Drug Concentrations In Tissues Research Articles

PH-sensitive, dynamic graft polymer micelles via simple synthesis for enhanced chemotherapeutic efficacy.

To promote chemotherapeutic efficacy and easier clinical transformation, a series of pH-sensitive and dynamic drug delivery systems with facile two-step synthesis and simple structure have been successfully constructed by the tunable grafting reaction between pH-sensitive ortho ester and poly(vinyl alcohol). The amphipathic graft macromolecules (PVA- g-OE x, x represents the percentage of feed between ortho esters and hydroxyl groups of polyvinyl alcohol) could self-assemble into micelles and doxorubicin was embedded. These micelles exhibited pH-sensitivity to both extracellular and intracellular pH and demonstrated the following characteristics: (i) maintaining long-term storage and blood circulation stability at pH 7.4; (ii) responding to tumoral extracellular pH value following gradually larger nanoparticles for improved drug accumulation and retention; (iii) being sensitive to tumoral intracellular pH value following disintegration for rapid drug release to improve toxicity to tumor cells. Moreover, the doxorubicin-loaded micelle (PVA- g-OE30-DOX) showed similar cytotoxicity to free doxorubicin in vitro, but stronger tumor penetration and inhibition ability in vitro human liver carcinoma cell line multicellular tumor spheroids. In vivo biodistribution and tumor inhibition examinations demonstrated that PVA- g-OE30-DOX had more superior efficacy in significantly enhancing drug accumulation in tumor, restraining tumor growth while decreasing drug concentration in normal tissues. The pH-sensitive, dynamic graft polymer micelles via simple synthesis could be considered as a promising and effective drug carrier in tumor therapy.

Clinical pharmacokinetics of flomoxef in prostate tissue and dosing considerations for prostatitis based on site-specific pharmacodynamic target attainment

Flomoxef is used to treat bacterial prostatitis; however, its prostatic pharmacokinetics have not been fully clarified. Flomoxef (500 or 1000 mg) was administered to patients with benign prostatic hypertrophy (n = 54). After a 0.5-h infusion, venous blood samples were drawn at time points of 0.5–5 h, and prostate tissue samples were collected at time points of 0.5–1.5 h during transurethral resection of the prostate. The drug concentrations in plasma and prostate tissue were analyzed pharmacokinetically and used for a stochastic simulation to predict the probability of attaining pharmacodynamic target in prostate tissue. Showing dose linearity in the prostatic pharmacokinetics, flomoxef rapidly penetrated into prostate tissue, with a prostate/plasma ratio of 0.48–0.50 (maximum drug concentration) and 0.42–0.55 (area under the drug concentration-time curve). Against the tested populations of Escherichia coli, Klebsiella and Proteus species isolates, 0.5-h infusion of 1000 mg three times daily achieved a ≥90% expected probability of attaining the bactericidal target (70% of the time above the minimum inhibitory concentration [MIC]) in prostate tissue. The site-specific pharmacodynamic-based breakpoint (the highest MIC at which the target-attainment probability in prostate tissue was >90%) values were 0.25 mg/L (MIC for 90th percentile of E. coli and Klebsiella species) for 500 mg four times daily and 0.5 mg/L (MIC90 of Proteus species) for 1000 mg four times daily. These results help to fully characterize the prostatic pharmacokinetics of flomoxef, while also helping to rationalize and optimize the dosing regimens for prostatitis based on site-specific pharmacodynamic target attainment.

Development and In Vivo Evaluation of Multidrug Ultradeformable Vesicles for the Treatment of Skin Inflammation.

The aim of this work was to evaluate the effect of two chemically different edge activators, i.e., Tween® 80 and sodium deoxycholate, on (i) the physical, mechanical, and biological properties of ultradeformable vesicles, and (ii) the administration of naproxen sodium-loaded multidrug ultradeformable vesicles for the transdermal route in order to obtain therapeutically meaningful drug concentrations in the target tissues and to potentiate its anti-inflammatory effect by association with the antioxidant drug idebenone. The results obtained in this investigation highlighted a synergistic action between naproxen and idebenone in the treatment of inflammatory disease with a more pronounced anti-inflammatory effect in multidrug ultradeformable vesicles compared to the commercial formulation of Naprosyn® gel. Systems made up of Tween® 80 appeared to be the most suitable in terms of percutaneous permeation and anti-inflammatory activity due to the greater deformability of these vesicles compared to multidrug ultradeformable vesicles with sodium deoxycholate. Our findings are very encouraging and suggest the use of these carriers in the topical treatment of inflammatory diseases.

