Review of Intraocular Pharmacokinetics of Anti-Infectives Commonly Used in the Treatment of Infectious Endophthalmitis

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Abstract

Although intravitreal administration of anti-infectives represents the standard treatment for infectious endophthalmitis, the knowledge about their pharmacokinetics is still limited. In this review, we aimed to summarise the factors influencing the pharmacokinetics of the anti-infective agents. We have conducted a comprehensive review of the preclinical pharmacokinetic parameters obtained in different studies of intravitreal injections of anti-infectives performed on animals, mainly rabbits. The two aspects with the biggest influence on pharmacokinetics are the distribution in the vitreous humour and the elimination through the posterior segment. The distribution can be affected by the molecular weight of the drug, the convection flow of the vitreous, the condition of the vitreous humour depending on the age of the patient, the possible interactions between the drug and the components of the vitreous, and the presence of vitrectomy. Meanwhile, the elimination includes the metabolism of the drug, the clearance via the anterior and posterior routes, and the possible inflammation of the eye resulting from the disease. Understanding the pharmacokinetics of the anti-infectives used in clinical practice is essential for a correct application. The information provided in this review could offer guidance for selecting the best therapeutic option according to the characteristics of the drugs.

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Pharmacokinetic aspects of retinal drug delivery

Maxim Antopolsky, Heidi Kidron, Marco G Casteleijn … (2017)

Drug delivery to the posterior eye segment is an important challenge in ophthalmology, because many diseases affect the retina and choroid leading to impaired vision or blindness. Currently, intravitreal injections are the method of choice to administer drugs to the retina, but this approach is applicable only in selected cases (e.g. anti-VEGF antibodies and soluble receptors). There are two basic approaches that can be adopted to improve retinal drug delivery: prolonged and/or retina targeted delivery of intravitreal drugs and use of other routes of drug administration, such as periocular, suprachoroidal, sub-retinal, systemic, or topical. Properties of the administration route, drug and delivery system determine the efficacy and safety of these approaches. Pharmacokinetic and pharmacodynamic factors determine the required dosing rates and doses that are needed for drug action. In addition, tolerability factors limit the use of many materials in ocular drug delivery. This review article provides a critical discussion of retinal drug delivery, particularly from the pharmacokinetic point of view. This article does not include an extensive review of drug delivery technologies, because they have already been reviewed several times recently. Instead, we aim to provide a systematic and quantitative view on the pharmacokinetic factors in drug delivery to the posterior eye segment. This review is based on the literature and unpublished data from the authors' laboratory.

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Role of P-glycoprotein in pharmacokinetics: clinical implications.

Hualiang Lin, Masayo Yamazaki (2002)

P-glycoprotein, the most extensively studied ATP-binding cassette (ABC) transporter, functions as a biological barrier by extruding toxins and xenobiotics out of cells. In vitro and in vivo studies have demonstrated that P-glycoprotein plays a significant role in drug absorption and disposition. Because of its localisation, P-glycoprotein appears to have a greater impact on limiting cellular uptake of drugs from blood circulation into brain and from intestinal lumen into epithelial cells than on enhancing the excretion of drugs out of hepatocytes and renal tubules into the adjacent luminal space. However, the relative contribution of intestinal P-glycoprotein to overall drug absorption is unlikely to be quantitatively important unless a very small oral dose is given, or the dissolution and diffusion rates of the drug are very slow. This is because P-glycoprotein transport activity becomes saturated by high concentrations of drug in the intestinal lumen. Because of its importance in pharmacokinetics, P-glycoprotein transport screening has been incorporated into the drug discovery process, aided by the availability of transgenic mdr knockout mice and in vitro cell systems. When applying in vitro and in vivo screening models to study P-glycoprotein function, there are two fundamental questions: (i) can in vitro data be accurately extrapolated to the in vivo situation; and (ii) can animal data be directly scaled up to humans? Current information from our laboratory suggests that in vivo P-glycoprotein activity for a given drug can be extrapolated reasonably well from in vitro data. On the other hand, there are significant species differences in P-glycoprotein transport activity between humans and animals, and the species differences appear to be substrate-dependent. Inhibition and induction of P-glycoprotein have been reported as the causes of drug-drug interactions. The potential risk of P-glycoprotein-mediated drug interactions may be greatly underestimated if only plasma concentration is monitored. From animal studies, it is clear that P-glycoprotein inhibition always has a much greater impact on tissue distribution, particularly with regard to the brain, than on plasma concentrations. Therefore, the potential risk of P-glycoprotein-mediated drug interactions should be assessed carefully. Because of overlapping substrate specificity between cytochrome P450 (CYP) 3A4 and P-glycoprotein, and because of similarities in P-glycoprotein and CYP3A4 inhibitors and inducers, many drug interactions involve both P-glycoprotein and CYP3A4. Unless the relative contribution of P-glycoprotein and CYP3A4 to drug interactions can be quantitatively estimated, care should be taken when exploring the underlying mechanism of such interactions.

