Amphotericin Clearance in Vitrectomized Versus Nonvitrectomized Eyes

Doft, Bernard H.; J, Weiskopf; Nilsson-Ehle, Ingrid; Wingard, Lemuel B.

doi:10.1016/s0161-6420(85)33838-1

Cited by 98 publications

(47 citation statements)

References 11 publications

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“…Firstly, the drug dose should be soluble in the formulation and in the vitreous. This is not the case in many studies (some examples (Chin et al, 2005;Doft et al, 1985;Wingard et al, 1989)). Then, the resulting data does not allow reliable determination of CL ivt , V ss, ivt and t 1/2, ivt for the drug.…”

Section: Design Of An Intravitreal Pharmacokinetic Studymentioning

confidence: 92%

“…Many studies suggest that the vitreous plays a role in ocular pharmacokinetics, because the clearance of small MW drugs is faster in vitrectomized and lensectomized rabbit eyes than in either lensectomized or control rabbit eyes (Doft et al, 1985;Ficker et al, 1990;Jarus et al, 1985;Mandell et al, 1993;Pearson et al, 1993;Pflugfelder et al, 1987;Wingard et al, 1989). However, there are many changing variables in such studies (Doft et al, 1985;Ficker et al, 1990;Mandell et al, 1993;Wingard et al, 1989), and it is impossible to distinguish the specific effects of vitreous from the experiments with vitrectomized and lensectomized eyes (Jarus et al, 1985;Pearson et al, 1993;Pflugfelder et al, 1987).…”

Section: Role Of the Vitreous In Intravitreal Pharmacokineticsmentioning

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

191

136

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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: Design Of An Intravitreal Pharmacokinetic Studymentioning

confidence: 92%

Section: Role Of the Vitreous In Intravitreal Pharmacokineticsmentioning

confidence: 99%

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

Amo

Urtti

2015

Experimental Eye Research

191

136

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“…The vitreous half-life of amphotericin-B was reduced from 9.1 to 1.4 days after vitrectomy and lensectomy. 10 5-fluorouracil clearance increased 2 times in aphakic vitrectomized rabbit eyes compared to phakic vitrectomized eyes. 13 A recent study by Kakinoki et al also reported shortened AH half-life (1.5 -0.6 days) of IVB in monkeys that underwent both lensectomy and vitrectomy compared to normal eyes (2.8 -0.6 days).…”

Section: Discussionmentioning

confidence: 83%

“…Up to now, based on past animal studies and some supportive clinical evidence, drug clearance has been generally assumed to increase and clinical drug effectiveness decrease, in vitrectomized eyes. [10][11][12][13][14][15] However, there is scarce data on the PK of intravitreally injected bevacizumab in vitrectomy only (without lensectomy) eyes and scant evidence to ascertain the most effective dosing schedule for IVB injection in vitrectomized eyes. 16 Hence, this study was performed to comparatively analyze the PK profiles of intravitreally injected bevacizumab in vitrectomized (V) eyes versus nonvitrectomized control (C) eyes and to ultimately suggest the most adequate treatment regimen for IVB injection in vitrectomized patients.…”

mentioning

confidence: 99%

Pharmacokinetics of Intravitreally Injected Bevacizumab in Vitrectomized Eyes

Ahn

Kim

Woo

et al. 2013

Journal of Ocular Pharmacology and Therapeutics

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Purpose: To compare the pharmacokinetics (PKs) of intravitreally injected bevacizumab in vitrectomized versus nonvitrectomized control rabbit eyes. Methods: Twenty-five-gauge pars plana vitrectomy without lensectomy was performed in 17 right rabbit eyes (V) and 18 nonvitrectomized right rabbit eyes served as controls (C). After 1.25 mg/0.05 mL intravitreal bevacizumab (IVB) injections, eyes were enucleated at 1 h, 1, 2, 5, 14, and 30 days after the injection and immediately frozen at -80°C. Bevacizumab concentrations were determined after separation of frozen vitreous and aqueous humor (AH) compartments using indirect enzyme-linked immunosorbent assay. Bevacizumab concentrationtime data were analyzed to obtain PK data. Results: Vitreous clearance of IVB consisted of 2 phases, the first fast distribution and second slow elimination phase. Clearance of IVB was accelerated in V eyes only during the first phase and not in the second phase. The vitreous concentration percent ratios between V and C eyes were 94.7% (1 h), 70.5% (1 day), 89.2% (2 days), 94.2% (5 days), 99.2% (14 days), and 79.1% (30 days). Overall vitreous half-lives were 6.99 and 7.06 days for V and C eyes, respectively (1.6-h difference). Conclusion: Overall IVB PKs in rabbit eyes after vitrectomy without lensectomy are not substantially different from nonvitrectomized control eyes.

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“…However, TA high dose (16 mg) was well fit in the models developed. In the two studies reporting the intravitreal clearance of amphotericin B (29,30), the time points included for half-life estimation were taken on days 1, 3, 6, 9, 12 or on days 1, 5, 10, and 15. Thus, insufficient time points were taken during the first 24 h, indicating that the half-life calculated with these points could be of the beta phase.…”

Section: Discussionmentioning

confidence: 99%