ACTR-09. A PHASE 0 PHARMACODYNAMIC AND PHARMACOKINETIC STUDY OF EVEROLIMUS IN VESTIBULAR SCHWANNOMA (VS) AND MENINGIOMA PATIENTS

Abstract BACKGROUND Inhibition of mTORC1 signaling has been shown to diminish growth of NF2 deficient tumors in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of adult and pediatric NF2 patients with VS. To assess the pharmacokinetics, pharmacodynamics and potential mechanisms of treatment resistance, we performed a pre-surgical (“phase 0”) clinical trial of everolimus in patients undergoing surgery for VS or meningiomas. METHODS Eligible patients with meningioma or VS requiring tumor resection received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately prior to and after surgery. Tumor samples were collected intraoperatively. RESULTS Ten patients completed protocol therapy, including 5 patients with NF2-related meningioma, 3 patients with sporadic meningioma, and 2 patients with NF2-related VS. Median pre- and post-operative plasma levels of everolimus were found to be in a high therapeutic range (17.4 ng/ml and 9.4 ng/ml, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 ng/g (range 9.2–169.2), and median tumor tissue to post-operative plasma drug concentration ratio was 0.39. We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared to matched control tissues from untreated patients (p = 0.005). Consistent with prior observations that inhibition of mTORC1 may lead to MAPK pathway activation through a PI3K-dependent feedback loop, we observed a statistically significant increase of phospho-ERK (p < 0.03) versus untreated controls. CONCLUSIONS In patients with meningioma or VS, treatment with everolimus leads to incomplete inhibition of mTORC1 signaling and upregulation phospho-ERK. These data may explain the limited anti-tumor effect of everolimus observed in clinical studies for NF2 patients and identify upregulation of phospho-ERK as a likely resistance mechanism that could be addressed with combination therapies.

Bifidobacterium spp: the promising Trojan Horse in the era of precision oncology.

Selective delivery of therapeutic agents into solid tumors has been a major challenge impeding the achievement of long-term disease remission and cure. The need to develop alternative drug delivery routes to achieve higher drug concentration in tumor tissue, reduce unwanted off-target side effects and thus achieve greater therapeutic efficacy, has resulted in an explosive body of research. Bifidobacterium spp. are anaerobic, nonpathogenic, Gram-positive bacteria, commensal to the human gut that are a possible anticancer drug-delivery vehicle. In this review, we describe Bifidobacterium's microbiology, current clinical applications, overview of the preclinical work investigating Bifidobacterium's potential to deliver anticancer therapy, and review the different strategies used up to date. Finally, we discuss both current challenges and future prospects.

CardiacPBPK: A tool for the prediction and visualization of time-concentration profiles of drugs in heart tissue

Background and objectivePrediction of drug concentration in heart tissue is important in terms of drug safety and efficacy. This work presents the Open-Source CardiacPBPK platform for the prediction of the time-concentration profile of drugs, which could potentially reduce the risk of drug development failure due to cardiotoxicity. The objective of the CardiacPBPK development is to accelerate and simplify the in-silico toxicological assessment of new drugs, and to provide supportive material for the research community to use. MethodsThe CardiacPBPK software provides a modular implementation of the PBPK model of heart tissue. It can be easily accessed via the Internet or installed locally. The graphical user interface and tabular design are easy to configure and use. ResultsCardiacPBPK is a tool designed to predict and visualize the time-concentration profiles of a parent compound, and one metabolite, in venous plasma and heart tissue after oral or intravenous drug administration. CardiacPBPK is built on the R-environment framework and supports shiny application features such as interactive visualization of the results, and web applications interface by default. A shiny application refers to a computer program created with the use of shiny package in R. The application is freely available at https://github.com/jszlek/CardiacPBPK and https://sourceforge.net/projects/cardiacpbpk/. This open-source application runs on all platforms supporting R-environment (Linux, Windows, Mac OS X, Solaris). ConclusionsWe demonstrate the application of CardiacPBPK by simulating the study of amitriptyline intoxication in the case of CYP2D6 genetic polymorphism.

