April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Plasma and ocular pharmacokinetic study comparing 3 µL micro-drop to typical 40 µL drop volume of timolol 0.5% in pigmented rabbits.
Author Affiliations & Notes
  • Hans van der Heiden
    mu-Drop, Apeldoorn, Netherlands
    ZAMB, Hospital Pharmacy, Tilburg, Netherlands
  • Thierry Amar
    Iris Pharma, La Gaude, France
  • Willem Frans Lichtenauer
    mu-Drop, Apeldoorn, Netherlands
  • Footnotes
    Commercial Relationships Hans van der Heiden, mu-Drop BV (E), mu-Drop BV (P); Thierry Amar, None; Willem Lichtenauer, mu-Drop BV (E)
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 453. doi:https://doi.org/
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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. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: 503 drug toxicity/drug effects • 675 receptors: pharmacology/physiology • 427 aqueous  
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