Pharmacokinetics of ranibizumab after intravitreal administration in patients
with retinal vein occlusion or diabetic macular edema.
Author(s): Zhang Y(1), Yao Z(1), Kaila N(2), Kuebler P(1), Visich J(1), Maia M(1), Tuomi
L(1), Ehrlich JS(1), Rubio RG(1), Campochiaro PA(3).
Affiliation(s): Author information:
(1)Genentech, Inc., South San Francisco, California. (2)Quantitative Solutions,
Menlo Park, California. (3)The Wilmer Eye Institute, Johns Hopkins School of
Medicine, Baltimore, Maryland. Electronic address: pcampo@jhmi.edu.
Publication date & source: 2014, Ophthalmology. , 121(11):2237-46
OBJECTIVE: To describe the systemic pharmacokinetics of ranibizumab after
intravitreal administration in patients with retinal vein occlusion (RVO) or
diabetic macular edema (DME).
DESIGN: A population approach of nonlinear mixed-effect pharmacokinetics modeling
based on serum concentrations of ranibizumab measured at various times after
intravitreal administration.
PARTICIPANTS: Patients with RVO (n = 441) and DME (n = 435) from 4 large,
randomized, phase 3 clinical trials of monthly ranibizumab intravitreal
administration.
METHODS: A 1-compartment pharmacokinetics model with first-order absorption and
elimination rate constants previously developed in patients with age-related
macular degeneration (AMD) was fitted separately to RVO and DME data. Population
pharmacokinetic parameters and interindividual variability were estimated for
each model. Baseline covariates were evaluated for potential effects on systemic
pharmacokinetics. Model performance was validated using general diagnostic plots
and a visual predictive check.
MAIN OUTCOME MEASURES: Ranibizumab disposition was determined in RVO and DME
patients and compared with that previously seen in AMD patients.
RESULTS: The AMD pharmacokinetics model correctly predicted the measured serum
ranibizumab concentration data for RVO and DME patients. Most observed data
points were within the simulated 90% confidence interval, indicating that
systemic ranibizumab concentrations were comparable among AMD, RVO, and DME
patients. No disease-related covariates were identified by the population
pharmacokinetics analysis.
CONCLUSIONS: The systemic pharmacokinetics of ranibizumab were similar among
patients with AMD, RVO, or DME. Disease-related differences and patient
demographics, measured in this study, did not lead to variability in ocular
elimination or in systemic exposure of ranibizumab after intravitreal
administration. In all disease processes tested, ranibizumab exits the eye slowly
and then is eliminated rapidly from the circulation, thus minimizing systemic
exposure.
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