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Nanoparticle diffusion in, and microrheology of, the bovine vitreous ex vivo

Elizabeth A. Nance, Qingguo Xu, Nicholas J Boylan … (2013)

Intravitreal injection of biodegradable nanoparticles (NP) holds promise for gene therapy and drug delivery to the back of the eye. In some cases, including gene therapy, NP need to diffuse rapidly from the site of injection in order to reach targeted cell types in the back of the eye, whereas in other cases it may be preferred for the particles to remain at the injection site and slowly release drugs that may then diffuse to the site of action. We studied the movements of polystyrene (PS) NP of various sizes and surface chemistries in fresh bovine vitreous. PS NP as large as 510nm rapidly penetrated the vitreous gel when coated with polyethylene glycol (PEG), whereas the movements of NP 1190nm in diameter or larger were highly restricted regardless of surface chemistry owing to steric obstruction. PS NP coated with primary amine groups (NH2) possessed positively charged surfaces at the pH of bovine vitreous (pH=7.2), and were immobilized within the vitreous gel. In comparison, PS NP coated with COOH (possessing negatively charged surfaces) in the size range of 100-200nm and at particle concentrations below 0.0025% (w/v) readily diffused through the vitreous meshwork; at higher concentrations (~0.1% w/v), these nanoparticles aggregated within vitreous. Based on the mobility of different sized PEGylated PS NP (PS-PEG), we estimated the average mesh size of fresh bovine vitreous to be ~550±50nm. The bovine vitreous behaved as an impermeable elastic barrier to objects sized 1190nm and larger, but as a highly permeable viscoelastic liquid to non-adhesive objects smaller than 510nm in diameter. Guided by these studies, we next sought to examine the transport of drug- and DNA-loaded nanoparticles in bovine vitreous. Biodegradable NP with a diameter of 227nm, composed of a poly(lactic-co-glycolic acid) (PLGA)-based core coated with poly(vinyl alcohol) rapidly penetrated vitreous. Rod-shaped, highly-compacted CK30PEG10k/DNA with PEG coating (neutral surface charge; hydrodynamic diameter ~60nm) also diffused rapidly within vitreous. These findings will help guide the development of nanoparticle-based therapeutics for the treatment of vision-threatening ocular diseases.

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Journal

Journal ID (nlm-ta): Pharmaceutics

Journal ID (iso-abbrev): Pharmaceutics

Journal ID (publisher-id): pharmaceutics

Title: Pharmaceutics

Publisher: MDPI

ISSN (Electronic): 1999-4923

Publication date (Electronic): 29 May 2018

Publication date Collection: June 2018

Volume: 10

Issue: 2

Electronic Location Identifier: 66

Affiliations

[1 ]Department of Pharmacology, Pharmacy and Pharmaceutical Technology and Industrial Pharmacy Institute, Faculty of Pharmacy, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain; andrealuaces21@ 123456gmail.com (A.L.-R.); Miguel.gonzalez.barcia@ 123456segas.es (M.G.-B.)

[2 ]Clinical Pharmacology Group, Health Research Institute of Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain; Maria.Jesus.Lamas.Diaz@ 123456sergas.es

[3 ]Pharmacy Department, Clinical University Hospital Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain

[4 ]Ophthalmology Department, Clinical University Hospital Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain; mariajose.blanco@ 123456usc.es (M.J.B.-T.); mariagilmtez@ 123456hotmail.com (M.G.-M.); francisco.gonzalez@ 123456usc.es (F.G.); franciscogomez-ulla@ 123456institutogomez-ulla.es (F.G.-U.)

[5 ]Department of Surgery and Medical-Surgical Specialties and CIMUS, University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain

Author notes

[* ]Correspondence: francisco.otero@ 123456usc.es (F.-J.O.-E.); anxordes@ 123456gmail.com (A.F.-F.); Tel.: +34-609718821 (F.-J.O.-E.); +34-659695693 (A.F.-F.)

Author information

Andrea Luaces-Rodríguez https://orcid.org/0000-0002-6794-3551

Francisco-Javier Otero-Espinar https://orcid.org/0000-0001-9030-2253

Anxo Fernández-Ferreiro https://orcid.org/0000-0002-7348-7337

Article

Publisher ID: pharmaceutics-10-00066

DOI: 10.3390/pharmaceutics10020066

PMC ID: 6027276

PubMed ID: 29844284

SO-VID: 498846a6-335d-4fcf-b9c5-7bc5cd4461ff

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Review of Intraocular Pharmacokinetics of Anti-Infectives Commonly Used in the Treatment of Infectious Endophthalmitis

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Abstract

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Dermal Microdialysis in Pharmacokinetics

Most cited references 84

Pharmacokinetic aspects of retinal drug delivery

Role of P-glycoprotein in pharmacokinetics: clinical implications.

Nanoparticle diffusion in, and microrheology of, the bovine vitreous ex vivo

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