June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Nonclinical Pharmacokinetics, Distribution and Excretion of 125I-KSI-301 after Intravenous Administration in Rats
Author Affiliations & Notes
  • Hong Liang
    Kodiak Sciences Inc, Palo Alto, California, United States
  • John Sinclair
    Kodiak Sciences Inc, Palo Alto, California, United States
  • Elizabeth Spencer
    Covance Laboratories, Wisconsin, United States
  • Matthew Parloto
    Covance Laboratories, Wisconsin, United States
  • Craig Struble
    Covance Laboratories, Wisconsin, United States
  • Victor Perlroth
    Kodiak Sciences Inc, Palo Alto, California, United States
  • Footnotes
    Commercial Relationships   Hong Liang Kodiak Sciences Inc., Code E (Employment); John Sinclair Kodiak Sciences Inc., Code E (Employment); Elizabeth Spencer Covance Laboratories, Code E (Employment); Matthew Parloto Covance Laboratories, Code E (Employment); Craig Struble Covance Laboratories, Code E (Employment); Victor Perlroth Kodiak Sciences Inc., Code E (Employment)
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 2606. doi:
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    • Get Citation

      Hong Liang, John Sinclair, Elizabeth Spencer, Matthew Parloto, Craig Struble, Victor Perlroth; Nonclinical Pharmacokinetics, Distribution and Excretion of 125I-KSI-301 after Intravenous Administration in Rats. Invest. Ophthalmol. Vis. Sci. 2023;64(8):2606.

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

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Abstract

Purpose : KSI-301 is an anti-VEGF antibody biopolymer conjugate designed for long durability treatment of retinal vascular diseases and a molecular weight of 950 kilodaltons. The pharmacokinetics (PK), distribution, and excretion after single or repeat intravenous (IV) administration of 125I-KSI-301 was assessed in pigmented Long Evans (LE) rats. In addition, size exclusion chromatography (SEC) profiling of 125I-KSI-301 and its metabolites were evaluated in samples of serum and urine.

Methods : Groups of female LE rats were administered a single or repeated (days 1, 3, 5, and 8) IV injection of 125I-KSI-301 at doses of 0.2 or 1.0 mg/kg (total radioactivity of 150 µCi/kg/animal). Blood and tissues were collected (3 animals/group) at 1, 24, 72, 168, and 336 hr post-dose (single dose groups) and 1, 24, 72, and 168 hr post-last dose (repeated dose groups). Urine and feces were collected at defined intervals. Samples were analyzed for radioactivity and mass balance analysis conducted. PK parameters of mean blood and serum concentrations were calculated by noncompartmental analysis. Pooled samples of serum and urine per group were analyzed for radioactivity metabolite profiles by SEC.

Results : Exposure measured in serum of 125I-KSI-301 was 2-fold greater than dose proportional in the 1.0 vs 0.2 mg/kg dose group with a slower clearance. In serum after repeated dosing, there was little systemic accumulation. The steady state volume of distribution after a single or repeated dose indicated that 125I-KSI-301 was not highly distributed into tissues, which was also confirmed by the low levels of radioactivity detected in tissues. Exposure in tissues was highest at 1 hr post-dose and declined over time with little to no accumulation. The majority of the radioactivity was eliminated through the urine. The metabolite profile in serum indicated the main circulating component was full length 125I-KSI-301, which demonstrated stability over the duration of the study. The metabolite profile in urine indicated the main component was low MW and associated with catabolism of 125I-KSI-301 and release of free 125I during elimination.

Conclusions : Despite its large size, KSI-301 is rapidly eliminated from the systemic circulation and is primarily excreted in the urine with little to no tissue accumulation. KSI-301 was stable as a conjugate and remained intact in the systemic circulation.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.

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