WITHDRAWN: Nemonoxacin treatment of patients with diabetic foot infection: A pilot study

Abstract Background/purpose Diabetic foot infections (DFIs) are typically polymicrobial, often involving staphylococci (including methicillin-resistant strains). To investigate if nemonoxacin, a broad-spectrum non-fluorinated quinolone with activity against methicillin-resistant Staphylococcus aureus (MRSA), is effective in DFIs, we evaluated the efficacy, safety, pharmacokinetics, and pharmacodynamics of nemonoxacin in DFI patients. Methods Patients with mild or moderate DFI received 750 mg nemonoxacin orally once daily for 7-14 days in this open-label, single-arm, multi-center study. We evaluated clinical and microbiological responses and collected blood and tissue samples to assess nemonoxacin’s penetration into infected soft tissue. Results Among 38 enrolled patients, 25 completed the study. Staphylococcus aureus was the predominant wound isolate (69.7%), including four MRSA strains. Clinical success rates at the test-of-cure (TOC) visit were 95.7% in the intent-to-treat (ITT) and 94.7% in the per-protocol (PP) populations. Microbiological success rates at TOC in ITT and PP populations were 82.6% and 89.5%, respectively. Validated wound scoring revealed that the treatment significantly reduced infection severity. Nemonoxacin was well tolerated, rapidly absorbed and distributed to soft tissues following oral administration, attaining Cmax,ss ∼2 hours after dosing. Drug concentrations in soft tissue were >2.5 times of that in plasma at most samplings. The AUC0-24 tissue/plasma ratio was 3.08, with ratio ranges of 13.1–1747.9 and 48.0–3200.0 for plasma fAUC/MIC and soft tissue AUC/MIC, respectively. Conclusion In this small DFI patient population, nemonoxacin produced excellent clinical and microbiological responses, was well tolerated, and effectively penetrated infected tissues. Once-daily oral nemonoxacin treatment appears effective in DFI patients. NCT registration number NCT00685698.

751 Safety, Tolerability, and Pharmacokinetics of PTG-200, an Oral GI-Restricted Peptide Antagonist of IL-23 Receptor, in Normal Healthy Volunteers

INTRODUCTION: PTG-200 (JNJ-67864238) is an oral peptide that acts locally in intestinal tissues to block IL-23 signaling by selectively binding the IL-23 receptor (IL-23R). The gastrointestinal (GI)-restriction of PTG-200 is demonstrated in vivo by marked drug concentrations in GI tissues and feces and limited systemic blood exposure. PTG-200 therapeutic potential was established in a rat model of TNBS-induced colitis, where its threshold concentration in colonic tissue and luminal feces associated with efficacy was determined to inform the human efficacious dose. 1 The objectives of this Phase 1 study were to assess safety, tolerability, and pharmacokinetics (PK) of PTG-200. METHODS: This first-in-human (FIH) Phase 1 study was a single-center, randomized, double-blind, placebo-controlled trial comprising single and 14-day multiple ascending dose (SAD and MAD) arms in 82 healthy male volunteers. Oral doses ranged from 150 mg to 900 mg once daily (QD, fasted or fed) or twice daily (BID, fed). Subjects were monitored for safety and tolerability. PK in plasma, urine and feces was evaluated. RESULTS: Oral administration of PTG-200 was well-tolerated. There were no serious adverse events, dose-limiting toxicities, or clinically significant adverse events. PTG-200 plasma exposure was low (Table 1), below that expected to result in systemic biological activity. Following single-dose oral administration under fasted conditions, plasma PTG-200 concentrations exhibited dose-related increases with a median time to maximal concentration (Tmax) at 2 h. Administration of a high-fat meal prolonged the median Tmax to 4 h and had a modest effect on peak concentration (Cmax) and estimated overall exposure. Repeat dosing led to dose-related increases in plasma exposure. Consistent with a terminal half-life of ∼1.5 h in plasma, PTG-200 showed no evidence of accumulation except for the 900 mg BID group. Fecal concentrations in several cohorts met or exceeded the targeted threshold concentration associated with efficacy as established using the preclinical colitis model. CONCLUSION: Orally administered PTG-200 was well-tolerated in this FIH study. Systemic PK was consistent with the GI-restricted design of PTG-200. These safety and PK characteristics, combined with fulfillment of fecal drug threshold concentrations, support further clinical development of PTG-200 for the treatment of IBD. A Phase 2 study in patients with moderate-to-severe Crohn's disease is planned.

