PHARMACOKINETIC RATIONALE FOR DOSING EVERY 2 WEEKS VERSUS 4 WEEKS WITH INTRAVITREAL RANIBIZUMAB, BEVACIZUMAB, AND AFLIBERCEPT (VASCULAR ENDOTHELIAL GROWTH FACTOR TRAP-EYE)

Purpose: Monthly dosing with inhibitors of vascular endothelial growth factor (VEGF) results in stable or improved visual acuity in most patients with neovascular age-related macular degeneration. However, a minority of patients show little if any response to therapy with persistent or worsening macular fluid. Pharmacokinetic modeling was performed to determine if more frequent dosing with anti-VEGF drugs could be theoretically beneficial. Methods: A mathematical model comparing the time-dependent relative binding activities of ranibizumab, bevacizumab, and aflibercept (VEGF Trap-eye; VTE) was used to determine the theoretical peak and trough binding activities when the drugs were injected every 14 days and every 28 days. The intravitreal half-lives of ranibizumab, bevacizumab, and the VTE were estimated to be 3.2, 5.6, and 4.8 days, respectively. The relative molar binding activities of ranibizumab, bevacizumab, and the VTE used in the analyses were 1, 0.05 to 0.2, and 140, respectively. The expected peak and trough binding activities for ranibizumab, bevacizumab, and VTE were calculated. Dosing every 2 weeks was performed on selected patients who had a poor response to monthly therapy. Results: Dosing of a drug every 2 weeks resulted in markedly improved trough binding activity, but had little impact on the peak binding activity when calculated through Day 28. The dosing of bevacizumab every 2 weeks resulted in trough binding levels that were superior to monthly dosing with ranibizumab at a dose of 0.5 mg and potentially superior to the levels achieved when ranibizumab was dosed monthly at a dose of 2.0 mg. The VTE displayed superior binding levels for both peak and trough levels even when compared with ranibizumab doses given every 2 weeks. Two case reports demonstrate the clinical usefulness of dosing with anti-VEGF therapy every 2 weeks in eyes with VEGF-dependent macular fluid appearing to be refractory to monthly dosing. Conclusion: The theoretical increase in trough binding levels when anti-VEGF drugs are dosed every 2 weeks most likely explains the clinical benefit observed in patients who received biweekly injections after their poor response to monthly therapy. The short-term use of biweekly dosing may be an attractive treatment option for those eyes that show a treatment response within 2 weeks of an injection, but rebound with increased macular fluid after a month. In the future, VTE should provide higher trough levels of anti-VEGF binding activity and eliminate the need for biweekly dosing in those eyes with VEGF-mediated exudation that appear unresponsive to monthly ranibizumab or bevacizumab. RETINA 32: 434-457, 2012