A Comparison of the Pharmacokinetics and Pulmonary Lymphatic Exposure of a Generation 4 PEGylated Dendrimer Following Intravenous and Aerosol Administration to Rats and Sheep

Ryan, Gemma; Bischof, Robert J.; Enkhbaatar, Perenlei; McLeod, Victoria M.; Chan, Linda J.; Jones, Seth; Owen, David J.; Porter, Christopher John; Kaminskas, Lisa M.

doi:10.1007/s11095-015-1806-z

Cited by 22 publications

(31 citation statements)

References 43 publications

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“…To ensure maximal delivery to the lung, the colistin and CMS formulations were nebulized via an endotracheal (ET) tube directly into the trachea, in a manner similar to that previously reported (54). Prior to administration, each animal was restrained and intubated with an ET tube (Smiths Medical, Bella Vista, NSW, Australia) (inner diameter [ID], 7.5 to 8 mm) via the nasal cavity using a fiber-optic endoscope (model FG-16X; Pentax, Montvale, NJ, USA).…”

Section: Methodsmentioning

confidence: 99%

Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model

Landersdorfer

Nguyen

Lieu

et al. 2017

Antimicrob Agents Chemother

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Colistin, administered as its inactive prodrug colistin methanesulfonate (CMS), is often used in multidrug-resistant Gram-negative pulmonary infections. The CMS and colistin pharmacokinetics in plasma and epithelial lining fluid (ELF) following intravenous and pulmonary dosing have not been evaluated in a large-animal model with pulmonary architecture similar to that of humans. Six merino sheep (34 to 43 kg body weight) received an intravenous or pulmonary dose of 4 to 8 mg/kg CMS (sodium) or 2 to 3 mg/kg colistin (sulfate) in a 4-way crossover study. Pulmonary dosing was achieved via jet nebulization through an endotracheal tube cuff. CMS and colistin were quantified in plasma and bronchoalveolar lavage fluid (BALF) samples by high-performance liquid chromatography (HPLC). ELF concentrations were calculated via the urea method. CMS and colistin were comodeled in S-ADAPT. Following intravenous CMS or colistin administration, no concentrations were quantifiable in BALF samples. Elimination clearance was 1.97 liters/h (4% interindividual variability) for CMS (other than conversion to colistin) and 1.08 liters/h (25%) for colistin. On average, 18% of a CMS dose was converted to colistin. Following pulmonary delivery, colistin was not quantifiable in plasma and CMS was detected in only one sheep. Average ELF concentrations (standard deviations [SD]) of formed colistin were 400 (243), 384 (187), and 184 (190) mg/liter at 1, 4, and 24 h after pulmonary CMS administration. The population pharmacokinetic model described well CMS and colistin in plasma and ELF following intravenous and pulmonary administration. Pulmonary dosing provided high ELF and low plasma colistin concentrations, representing a substantial targeting advantage over intravenous administration. Predictions from the pharmacokinetic model indicate that sheep are an advantageous model for translational research.

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Section: Methodsmentioning

confidence: 99%

Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model

Landersdorfer

Nguyen

Lieu

et al. 2017

Antimicrob Agents Chemother

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“…The dendrimer containing the DGA-VCit linker was cleared ~2 fold slower than G4 PEG570-DGA-GLFG after IV administration, although terminal half-lives (approximately 1.5 days) were similar, indicating reductions in volume of distribution of a similar magnitude (Fig 2, Table 1). In contrast, a corresponding fully PEGylated construct (ie non-drug conjugated, G4 100% PEG 570 conjugated) reported previously, was cleared from plasma ~1.5 to 3 fold faster, although terminal half-life was similar (supporting information) 3 . These differences may reflect changes in the interaction of dendrimers with membranes and plasma proteins as a result of differences in the presentation or orientation of Dox which is extensively protein bound in plasma.…”

Section: Intravenous Pharmacokinetics and Biodistributionmentioning

confidence: 64%

“…Dendrimers were synthesised and characterised as described previously 9 , with modification (see supplementary information for synthetic details). 3 H-lysine was incorporated into the penultimate generation to enable pharmacokinetic characterisation of the dendrimer construct. The specific activity of the dendrimers was determined via scintillation counting 10 .…”

Section: Methodsmentioning

confidence: 99%

“…A series of G4 dendrimers conjugated with PEG570 and doxorubicin (20-30 kDa in size) were synthesised based on previous data showing that this scaffold construction offers both prolonged systemic exposure and good lung absorption 2,3 (see figure in supporting information). Three peptide-based drug linkers that are specifically cleavable by cathepsin B were used to conjugate doxorubicin to this dendrimer scaffold: a pentapeptide (Glu-GLFG 4 ) that results in the liberation of both peptide-modified and unmodified doxorubicin, and two self-emolative systems (diglycolic acid-GLFG-para-amino benzoic acid 4 and diglycolic acid-Valine-Citrulline (VCit)-para-amino benzoic acid 5 ) that facilitate the liberation of unmodified doxorubicin.…”

