Pharmacokinetics of Ranibizumab in Patients with Neovascular Age-Related Macular Degeneration: A Population Approach

Abstract

PURPOSE. To characterize ranibizumab pharmacokinetics in patients with AMD. METHODS.A population approach of nonlinear mixed-effect pharmacokinetic modeling based on concentration-time data from 2993 serum samples from 674 AMD patients enrolled in 5 phase 1 to 3 clinical trials of single or multiple intravitreal (ITV) doses of ranibizumab (0.3-2.0 mg/eye) administered biweekly or monthly for up to 24 months. RESULTS.A total of 696 concentration-time records from 229 subjects with one or more measurable total serum ranibizumab concentrations were analyzed. The systemic concentration-time data for ranibizumab were best described by a one-compartment model with first-order absorption into and first-order elimination from the systemic circulation. Vitreous elimination half-life (t 1/2 ) was calculated to be 9 days and the intrinsic systemic elimination t 1/2 was calculated to be approximately 2 hours. Following ITV administration, ranibizumab egresses slowly into the systemic circulation, resulting in an apparent serum t 1/2 of 9 days. Systemic-to-vitreous exposure ratio was estimated to be 1:90,000. With monthly and quarterly ITV regimens, the serum concentrations of ranibizumab at steadystate for both the 0.3 and 0.5 mg/eye dose levels were estimated to be below the range needed to inhibit VEGF-A-induced endothelial cell proliferation in vitro by 50% at all times.CONCLUSIONS. Systemic exposure to ranibizumab after ITV injection was very low due to elimination on reaching systemic circulation from the vitreous. Population pharmacokinetic analysis of data from a representative sample of AMD patients did not identify clinically significant sources or correlates of variability in ranibizumab exposure. (ClinicalTrials.gov numbers, NCT00056836, NCT00056823.) (Invest Ophthalmol Vis

A Mechanistic Pharmacokinetic/Pharmacodynamic Model of Factor D Inhibition in Cynomolgus Monkeys by Lampalizumab for the Treatment of Geographic Atrophy

“…A similar difference between the ocular and systemic half-life was noted in a TMDD model of lampalizumab in humans (Le et al, 2015), in which the vitreous half-life was 5.9 days compared with a systemic half-life of 9 hours. The shorter ocular half-life in monkeys (3 days) compared with humans (7-9 days) was also reported for ranibizumab (Gaudreault et al, 2005;Krohne et al, 2012;Xu et al, 2013). Similar to the clinical results, lampalizumab in the cynomolgus monkey also exhibits flipflop pharmacokinetics, a phenomenon in which the rate of drug egressing out of the vitreous humor is much slower than …”

Systemic levels of vascular endothelial growth factor before and after intravitreal injection of aflibercept or ranibizumab in patients with age‐related macular degeneration: a randomised, prospective trial

“…The average half-life of serum proteins is about 1 day and even shorter for those that are freely filtered by the kidney. The half-life of aflibercept and bevacizumab, which are both molecules with Fc regions, is up to 3 weeks in systemic circulation (Lu et al 2008;Xu et al 2013). It has been established that the long persistence in systemic circulation of IgG and other Fc-conjugated proteins like aflibercept are due to their recycling and rescue from catabolic elimination by the FcRn via direct engagement of the Fc fragment (Roopenian & Akilesh 2007).…”

“…In contrast to that ranibizumab, lacking the Fc region, only persists for a few hours. Additionally, ranibizumab is subject to renal catabolism as it is small enough to be filtered by the kidney (Renard et al 1997;Xu et al 2013).…”

The Value of Area Under the Curve Analysis as an Outcome Measure in the Assessment of a Continuous Microdosing Fluocinolone Acetonide Implant (ILUVIEN®)

“…21 Nevertheless, considering these structural differences, the half-life of ranibizumab is markedly shorter than bevacizumab and the medication clears more quickly from systemic circulation following an intravitreal injection with half-lives of 2 hours and 20 days, respectively. [22][23][24][25] The READ-2 study (Ranibizumab for Edema of the mAcula in Diabetes) was a pioneering work that demonstrated a significantly better BCVA outcome for DME patients following ranibizumab (0.5 mg) injection compared to laser treatment: A BCVA gain of 7.24 letters in the ranibizumab arm compared to a loss of 0.43 letters in the laser arm at month 6. 26 Later studies continued to support the effectiveness of ranibizumab in treatment of DME as well as its superiority over laser treatment.…”