Intraocular Pharmacokinetics of Ranibizumab Following a Single Intravitreal Injection in Humans

Krohne, Tim U.; Liu, Zengping; Holz, Frank G.; Meyer, Carsten H.

doi:10.1016/j.ajo.2012.03.047

Cited by 203 publications

(134 citation statements)

References 23 publications

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“…A similar difference between the ocular and systemic half-life was noted in a TMDD model of lampalizumab in humans (Le et al, 2015), in which the vitreous half-life was 5.9 days compared with a systemic half-life of 9 hours. The shorter ocular half-life in monkeys (3 days) compared with humans (7-9 days) was also reported for ranibizumab (Gaudreault et al, 2005;Krohne et al, 2012;Xu et al, 2013). Similar to the clinical results, lampalizumab in the cynomolgus monkey also exhibits flipflop pharmacokinetics, a phenomenon in which the rate of drug egressing out of the vitreous humor is much slower than …”

Section: Discussionsupporting

confidence: 69%

“…The relationship between the ocular half-life and molecular size is unknown beyond this range. However, literature on ITV administration of anti-vascular endothelial growth factor therapy suggested that the half-life of ranibizumab (7-9 days) (Krohne et al, 2012;Xu et al, 2013) was only slightly shorter than that for bevacizumab (9.8 days) (Krohne et al, 2012) in humans. Notably, the quasi-steady state equilibrium constant K ss was fixed to the in vitro measured value of the dissociation equilibrium constant (K D ) of 11.7 pM (Loyet et al, 2014) and was able to describe the data quite well.…”

Section: Tmdd Model Of Lampalizumab In Cynomolgus Monkeysmentioning

confidence: 99%

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

Le¹,

Gibiansky²,

Good³

et al. 2015

J Pharmacol Exp Ther

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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.

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Section: Discussionsupporting

confidence: 69%

Section: Tmdd Model Of Lampalizumab In Cynomolgus Monkeysmentioning

confidence: 99%

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

Le¹,

Gibiansky²,

Good³

et al. 2015

J Pharmacol Exp Ther

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“…They reported that vitreous concentrations of ranibizumab declined in a monoexponential fashion with a half-life of 2.88 days; concentrations of >0.1 μg/ml ranibizumab were maintained in the vitreous humor for 29 days [18]. Krohne et al found that the aqueous halflife of 0.5 mg of intravitreal injected ranibizunab was 7.19 days in nonvitrectomized human eyes [19]. Xu et al demonstrated that due to the slow release of ranibizumab from the stagnant vitreous, the apparent serum half-life following intravitreal ranibizumab administration was 9 days in adult patients.…”

Section: Discussionmentioning

confidence: 96%

Vascular endothelial growth factor plasma levels before and after treatment of retinopathy of prematurity with ranibizumab

Zhou

Jiang

Bai

et al. 2015

Graefes Arch Clin Exp Ophthalmol

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“…18 Relative to bevacizumab, ranibizumab has been reported to have a somewhat shorter vitreous half-life, but has 5-to 20-fold higher biologic activity. 19,20 This increased activity, coupled with the smaller molecular size of ranibizumab, may further benefit eyes with DME. The US Food and Drug Administration approval for ranibizumab 0.3-mg for the treatment of DME was granted in August 2012.…”

Section: Introductionmentioning

confidence: 99%

Residual edema evaluation with ranibizumab 0.5 mg and 2.0 mg formulations for diabetic macular edema (REEF study)

Dhoot

Pieramici

Nasir

et al. 2015

Eye

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Purpose To compare the efficacy of ranibizumab 0.5-mg and 2.0-mg intravitreal injections for persistent diabetic macular edema (DME) previously treated with bevacizumab. Methods In all, 43 patients with residual center-involved DME following intravitreal bevacizumab were included in this 12-month prospective, nonrandomized, multicenter study. Enrolled patients received three monthly ranibizumab 0.5-mg injections. At month 3, patients with residual macular edema switched to three monthly injections of ranibizumab 2.0-mg. Assessments included monthly visual acuity and spectraldomain optical coherence tomography. Results Mean visual acuity improved by þ 6.4 letters at month 3 and þ 8.8 letters at month 6. Mean central subfield thickness (CST) decreased by -113 mm at month 3 and -165 mm at month 6. Before enrollment, 29/43 (67.4%) patients showed o10% CST reduction following monthly bevacizumab treatment. After three monthly ranibizumab 0.5-mg injections, 22/29 (75.9%) patients showed 410% reduction in CST, whereas 6 showed o10% reduction. Of these six, three (50%) showed 410% reduction in CST after switching to three monthly ranibizumab 2.0-mg doses. No serious adverse events were observed to month 6. Conclusion Ranibizumab 0.5-mg or 2.0-mg may improve visual and anatomic outcomes in patients with DME who demonstrated minimal or no response to bevacizumab therapy. Moreover, increased dosage of ranibizumab (2.0-mg) may provide additional benefit over ranibizumab 0.5-mg in some patients. However, 2.0-mg ranibizumab is not currently commercially licensed or available.

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Intraocular Pharmacokinetics of Ranibizumab Following a Single Intravitreal Injection in Humans

Cited by 203 publications

References 23 publications

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

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

Vascular endothelial growth factor plasma levels before and after treatment of retinopathy of prematurity with ranibizumab

Residual edema evaluation with ranibizumab 0.5 mg and 2.0 mg formulations for diabetic macular edema (REEF study)

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