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Matthias Machacek, Pascal Deschatelets, Robert Kim, Patrick Johnson, Federico Grossi; Prediction of duration of C3 inhibition with APL-2 in human eyes using a PK/PD binding model. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1971.
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© ARVO (1962-2015); The Authors (2016-present)
APL-2 is an anti-C3 PEGylated peptide in clinical development for geographic atrophy. The effect duration and the optimal treatment interval with intravitreal (IVT) administered APL-2 are under investigation. Our goal was to develop a PK/PD binding model based on first principles, preclinical data from non-human primates (NHP) and published data to predict the duration of inhibition of free C3 by APL-2 in the human eye.
It was assumed that free C3 is a valid surrogate for the duration of effect. The Kd of APL-2 was set to 0.52 nM based on surface plasmon resonance data for the APL-2 subunit. C3 concentration in vitreous was assumed to be 70 nM (IOVS 2012;53:6628–6637). For PK modeling, APL-2 observations in NHP vitreous after a single IVT dose of 10 mg were used. No data have previously been reported on C3 kinetics in vitreous. For purposes of the present study, it was therefore assumed that the half-life of C3 and the drug-target complexes were dependent on their molecular weights (MW) (Fig 1 A). Data on molecules with a MW from 45 to 150 kDa were collected from literature and fitted with the relationship T1/2 = a MW1/3 which assumed that the half-life was a result of diffusion limited distribution in the vitreous. For scaling, diffusion limited distribution was also assumed, with the eye radius r as the only difference between NHP and human resulting in the relationship T1/2,human = T1/2,NHP(rhuman/rNHP)2.
An APL-2 half-life of 3.2 days in NHP vitreous was obtained from the PK modeling. The half-lives of free C3, APL-2 bound to one C3 (APL-2:C3), and APL-2 bound to two C3 (C3:APL-2:C3) molecules were estimated to be 4.4, 4.6 and 5.6 days, respectively. Thus, binding to C3 was predicted to prolong the residence time of APL-2 in the vitreous. Using scaling, half-lives in human vitreous of 6.0, 8.2, 8.6 and 10.5 days were obtained for free APL-2, free C3, APL-2:C3 and C3:APL-2:C3, respectively. Simulations predicted that a single IVT dose of 15 mg of APL-2 inhibited free C3 for about 60 days in human vitreous (Fig 1 B). Reducing the dose to 5 mg reduced the effect duration by 10 days.
Model predictions support a monthly treatment interval with APL-2 and suggest also that a two-month interval is a reasonable hypothesis for testing in a clinical study.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
A) Model outline. B) Predicted total APL-2 and free C3 in human vitreous after a single IVT dose of 15, 10, 7.5 and 5 mg.
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