471 Investigating the Tissue Distribution of [14C]-Prucalopride Following a Single Oral Dose in Rats

INTRODUCTION: Prucalopride is a selective, high-affinity agonist of the 5-hydroxytryptamine-4 (5-HT4) receptor and is indicated for the treatment of adult patients with chronic constipation. In humans, prucalopride is rapidly absorbed and extensively distributed, reaching maximum plasma concentration 2–3 h after a 2 mg oral dose. We report three studies investigating tissue distribution of prucalopride in rats. METHODS: A single oral dose of 14C-labelled prucalopride at 5mg base-equivalent(eq)/kg was administered to 30 SPF Wistar rats (5 males, seven groups of 3 non-pregnant females and 4 pregnant females [dose administered on day 18 of gestation]). Total radioactivity (TR) in various tissues was measured up to 96h. In females, the area under the TR concentration curve for up to 8h (AUC0–8h) and the AUC0–8h tissue:plasma ratio was calculated. The tissue concentration of unchanged drug (UD) was measured up to 48 h. RESULTS: The highest mean TR for all rats was detected in the pancreas (8.9µg-eq/g within 30 min of dosing; below the limit of detection [LOD] after 24 h), the liver (12.5 µg-eq/g within 20 min; 0.3 µg-eq/g after 96 h) and the small intestine (15.6µg-eq/g within 30 min; below the LOD after 24 h). The highest mean concentration of UD in non-pregnant females was detected in the small intestine (10.1 µg-eq/g within 20 min; below the LOD after 24 h). The lowest mean TR was detected in the brain, in males (0.12 µg-eq/g within 30 min), non-pregnant females (0.21 µg-eq/g within 1 h) and pregnant females (0.21 µg-eq/g within 30 min). TR in the brain was below the LOD within 2, 24 and 8 h of dosing, respectively. In non-pregnant females, the highest AUC0–8h and AUC0–8h tissue:plasma ratios of TR were observed in the small intestine (75.3 and 31.3, respectively); the lowest values were observed in the brain (0.85 and 0.35, respectively). Findings were similar for UD. In pregnant females the highest AUC0–8h and AUC0–8h tissue:plasma ratios of TR were observed in rectal (mucosa) and salivary gland tissue (122 and 20.5, respectively, for both); the lowest values were observed in the brain (0.33 and 0.17 [AUC0–2h], respectively). CONCLUSION: After a single oral dose of prucalopride, high concentrations were detected in the pancreas, liver and small intestine, and very low concentrations in the brain (∼0.05% of the dose in non-pregnant female rats). Mean concentrations of TR and UD in the brain were below the LOD within 24h of dosing, suggesting prucalopride is not unduly retained in the brain.

Uptake and release profiles of PEGylated liposomal doxorubicin nanoparticles: A comprehensive picture based on separate determination of encapsulated and total drug concentrations in tissues of tumor-bearing mice

The PEGylated liposomal nanoparticle has been widely used as a carrier in drug delivery system. To become biologically active, the encapsulated drug must be released from the nanoparticle vehicle. However, due to limitations of current bioanalytical methods, the characterization of this release process has been restricted to determination of total drug in tissues and tumor. As a result, the fate of liposomal nanoparticles including their uptake into target tissue has not been fully characterized. In this study, we developed a novel two-step solid phase extraction on two separated columns procedure to separate liposomes from tissues and tumors without liposomal leakage. This allowed us to determine encapsulated drug, total drug and, by difference, released drug and compare the release and uptake profiles of PEGylated liposomal doxorubicin in tissues and tumor of tumor-bearing mice with corresponding profiles for free doxorubicin. The liposomal nanoparticles released doxorubicin into tumor efficiently and, compared with administration of free drug, increased doxorubicin uptake into tumor by 1.8-fold. It also decreased doxorubicin uptake into heart (0.78-fold lower) with the potential to reduce doxorubicin cardiotoxicity. Drug release reached constant levels in tissues and tumor after 12 h with released doxorubicin concentration remaining at 70–80% of total doxorubicin concentration and in tumor at 86% of total drug concentration. The assay also included determination of the main doxorubicin metabolites. Determination of the metabolites showed that liposomal entrapment delays and decreases the metabolism of doxorubicin but does not alter the metabolic pathway. These results provide a clear and comprehensive picture of the biodistribution of doxorubicin administered in liposomal nanoparticles which may assist in the rational design of other liposomal nanoparticles.

