Assessment of in vivo pharmacokinetics following topical administration (eye-drop) using PET and a radiolabeled drug for macular degeneration treatment

Objectives Examination of drug delivery and excretion in the early stage of drug development is critical to predict viability of investigational new drugs with topical administration route. Here we assessed in vivo whole-body organ and regional eyeball pharmacokinetics (PK) of ¹⁸F-labeled new drug candidate for age-related macular degeneration treatment, [¹⁸F]CK41016, following eye-dropping using an animal dedicated PET/CT system.

Methods [¹⁸F]CK41016 in form of eye-drop (E-[¹⁸F]CK41016, injected dose = ~50 µCi) was administered into the right eyeball of the SD rats (whole-body PK study) and NZW rabbits (regional eyeball PK study) then the animals underwent PET studies for 8 h. Whole-body organs- and eyeball regions-of-interest (aqueous humor, cornea, vitreous and retina) were delineated on the PET-CT fused images. PK of the E-[¹⁸F]CK41016 was assessed in terms of T_max, C_max, AUC and T_1/2.

Results Distribution of the E-[¹⁸F]CK41016 was well visualized in the whole-body organs of SD rats and eyeball regions of NZW rabbits. E-[¹⁸F]CK41016 showed tissue clearance of T_1/2 = 8 h at the eyeball. The drug attained the peak concentration in the pulmonary (the lung) and systemic circulation (the heart) within 2 h after the eye-dropping (T_max = 120 - 130 min). Accumulation of E-[¹⁸F]CK41016 in the urinary bladder and the intestine with the peak concentration (C_max) of 1 - 2%ID/g suggested the fecal and urine excretion of the eye-dropped drug. In NZW rabbit’s eyeball, E-[¹⁸F]CK41016 was mainly accumulated in the aqueous humor (T_max = 90 - 110 min, T_1/2 = 290 - 310 min).

Conclusions In the present study, we successfully characterized in vivo PK of an investigational new drug for age-related macular degeneration treatment in form of eye-drop using PET. Data demonstrated that the application of PET and radiolabeled drug provide valuable information also for drugs with topical administration route.