A Mechanistic Pharmacokinetic/Pharmacodynamic Model of Factor D Inhibition in Cynomolgus Monkeys by Lampalizumab for the Treatment of Geographic Atrophy

Abstract

Lampalizumab is an antigen-binding fragment of a humanized monoclonal antibody against complement factor D (CFD), a ratelimiting 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 ocularsystemic 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 targetmediated 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 t 1/2 of approximately 3 days, whereas systemic elimination is rapid, with a t 1/2 of 0.8 hours. Target-independent linear clearance is predominant in the eye, whereas targetmediated 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.

The Pathophysiology of Geographic Atrophy Secondary to Age-Related Macular Degeneration and the Complement Pathway as a Therapeutic Target

“…93,96 Inhibiting CFD decreases, but does not eliminate, classical and lectin-activated complement initiation. 68,69 Intravitreal clinically relevant doses were demonstrated to have minimal systemic inhibition of the alternative complement pathway in pharmacokinetic studies in monkeys 148,149 and in subjects participating in the Phase 1 and Phase 2 lampalizumab trials (NCT00973011; NCT01229215). 150,151 The low levels of lampalizumab in systemic circulation resulting from intravitreal administration are not expected to affect systemic alternative complement pathway activity.…”

A comprehensive insight on ocular pharmacokinetics

“…Those differences are acceptable to have some idea to predict about the pharmacokinetic profile of any drugs. Le et al has also investigated the lampalizumab elimination following the intravitreal injection (51). The slow ocular elimination was observed compared to systemic elimination.…”

“…Pharmacokinetic/pharmacodynamics (PK/PD) model of Factor D inhibition in monkeys by lampalizumab for the treatment of geographic atrophy was developed by Le et al In addition, intravitreal administration of lampalizumab showed therapeutic levels at the target site while minimizing systemic drug exposure to patient (51). Intravitreal injection of lampalizumab resulted in slow ocular elimination compared to systemic elimination (51).…”

“…Intravitreal injection of lampalizumab resulted in slow ocular elimination compared to systemic elimination (51). These results may be helpful in predicting human PK/PD for lampalizumab.…”

Recent perspectives on the delivery of biologics to back of the eye

“…Vitreous humor had a maximum concentration of 169 μ g/ml at 6 hours in monkeys relative to 162 μ g/ml at 24 hours in rabbit [71,76]. Lampalizumab elimination following an intravitreal injection in cynomolgus monkeys indicated slower ocular elimination with a T 1/2 approximately 3 days compared to systemic elimination with T 1/2 of 0.8 hours [77]. Drolet DW et al have studied the pharmacokinetic and safety profile of an anti-vascular endothelial growth factor aptamer (NX1838) in rhesus monkeys [78].…”