A real-time ex vivo model (eIBUB) for optimizing intraperitoneal drug delivery as an alternative to living animal models.

BackgroundOptimization of intraperitoneal drug delivery systems requires functional models. We proposed the Inverted Bovine Urinary Bladder Model (IBUB), but IBUB does not allow repeated measurements over time and there is a significant biological variability between organs.MethodsA further development of IBUB is presented, based on the physical principle of communicating vessels. Fresh bovine bladders were inverted so that the peritoneum lines up the inner surface. The IBUB and a second vessel were then interconnected under the same CO2 pressure and placed on two scales. The therapeutic solution (Doxorubicin 2.7 mg and Cisplatin 13.5 mg) was delivered via an aerosolizer. All experiments were in triplicate and blinded to the origin of samples, measurements in a GLP-certified laboratory.ResultsThe enhanced IBUB (eIBUB) model allows measurements of tissue drug concentration, depth of tissue penetration and spatial distribution. The homogeneous morphology of the peritoneum enables standardized, multiple tissue sampling. eIBUB minimizes biological variability between different bladders and eliminates the bias caused by the liquid collecting at the bottom of the model. Concentration of doxorubicin in the eIBUB (mean ± STDV: 18.5 ± 22.6 ng/mg) were comparable to clinical peritoneal biopsies (19.2 ± 38.6 ng/mg), as was depth of drug penetration (eIBUB: mean (min-max) 433 (381–486) µm, clinical ~ 500 µm).ConclusionsThe eIBUB model is a simple and powerful ex vivo model for optimizing intraperitoneal drug delivery and represents an attractive alternative to animal models. Results obtained are similar to those obtained in the human patient.

Drug Concentration Asymmetry in Tissues and Plasma for Small Molecule-Related Therapeutic Modalities.

The well accepted "free drug hypothesis" for small-molecule drugs assumes that only the free (unbound) drug concentration at the therapeutic target can elicit a pharmacologic effect. Unbound (free) drug concentrations in plasma are readily measurable and are often used as surrogates for the drug concentrations at the site of pharmacologic action in pharmacokinetic-pharmacodynamic analysis and clinical dose projection in drug discovery. Furthermore, for permeable compounds at pharmacokinetic steady state, the free drug concentration in tissue is likely a close approximation of that in plasma; however, several factors can create and maintain disequilibrium between the free drug concentration in plasma and tissue, leading to free drug concentration asymmetry. These factors include drug uptake and extrusion mechanisms involving the uptake and efflux drug transporters, intracellular biotransformation of prodrugs, membrane receptor-mediated uptake of antibody-drug conjugates, pH gradients, unique distribution properties (covalent binders, nanoparticles), and local drug delivery (e.g., inhalation). The impact of these factors on the free drug concentrations in tissues can be represented by K p,uu, the ratio of free drug concentration between tissue and plasma at steady state. This review focuses on situations in which free drug concentrations in tissues may differ from those in plasma (e.g., K p,uu > or <1) and discusses the limitations of the surrogate approach of using plasma-free drug concentration to predict free drug concentrations in tissue. This is an important consideration for novel therapeutic modalities since systemic exposure as a driver of pharmacologic effects may provide limited value in guiding compound optimization, selection, and advancement. Ultimately, a deeper understanding of the relationship between free drug concentrations in plasma and tissues is needed.

Microdialysis combined with liquid chromatography-tandem mass spectrometry for the quantitation of gemifloxacin and its application to a muscle penetration study in healthy and MRSA-infected rats.

