Therapeutic antibodies administered
intravitreally are the current
standard of care to treat retinal diseases. The ocular half-life (t
1/2) is a key determinant of the duration of
target suppression. To support the development of novel, longer-acting
drugs, a reliable determination of t
1/2 is needed together with an improved understanding of the factors
that influence it. A model-based meta-analysis was conducted in humans
and nonclinical species (rat, rabbit, monkey, and pig) to determine
consensus values for the ocular t
1/2 of
IgG antibodies and Fab fragments. Results from multiple literature
and in-house pharmacokinetic studies are presented within a mechanistic
framework that assumes diffusion-controlled drug elimination from
the vitreous. Our analysis shows, both theoretically and experimentally,
that the ocular t
1/2 increases in direct
proportion to the product of the hydrodynamic radius of the macromolecule
(3.0 nm for Fab and 5.0 nm for IgG) and the square of the radius of
the vitreous globe, which varies approximately 24-fold from the rat
to the human. Interspecies differences in the proportionality factors
are observed and discussed in mechanistic terms. In addition, mathematical
formulae are presented that allow prediction of the ocular t
1/2 for molecules of interest. The utility of
these formulae is successfully demonstrated in case studies of aflibercept,
brolucizumab, and PEGylated Fabs, where the predicted ocular t
1/2 values are found to be in reasonable agreement
with the experimental data available for these molecules.
Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer's disease. Among the agents explored in clinical trials are anti-A peptide antibodies and secretase inhibitors. Most anti-A antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid, although secretase inhibitors reduce the de novo production of A. Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment. We performed a chronic study in APP London transgenic mice that received treatment with anti-A antibody gantenerumab and BACE inhibitor RO5508887, either as mono-or combination treatment. Treatment aimed to evaluate efficacy on amyloid progression, similar to preexisting amyloidosis as present in Alzheimer's disease patients. Mono-treatments with either compound caused a dose-dependent reduction of total brain A and amyloid burden. Combination treatment with both compounds significantly enhanced the antiamyloid effect. The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number, which suggests effective inhibition of de novo plaque formation. Moreover, significantly enhanced clearance of preexisting amyloid plaques was observed when gantenerumab was coadministered with RO5508887. BACE inhibition led to a significant time-and dose-dependent decrease in CSF A, which was not observed for gantenerumab treatment. Our results demonstrate that combining these two antiamyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance.
HighlightsModelling and simulation can streamline decision making in drug safety testing.Computational cardiac electrophysiology is a mature technology with a long heritage.There are many challenges and opportunities in using in silico techniques in future.We discuss how models can be used at different stages of drug discovery.CiPA will combine screening platforms, human cell assays and in silico predictions.
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