RT Journal Article
SR Electronic
T1 A Mechanistic PK/PD Model of Factor D Inhibition in Cynomolgus Monkeys by Lampalizumab for the Treatment of Geographic Atrophy
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.115.227223
DO 10.1124/jpet.115.227223
A1 Le, Kha N
A1 Gibiansky, Leonid
A1 Good, Jeremy
A1 Davancaze, Teresa
A1 van Lookeren Campagne, Menno
A1 Loyet, Kelly M
A1 Morimoto, Alyssa
A1 Jin, Jin
A1 Damico-Beyer, Lisa A
A1 Hanley, WIlliam D
YR 2015
UL http://jpet.aspetjournals.org/content/early/2015/09/10/jpet.115.227223.abstract
AB Lampalizumab is an antigen-binding fragment of a humanized monoclonal antibody against complement factor D (CFD), a rate-limiting enzyme in the activation and amplification of the alternative complement pathway (ACP), that is in phase III clinical trials for the treatment of geographic atrophy. Understanding of the pharmacokinetics, pharmacodynamics, and biodistribution of lampalizumab following intravitreal administration in the ocular compartments and systemic circulation is limited, but crucial for selecting doses that provide optimal efficacy and safety. Here we sought to construct a semi-mechanistic and integrated ocular-systemic pharmacokinetic-pharmacodynamic model of lampalizumab in the cynomolgus monkey to provide a quantitative understanding of the ocular and systemic disposition of lampalizumab and CFD inhibition. The model takes into account target-mediated drug disposition, target turnover, and drug distribution across ocular tissues and systemic circulation. Following intravitreal administration, lampalizumab achieves rapid equilibration across ocular tissues. Lampalizumab ocular elimination is relatively slow with a τ1/2 of approximately 3 days, while systemic elimination is rapid with a τ1/2 of 0.8 hours. Target-independent linear clearance is predominant in the eye, whereas target-mediated clearance is predominant in the systemic circulation. Systemic CFD synthesis was estimated to be high (7.8 mg/day); however, the amount of CFD entering the eye due to influx from the systemic circulation was small (<10%) compared with the lampalizumab dose and is thus expected to have an insignificant impact on the clinical dose-regimen decision. Our findings support the clinical use of intravitreal lampalizumab to achieve significant ocular ACP inhibition while maintaining low systemic exposure and minimal systemic ACP inhibition.