Pharmacological efficacy is based on the drug concentration in target tissues, which usually cannot be represented by the plasma concentration. The purpose of this study was to compare the pharmacokinetic characteristics of gemifloxacin in plasma and skeletal muscle and evaluate its tissue penetration in both healthy and MRSA (methicillin-resistant Staphylococcus aureus)-infected rats. A microdialysis (MD) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine free gemifloxacin concentrations in rat plasma and skeletal muscle simultaneously. The in vivo recoveries of MD were 23.21% ± 3.42% for skeletal muscle and 20.62% ± 3.19% for plasma, and were concentration independent. We provided evidence that the method developed here meets FDA requirements. Additionally, this method was successfully applied to the determination of free gemifloxacin in rats. Muscle and blood dialysates were collected after an 18 mg/kg intravenous bolus dose. The mean areas under the concentration-time curves (AUCs) from 0 to 9 h for skeletal muscle and plasma were 3641.50 ± 915.65 h*ng/mL and 7068.32 ± 1964.19 h*ng/mL in MRSA-infected rats and 3774.72 ± 700.36 h*ng/mL and 6927.49 ± 1714.86 h*ng/mL in healthy rats, respectively. There was no significant difference (P>0.05) in gemifloxacin exposure between healthy rats and MRSA-infected rats for plasma or muscle. The low ratio of AUC0-9 muscle to AUC0-9 plasma suggested lower drug exposure in skeletal muscle than in plasma for both healthy and MRSA-infected rats. Our study suggested that the administration of gemifloxacin according to drug levels in plasma to treat local infection is unreasonable and might result in an inadequate dose regimen.

Multifunctional Nanocomposites Based on Liposomes and Layered Double Hydroxides Conjugated with Glycylsarcosine for Efficient Topical Drug Delivery to the Posterior Segment of the Eye.

To achieve efficient drug delivery to the posterior segment of the eye via topical instillation, novel multifunctional nanocomposites were prepared by hybridizing dexamethasone disodium phosphate (DEXP)-loaded liposome (LP) glycylsarcosine (GS)-anchored layered double hydroxides (named DEXP-HSPC@LDH-GS) and then fully characterized. The nanocomposites exhibited sustained-release performance as well as prolonged precorneal retention ability. MTT assays showed that the nanocomposites were not cytotoxic to both human corneal epithelial cells (HCEpiC) and human conjunctival epithelial cells (HConEpiC) at an LDH concentration of 100 μg/mL. The DEXP-HSPC@LDH-GS nanocomposites showed superior in vitro permeability on the HConEpiC-cell-based model. In the case of HConEpiC cells, both clathrin-mediated endocytosis and active transport by the peptide transporter-1 (PepT-1) were involved in the internalization of the nanocomposites. Fluorescent images of frozen sections of ocular tissues suggested that the possible route for the delivery of doxorubicin hydrochloride (DOX)-labeled nanocomposites from the ocular surface to the back of the eye was a non-corneal pathway. Furthermore, in rabbit eyes, the hybrid nanocomposites displayed markedly higher drug concentration in choroid-retina tissue than other single nanocarriers, such as LPs and LDH. Besides, the results of the eye irritancy test showed that nanocomposite eye drops can be classified as nonirritant, which are suitable to be used as eye drops. In a word, multifunctional nanocomposites based on LPs and LDH could be used as promising vehicles for efficient noninvasive drug delivery to the posterior segment of the eye.

Measurement of Free Drug Concentration from Biological Tissue by Solid-Phase Microextraction: In Silico and Experimental Study.

In this article, the use of an SPME technique is reported for the first time for direct measurement of free drug concentration in solid tissue. In our investigations, we considered doxorubicin (DOX) spiked in homogenized tissue matrix at transient and equilibrium extraction conditions, with subsequent assessment of obtained experimental results by an in silico approach using mathematical models developed in COMSOL Multyphysics. In silico studies were performed on the basis of transported diluted species (tds) and reaction engineering (re) modules from COMSOL Multiphysics, using the same conditions as those used to attain experimental results. To determine the apparent binding affinity of DOX to the tissue matrix which contains multiple binding species, the experimentally determined binding affinity of DOX with human serum albumin (HSA) was considered to simplify the mathematical calculations. Here, the value of the binding affinity was considered for a single binding site and adjusted by fitting the experimental results with the mathematical model. Bovine lung tissue homogenate was selected as a surrogate matrix, and a biocompatible C-8 commercial SPME fiber was used for extraction of DOX. In total, four mathematical models were herein developed to describe the mass transfer kinetics of solid coatings: in agar gel at static conditions, in PBS solution with agitated conditions, extraction in PBS solution in the presence of an HSA binding matrix, and static extraction in homogenized lung tissue. For all conditions, simulated results were in good agreement with experimental results. The developed mathematical model allows for measurements of free drug concentrations inside the tissue matrix and facilitates calculations of local depletion of DOX by a solid SPME coating. Results of the investigations indicate that local depletion of the free form of DOX, even at the kinetic stage, is negligible for tissue extraction, as the release of the heavily bound analyte (over 99% binding to tissue matrix) is very rapid, thus easily compensating for the loss of the drug to the SPME coating. This indicates that the dissociation rate constant of DOX from lung tissue components is very rapid; therefore, the mass transfer of drug to the fiber coating via free from is very efficient. Our results also indicate that thin coating SPME fibers provide a good way to measure drug distribution after dosing, as extractions via thin coating SPME fibers do not affect the free concentration of the drug, which is responsible for drug distribution in tissue.

