0.5% timolol versus 8.8 ng/mL after 40 µL 0.5% timolol instillation. The systemic exposure, as determined by the AUC for plasma, was 0.5 ng/mL/24 h with 3 µL 0.5% timolol versus 8.6 ng/mL/24 h for 40 µL 0.5% timolol instillation. Timolol was eliminated from plasma and aqueous humor, with half-lives ranging from 0.4 to 1.3 h.
After a single 3 µL micro-drop of 0.5% timolol vs a 40 µL typical drop, plasma levels of timolol were reduced by a factor of 17, while the aqueous humor levels were reduced by a factor of 3.3. Systemic exposure of timolol can be reduced by installing smaller eye-drops while quantifiable levels of timolol remain in the aqueous humor.
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