Intravitreal clearance and volume of distribution of compounds in rabbits: In silico prediction and pharmacokinetic simulations for drug development

Amo, Eva M. del; Vellonen, Kati‐Sisko; Kidron, Heidi; Urtti, Arto

doi:10.1016/j.ejpb.2015.01.003

Cited by 118 publications

(151 citation statements)

References 59 publications

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“…Distribution depends on the ability of drug to partition into the tissues and it is described as volume of drug distribution. Drug elimination may take place posteriorly through the blood-retina barrier (Duvvuri et al, 2003;Gupta et al, 2000;Maurice and Mishima, 1984;Shen et al, 2007) to the choroidal blood circulation that constitutes most of the ocular blood flow (del Amo et al, 2015;Roh et al, 2006). Intravitreal drug is eliminated also anteriorly via aqueous humor turnover and uveal blood flow.…”

Section: Introductionmentioning

confidence: 98%

“…We did not find any convincing evidence to justify the criticism of the rabbit model. Moreover, during the process of analyzing the intravitreal pharmacokinetic parameters in the rabbit eyes (del Amo et al, 2015), we noticed another remarkable problem: many published studies are based on suboptimal study designs, and actually 58% of the studies were discarded from the pharmacokinetic data analysis.…”

Section: Introductionmentioning

confidence: 99%

“…fluconazole; vitreal clearance 0.753 ml/h (Gupta et al, 2000)), whereas elimination of large and hydrophilic compounds is restricted to the anterior route (e.g. bevacizumab; vitreal clearance 0.019 ml/h (Bakri et al, 2007;Christoforidis et al, 2011;del Amo et al, 2015)). These processes determine drug elimination in rabbit and human eyes and it is described as intravitreal clearance.…”

Section: Introductionmentioning

confidence: 99%

“…Recently, the rabbit eye has been criticized for being a poor model of the human eye (Laude et al, 2010;Rowe-Rendleman et al, 2014). Therefore, we investigated all available intravitreal pharmacokinetic data in rabbits (del Amo et al, 2015) and humans (this review) and derived the pharmacokinetic parameters (clearance, volume of distribution) to compare systematically intravitreal pharmacokinetics in man and rabbit. We did not find any convincing evidence to justify the criticism of the rabbit model.…”

Section: Introductionmentioning

confidence: 99%

“…They allow estimation of average steady-state concentrations, concentration profiles, half-life (t 1/2, ivt ) and amount of drug in the eye after administration of different doses or dosage forms (del Amo et al, 2015). V ss, ivt and CL ivt can be linked to the fundamental factors, anatomy, physiology, and drug interactions with tissues, thereby providing understanding of ocular pharmacokinetics in the physiological context and generating tools for bottom-up simulation models (del Amo et al, 2015). Noteworthy, the most frequently used intravitreal pharmacokinetic parameter, t 1/2, ivt depends on both drug distribution and elimination,…”

Section: Introduction Of Conceptsmentioning

confidence: 99%

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Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data

Amo

Urtti

2015

Experimental Eye Research

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Intravitreal administration is the method of choice in drug delivery to the retina and/or choroid. Rabbit is the most commonly used animal species in intravitreal pharmacokinetics, but it has been criticized as being a poor model of human eye. The critique is based on some anatomical differences, properties of the vitreous humor, and observed differences in drug concentrations in the anterior chamber after intravitreal injections. We have systematically analyzed all published information on intravitreal pharmacokinetics in the rabbit and human eye. The analysis revealed major problems in the design of the pharmacokinetic studies. In this review we provide advice for study design. Overall, the pharmacokinetic parameters (clearance, volume of distribution, half-life) in the human and rabbit eye have good correlation and comparable absolute values. Therefore, reliable rabbit-to-man translation of intravitreal pharmacokinetics should be feasible. The relevant anatomical and physiological parameters in rabbit and man show only small differences. Furthermore, the claimed discrepancy between drug concentrations in the human and rabbit aqueous humor is not supported by the data analysis. Based on the available and properly conducted pharmacokinetic studies, the differences in the vitreous structure in rabbits and human patients do not lead to significant pharmacokinetic differences. This review is the first step towards inter-species translation of intravitreal pharmacokinetics. More information is still needed to dissect the roles of drug delivery systems, disease states, age and ocular manipulation on the intravitreal pharmacokinetics in rabbit and man. Anyway, the published data and the derived pharmacokinetic parameters indicate that the rabbit is a useful animal model in intravitreal pharmacokinetics.

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introduction Of Conceptsmentioning

confidence: 99%

See 3 more Smart Citations

Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data

Amo

Urtti

2015

Experimental Eye Research

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183

158

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Hyaluronic Acid Graft Copolymers with Cleavable Arms as Potential Intravitreal Drug Delivery Vehicles

Borke

Najberg

Ilina

et al. 2017

Macromolecular Bioscience

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Treatment of retinal diseases currently demands frequent intravitreal injections due to rapid clearance of the therapeutics. The use of high molecular weight polymers can extend the residence time in the vitreous and prolong the injection intervals. This study reports a water soluble graft copolymer as a potential vehicle for sustained intravitreal drug delivery. The copolymer features a high molecular weight hyaluronic acid (HA) backbone and poly(glyceryl glycerol) (PGG) side chains attached via hydrolysable ester linkers. PGG, a polyether with 1,2‐diol groups in every repeating unit available for conjugation, serves as a detachable carrier. The influence of synthesis conditions and incubation in physiological media on the molecular weight of HA is studied. The cleavage of the PGG grafts from the HA backbone is quantified and polymer‐from‐polymer release kinetics are determined. The biocompatibility of the materials is tested in different cell cultures.

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Mass spectrometry in ocular drug research

del Amo,

Vellonen,

Urtti

et al. 2023

Mass Spectrometry Reviews

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Mass spectrometry (MS) has been proven as an excellent tool in ocular drug research allowing analyzes from small samples and low concentrations. This review begins with a short introduction to eye physiology and ocular pharmacokinetics and the relevance of advancing ophthalmic treatments. The second part of the review consists of an introduction to ocular proteomics, with special emphasis on targeted absolute quantitation of membrane transporters and metabolizing enzymes. The third part of the review deals with liquid chromatography–MS (LC‐MS) and MS imaging (MSI) methods used in the analysis of drugs and metabolites in ocular samples. The sensitivity and speed of LC‐MS make simultaneous quantitation of various drugs and metabolites possible in minute tissue samples, even though ocular sample preparation requires careful handling. The MSI methodology is on the verge of becoming as important as LC‐MS in ocular pharmacokinetic studies, since the spatial resolution has reached the level, where cell layers can be separated, and quantitation with isotope‐labeled standards has come more reliable. MS will remain in the foreseeable future as the main analytical method that will progress our understanding of ocular pharmacokinetics.

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Intravitreal clearance and volume of distribution of compounds in rabbits: In silico prediction and pharmacokinetic simulations for drug development

Cited by 118 publications

References 59 publications

Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data

Rabbit as an animal model for intravitreal pharmacokinetics: Clinical predictability and quality of the published data

Hyaluronic Acid Graft Copolymers with Cleavable Arms as Potential Intravitreal Drug Delivery Vehicles

Mass spectrometry in ocular drug research

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