Population pharmacokinetics of pegaptanib in patients with neovascular, age-related macular degeneration.

The anti-vascular endothelial growth factor (VEGF) aptamer pegaptanib is eliminated primarily by renal clearance. Because renal function declines with age, pegaptanib exposure in patients with age-related macular degeneration (AMD) may increase. Therefore, a population pharmacokinetic (PK) analysis of pegaptanib was undertaken in Western and Asian AMD patients to determine the influence of renal function on apparent pegaptanib clearance (CL). Pegaptanib (0.3-3 mg per eye) was administered every 4 to 6 weeks to 262 AMD patients in 4 studies. Pegaptanib exposures (area under the concentration-time curve [AUC] and maximum plasma concentration) after 8 doses were similar to exposures following the first dose, consistent with the absence of plasma accumulation. A 1-compartment model parameterized in terms of the absorption rate constant, apparent volume of distribution, and CL was used to describe the pegaptanib plasma concentration data. Creatinine clearance (CLCR), body weight (WT), and age influenced pegaptanib PK. Decreasing CLCR from 70 to 30 mL/min doubled AUC. After adjustment for CLCR, WT, and age, the model predicted no race differences in CL or AUC. Given that the therapeutic 0.3 mg per eye dose of pegaptanib results in exposures one-tenth of those observed following the well-tolerated 3-mg dose, these results suggest that no dose adjustment is warranted for AMD patients with moderate renal insufficiency (CLCR >30 mL/min).