Section: Introductionmentioning

confidence: 99%

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Doxorubicin Conjugation and Drug Linker Chemistry Alter the Intravenous and Pulmonary Pharmacokinetics of a PEGylated Generation 4 Polylysine Dendrimer in Rats

Leong

Mehta

McLeod

et al. 2018

Journal of Pharmaceutical Sciences

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PEGylated polylysine dendrimers have demonstrated potential as inhalable drug delivery systems that can improve the treatment of lung cancers. Their treatment potential may be enhanced by developing constructs that display prolonged lung retention, together with good systemic absorption, the capacity to passively target lung tumors from the blood and highly selective, yet rapid liberation in the tumor microenvironment. This study sought to characterize how the nature of cathepsin B-cleavable peptide linkers, used to conjugate doxorubicin (Dox) to a PEGylated (PEG570) G4 polylysine dendrimer, affects drug liberation kinetics and intravenous and pulmonary pharmacokinetics in rats. The construct bearing a self-emolative diglycolic acid-V-Citrulline linker exhibited faster Dox release kinetics compared to constructs bearing self-emolative diglycolic acid-glycine-leucine-phenylalanine-glycine (GLFG), or non-self-emolative glutaric acid-GLFG linkers. The V-Citrulline construct exhibited slower plasma clearance, but faster absorption from the lungs than a GLFG construct, although mucociliary clearance and urinary elimination were unchanged. Dox-conjugation enhanced localization in the bronchoalveolar lavage fluid compared to lung tissue, suggesting that projection of Dox from the dendrimer surface reduced tissue uptake. These data show that the linker chemistry employed to conjugate drugs to PEGylated carriers can affect drug release profiles and systemic and lung disposition.

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“…Studies have reported that inhalation administration has an apparent advantage over oral administration in the treatment of certain diseases (Levet et al, 2017;Ryan et al, 2015). More significantly, Wattenberg & Coccia (1991) found that oral administration DL to mice could inhibit carcinogen-induced lung neoplasia.…”

Section: Introductionmentioning

confidence: 99%

Determination of d‐limonene in mice plasma and tissues by a new GC–MS/MS method: Comparison of the pharmacokinetics and tissue distribution by oral and inhalation administration in mice

Chen

Sheng

et al. 2019

Biomedical Chromatography

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The aim of the present study was to develop a method based on gas chromatography–tandem mass spectrometry (GC–MS/MS) to determine and quantify the d‐limonene in mouse plasma and tissue samples. This new method was validated for the quantification of d‐limonene with the linearity ranges 1.0–1000.0 ng/mL (r2 > 0.9952) for plasma samples and 5.0–5000.0 ng/g (r2 > 0.9940) for tissue samples. The intra‐ and inter‐day assay of precisions in plasma and tissues were <13.4% and the accuracies were within 91.1–105.8%. In the oral/inhalation administration pharmacokinetics and tissue distribution studies, the main pharmacokinetic parameters were the peak concentration = (97.150 ± 34.450)/(4336.415 ± 1142.418) ng/mL, the area under the curve = (162.828± 27.447)/(2085.721 ± 547.787) h ng/mL and the half‐life = (3.196 ± 0.825)/(0.989 ± 0.095) h. The tissue distribution of d‐limonene in mice after oral/inhalation administration demonstrated a decreasing tendency in different tissues (liver > kidney > heart > lung > spleen).

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A Comparison of the Pharmacokinetics and Pulmonary Lymphatic Exposure of a Generation 4 PEGylated Dendrimer Following Intravenous and Aerosol Administration to Rats and Sheep

Abstract: The data suggest that rats provide a relevant model for assessing the pharmacokinetics of inhaled macromolecules prior to evaluation in larger animals, but that the pulmonary lymphatics are unlikely to play a major role in the absorption of nanocarriers from the lungs.

Cited by 22 publications

References 43 publications

Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model

Substantial Targeting Advantage Achieved by Pulmonary Administration of Colistin Methanesulfonate in a Large-Animal Model

Doxorubicin Conjugation and Drug Linker Chemistry Alter the Intravenous and Pulmonary Pharmacokinetics of a PEGylated Generation 4 Polylysine Dendrimer in Rats

Determination of d‐limonene in mice plasma and tissues by a new GC–MS/MS method: Comparison of the pharmacokinetics and tissue distribution by oral and inhalation administration in mice

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