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M. Patel, L. Whitfield, M. Hutmacher, K. Kowalski, P. Burger, B. Dessalegn, M. Modi, Macugen Study Group; Population Pharmacokinetics/Pharmacodynamics (PK/PD) of Pegaptanib Sodium (Macugen®) in Patients with Age–Related Macular Degeneration (AMD) . Invest. Ophthalmol. Vis. Sci. 2006;47(13):2623.
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To describe pegaptanib PK in patients with AMD, to assess patient factors or covariates (i.e., predictors) that influence PK, and to evaluate the relationship between pegaptanib exposure and visual acuity (PD).
Intravitreous doses of 1 or 3 mg/eye were administered every 4 or 6 weeks. Serial blood samples were collected for plasma pegaptanib concentrations throughout a 3–month or 1– year period. Data from 168 patients enrolled in 2 phase 1/2 clinical trials and a phase 2 safety study were pooled to model pegaptanib PK and PD. A 1–compartment model parameterized in terms of an absorption rate constant representing the transfer of pegaptanib from the eye compartment to the systemic circulation, the apparent steady–state volume of distribution (V), and the apparent clearance (CL) was developed to describe pegaptanib PK. The exposure–response (E–R) relationship between pegaptanib exposure and visual acuity was modeled in an exploratory fashion. Baseline demographics, disease characteristics and the use of photodynamic therapy (PDT) were evaluated as potential covariates for population PK and PD parameters. The full models were subjected to the Wald’s Approximation Method procedure to develop final and more parsimonious models.
Creatinine clearance (CLCR) was a predictor of pegaptanib CL. Patients with lower CLCR had higher pegaptanib plasma concentrations. Weight (WGT) was also a predictor of CL, with lower WGT associated with higher pegaptanib plasma concentrations. However, a less than proportional increase in CL is expected as a function of WGT or CLCR. After taking into account the effects of CLCR and WGT, age, gender, and PDT did not influence CL. Estimated V was 3.3 liters. Mean apparent half–life was 8 ± 7 days. An E–R relationship could not be established as doses tested were at the plateau of the dose–response curve. A model–based analysis indicated no effect of PDT on visual acuity.
Given these relationships and the excellent safety profile of pegaptanib sodium at doses 3– to 10–fold higher than the recommended 0.3 mg/eye dose, a dosage adjustment for patients with CLCR >20 mL/min and WGT > 39 kg is not needed. Mean apparent half–life was consistent with the previously reported value of 10 ± 4 days.
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