Pharmacological Profile and Ocular Hypotensive Effects of Cromakalim Prodrug 1, a Novel ATP-Sensitive Potassium Channel Opener, in Normotensive Dogs and Nonhuman Primates
To evaluate pharmacokinetic parameters and ocular hypotensive effects of cromakalim prodrug 1 (CKLP1) in normotensive large animal models. Optimal CKLP1 concentration was determined by dose response and utilized in short- (5-8 days) and long-term (60 days) evaluation in hound dogs ( = 5) and Africa...
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Veröffentlicht in: | Journal of ocular pharmacology and therapeutics 2021-06, Vol.37 (5), p.251-260 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | To evaluate pharmacokinetic parameters and ocular hypotensive effects of cromakalim prodrug 1 (CKLP1) in normotensive large animal models.
Optimal CKLP1 concentration was determined by dose response and utilized in short- (5-8 days) and long-term (60 days) evaluation in hound dogs (
= 5) and African Green Monkeys (
= 5). Blood pressure was recorded 3-5 times per week with a tail cuff. Concentrations of CKLP1 and the parent compound levcromakalim were assessed in hound dog plasma and select tissues by LC-MS/MS after bilateral ocular treatment with CKLP1 for 8 days. Pharmacokinetic parameters were calculated from days 1, 4, and 8 data. After necropsy, histology was assessed in 43 tissue samples from each animal.
In hound dogs and African Green monkeys, 10 mM CKLP1 (optimal concentration) significantly lowered intraocular pressure (IOP) by 18.9% ± 1.1% and 16.7% ± 6.7%, respectively, compared with control eyes (
0.1). Average values for half-life of CKLP1 was 295.3 ± 140.4 min, C
10.5 ± 1.6 ng/mL, and area under the concentration vs. time curve (AUC
) 5261.4 ± 918.9 ng·min/mL. For levcromakalim, average values of half-life were 96.2 ± 27 min, C
1.2 ± 0.2 ng/mL, and AUC
281.2 ± 110.8 ng·min/mL. No significant pathology was identified.
CKLP1 lowered IOP in hound dogs and African green monkeys with no effect on systemic blood pressure. Ocular topical treatment of CKLP1 showed excellent tolerability even after extended treatment periods. |
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ISSN: | 1080-7683 1557-7732 |
DOI: | 10.1089/jop.2020.0137 |