Sr Scientist Boehringer Ingelheim Ridgefield, Connecticut, United States
Disclosure(s):
Xianwei Zhang: No financial relationships to disclose
Objectives: BI-S is engineered as a potent and specific complement C3 inhibitor to treat geographic atrophy (GA). It is a polypeptide with molecular weight about 26 kDa. The KD is approximately 0.3 nM by surface plasmon resonance (SPR) analysis. The pharmacokinetics (PK) of total BI-S in the blood and the aqueous humor after intravenous (IV) administration were explored to investigate its capability to cross the blood-ocular barrier (BOB). The total target concentration in the blood was also measured. Simulations were conducted to estimate the BI-S permeability cross the BOB.
Methods: The PK of BI-S in cynomolgus monkeys blood and aqueous humor was characterized following single dose of 0.1, 1, and 15 mg/kg via IV injection. Compartmental modeling of BI-S PK-PD was performed to estimate the permeability of BI-S across the BOB. The compartment model includes both the systemic circulation as well as the ocular tissues. Parameters were either from literature or calibration.
Results: BI-S systemic and ocular exposure increased with dose across the dose range of 0.1 to 15 mg/kg following IV injection of BI-S. The total target concentration was stable over the study period. A multi-compartment PK model with linear and target-mediated clearance was used to describe the data. The permeability across BOB was estimated.
Conclusions: Large biologics, such as BI-S, can move from the systemic circulation to the ocular tissues. This transport phenomenon has been investigated using BI-S. This work has helped us to evaluate the impact of unilateral IVT injection to the fellow eye and the impact of IV injection to the eyes.
