In Vivo Ocular Pharmacokinetics and Toxicity of Siponimod in Albino Rabbits

Mol Pharm. 2024 Jul 1;21(7):3310-3320. doi: 10.1021/acs.molpharmaceut.4c00063. Epub 2024 Jun 10.

Abstract

Siponimod is a promising agent for the inhibition of ocular neovascularization in diabetic retinopathy and age-related macular degeneration. Siponimod's development for ophthalmological application is hindered by the limited information available on the drug's solubility, stability, ocular pharmacokinetics (PK), and toxicity in vivo. In this study, we investigated the aqueous stability of siponimod under stress conditions (up to 60 °C) and its degradation behavior in solution. Additionally, siponimod's ocular PK and toxicity were investigated using intravitreal injection of two different doses (either 1300 or 6500 ng) in an albino rabbit model. Siponimod concentration was quantified in the extracted vitreous, and the PK parameters were calculated. The drug half-life after administration of the low and high doses was 2.8 and 3.9 h, respectively. The data obtained in vivo was used to test the ability of published in silico models to predict siponimod's PK accurately. Two models that correlated siponimod's molecular descriptors with its elimination from the vitreous closely predicted the half-life. Furthermore, 24 h and 7 days after intravitreal injections, the retinas showed no signs of toxicity. This study provides important information necessary for the formulation and development of siponimod for ophthalmologic applications. The short half-life of siponimod necessitates the development of a sustained drug delivery system to maintain therapeutic concentrations over an extended period, while the lack of short-term ocular toxicity observed in the retinas of siponimod-treated rabbits supports possible clinical use.

Keywords: age-related macular degeneration; diabetes mellitus; intravitreal administration; neovascularization; ocular half-life; siponimod degradation; siponimod stability.

MeSH terms

  • Angiogenesis Inhibitors / administration & dosage
  • Angiogenesis Inhibitors / pharmacokinetics
  • Angiogenesis Inhibitors / toxicity
  • Animals
  • Azetidines* / administration & dosage
  • Azetidines* / pharmacokinetics
  • Benzyl Compounds
  • Diabetic Retinopathy / drug therapy
  • Eye / drug effects
  • Eye / metabolism
  • Half-Life
  • Intravitreal Injections*
  • Macular Degeneration / drug therapy
  • Male
  • Rabbits
  • Retina / drug effects
  • Retina / metabolism
  • Solubility
  • Vitreous Body / drug effects
  • Vitreous Body / metabolism

Substances

  • Azetidines
  • siponimod
  • Angiogenesis Inhibitors
  • Benzyl Compounds