PET imaging of α-galactosidase A pharmacokinetics in rats and monkeys

Objectives A human a-galactosidase A (aGal) has been developed for therapy of Fabry disease, a genetic deficiency resulting in accumulation of a-Gal substrate Gb3 throughout the body, which leads to debilitating tissue damage. Renal failure is the principal cause of death. Renal cells are the principal target for enzyme replacement therapies; currently they are administered by IV infusion. Our objective was to determine whether SC route is suitable for administration of aGal.

Methods aGal was labeled with ¹²⁴I with preservation of the active dimeric form. [¹²⁴I]a-Gal was administered IV and SC in rats (n=24, 0.25 mCi/animal) and cynomolgus monkeys (n=8, 1 mCi/animal) at 1 mg/kg in a variety of dosing schedules. Dynamic imaging data and multiple static images were acquired over 8d post injection to determine the PK parameters.

Results After IV administration, the blood kinetics of aGal in both rats and monkeys were found to be monoexponential, with blood ½ lives of 3.5 and 6.2 min, respectively. Uptake from the SC site was biexponential, with ½ uptake time of 6h for the major fraction in both species and 80±20 h for the residual fraction. In both species, >90% of the SC dose reached the systemic circulation; a minor fraction was deposited in the sentinel lymph nodes. Renal AUC of a-Gal after SC administration was ~ 50% and 75% of that following IV administration in monkeys and rats, respectively.

Conclusions Although the PK of aGal after IV and SC administration differ appreciably, both administrations show high renal accumulation, suggesting feasibility of the SC administration route.