June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Pharmacologic profile and distribution of CKLP1, a novel prodrug of the ATP sensitive potassium channel opener levcromakalim, following various modes of administration
Author Affiliations & Notes
  • Uttio Roy Chowdhury
    Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States
  • Rachel A Kudgus
    Oncology Research, Mayo Clinic, Rochester, Minnesota, United States
  • Tommy A. Rinkoski
    Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States
  • Joel M Reid
    Oncology Research, Mayo Clinic, Rochester, Minnesota, United States
  • Michael P Fautsch
    Ophthalmology, Mayo Clinic, Rochester, Minnesota, United States
  • Footnotes
    Commercial Relationships   Uttio Roy Chowdhury, None; Rachel Kudgus, None; Tommy Rinkoski, None; Joel Reid, None; Michael Fautsch, None
  • Footnotes
    Support  : NIH grant EY21727, MN Partnership for Biotechnology and Medical Genomics, Research to Prevent Blindness, and Mayo Foundation
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4595. doi:
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      Uttio Roy Chowdhury, Rachel A Kudgus, Tommy A. Rinkoski, Joel M Reid, Michael P Fautsch; Pharmacologic profile and distribution of CKLP1, a novel prodrug of the ATP sensitive potassium channel opener levcromakalim, following various modes of administration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4595.

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

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Abstract

Purpose : To evaluate the pharmacologic profile and distribution of CKLP1 following intravenous and topical eye administration.

Methods : CKLP1 and its active parent compound levcromakalim were evaluated in blood, plasma, aqueous humor, vitreous humor and selected tissues (brain, heart, kidney, liver, lung, muscle) by LC/MS/MS, following intravenous (IV; single injection, 0.25 mg/kg, n=6) and short (50 ul of a 10 mM solution, once daily for 8 days, n=12) or long term ( 50 ul of a 10 mM solution, once daily for 90 days, n=6) topical eye treatment in female Dutch belted pigmented rabbits. IOP in the topically treated animals was measured with a hand held rebound tonometer 3 times daily during the short treatment period and twice weekly for the long-term treatment study. Necropsy was performed on all animals and histology was assessed masked in ocular and non-ocular tissue samples.

Results : Following IV and topical administration, CKLP1 was rapidly converted into its active parent compound levcromakalim. In IV treated animals, CKLP1 and levcromakalim showed an average terminal half-life in plasma of 61.8 ± 55.2 min and 85.0 ± 37.3 min respectively. Mean maximum plasma concentration of levcromakalim was 10.6 ng/ml at 1h and 5.9 ng/ml by 8 h. In the short-term topical treatment group, the mean terminal half-life was 30 min for CKLP1 and 2 h for levcromakalim. Maximum plasma concentration of levcromakalim was 0.62 ng/ml at 4 h. Average concentration of levcromakalim was 0.15 ng/ml and 0.13 ng/ml in aqueous and vitreous humor respectively, while CKLP1 was below quantifiable levels. Long term topical treatment with CKLP1 resulted in significant IOP reduction (14.1 ± 1.0%, p<0.0001). No significant pathology was noted in any of the studied ocular and non-ocular tissues. Following 90 days of topical treatment, CKLP1 was detected in kidney (15.8 ng/ml, n=6) while levcromakalim was only detected in lung (1.6 ng/ml, n=6) and liver (5.9 ng/ml, n=4).

Conclusions : The prodrug CKLP1 is readily converted to its active parent compound levcromakalim following intravenous and topical eye administration. Long-term treatment results in significant reduction in IOP with no apparent toxicity to ocular and non-ocular tissues.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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