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), which 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 semimechanistic 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, whereas 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.