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Jennifer Seal, Werhner Orilla, Edward Chow, James A Burke, Jie Shen; Interspecies Comparison of Small Molecule Distribution Into the Anterior Chamber Following Intravitreal Administration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):439. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Drug delivery of small molecules via intravitreal (IVT) administration has been beneficial for the treatment of retinal diseases. Besides rabbit studies, the nonclinical pharmacokinetics (PK) and safety of such therapeutics are often characterized in a higher species (dog or monkey). The species selection may be based on several factors including drug distribution pattern into the anterior chamber (AC). The purpose of these studies was to understand interspecies differences in distribution of IVT small molecules to the AC and to determine which species best represented human.
Following IVT injection of 0.05% sodium fluorescein (NaFl), 300 µg beclamethasone dipropionate (BDP) suspension, or 4 mg triamcinolone acetonide (TA) suspension to rabbit, dog, monkey, and pig (TA only), aqueous humor (AH) concentrations were measured up to 6 months post dose using a Fluorotron (NaFl) or liquid chromatography tandem mass spectrometry (BDP and TA). Nonclinical AH TA concentrations were compared to human AH concentrations obtained from a published clinical study following IVT dose of 4 mg TA.
1) Maximal AH concentrations (Cmax) of NaFl in dogs were 9x and 30x higher than in monkey and rabbit, respectively.2) The AH Cmax for BDP in dogs was 1500x and 11,000x higher than in monkey and rabbit, respectively. Concentrations in dogs reached ~10 µg/mL and remained above the BDP solubility limit (0.2 µg/mL) for ~14 days.3) The AH Cmax for TA in dogs was 2x, 4x, 40x, and 70x higher than human, monkey, pig, and rabbit, respectively. However, TA was more rapidly cleared from the dog AH than in the other species. Due to this rapid clearance, AH AUC rank ordering was human > monkey > dog > pig > and rabbit. Overall, monkey AH TA concentrations most closely approximated human exposure (Cmax and AUC).
Following IVT administration of all tested molecules the AH Cmax rank ordering was dog > monkey > rabbit, though the relative magnitude of exposure varied. For TA, the dog data overestimated human AH Cmax but underestimated AUC. These studies indicate that while rabbit is a common animal model for PK evaluation of IVT drugs, interpretation of drug distribution to the AC needs caution especially if AC exposure is an important safety concern. Overall, monkey may be the more appropriate higher species for IVT drug development.
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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