Measurement of soft tissue drug concentrations in morbidly obese and non-obese patients – A prospective, parallel group, open-labeled, controlled, phase IV, single center clinical trial

BackgroundPharmacokinetic (PK) and pharmacodynamic (PD) data on perioperative antibiotic prophylaxis or antibiotic therapy are rare in patients suffering from morbid obesity. Furthermore, dosing regimens should be based on PK/PD models that ensure effective antibiotic exposure not in plasma, but primarily at the site of infection, mostly in the interstitial fluid (ISF). The aim of this trial is to investigate whether current dosing regimens of various antibiotics lead to effective concentrations in the ISF of morbidly obese patients. MethodsWe designed a prospective, parallel group, open-labeled, controlled single center trial to investigate the plasma and tissue pharmacokinetics of the antibiotics linezolid, meropenem, tigecycline, piperacillin/tazobactam, fosfomcyine, cefazolin, metronidazole and as secondary aim the analgesics metamizole and acetaminophen. Inclusion criteria comprise body mass index ≥35 kg/m2 for obese or between 18.5 and 30 kg/m2 for non-obese patients scheduled for elective abdominal surgery. For PK analysis, blood and microdialysate samples of subcutaneous tissue were collected 0–8 h after study drug administration. The primary endpoint is to investigate a possible dependency of the area-under-the-curve (AUC0-8) in the interstitial fluid on body weight and obesity with population based pharmacokinetic analysis. DiscussionInadequate dosing regimes of antibiotics may be a relevant factor for morbidity and mortality of patients, as well as for the development of bacterial antibiotic resistance. The measurement of plasma and tissue concentrations will provide information necessary for PK/PD-modelling. These data about antibiotic PK/PDcharacteristics in soft tissue and their dependence on weight should help to develop weight-dependent models for calculation of patient's individual doses of different antibiotics. Trial registrationEU clinical trials register (EudraCT-No. 2012-004383-22) and German Clinical trials Register (DRKS00004776);

Biodistribution, Safety and Organ Toxicity of Docetaxel-Loaded in HER-2 Aptamer Conjugated Ecoflex® Nanoparticles in a Mouse Xenograft Model of Ovarian Cancer.

Docetaxel is a notably efficient anticancer drug administered for several types of malignancies including ovarian cancer. However, various side effects caused either by the nonspecific distribution of the active ingredient or by high contents of Tween 80 and ethanol in the currently marketed formulations, could even deprive the patients of the treatment. In the current study, a novel targeted delivery system composed of Ecoflex® polymeric nanoparticles loaded with docetaxel and equipped with HER-2 specific aptamer molecules was evaluated regarding blood and tissue toxicity, and biodistribution. The tumor-bearing nude mice, achieved by subcutaneous injection of SKOV-3 cells, were divided into four groups treated with normal saline, Taxotere®, targeted docetaxel nanoparticles, and non-targeted docetaxel nanoparticles. Few patents were alos cied in the article. According to the results of hematologic evaluations, almost all hematologic parameters were in normal range with no significant difference among the four groups. Histopathological studies revealed that treatment with targeted nanoparticles caused a remarkable reduction in mitosis in tumor sections and overall reduced organ toxicity compared with Taxotere®. The only exception was spleen in which more damage was caused by the nanoparticles. The results of the biodistribution study were also in accordance with pathological assessments, with significantly lower drug concentration in non-tumor tissues, except for spleen, when targeted nanoparticles were used compared with Taxotere®. These results could evidence the efficiency of the targeted delivery system in concentrating the drug cargo mostly in its site of action leading to the elimination of its adverse effects caused by exposure of other tissues to the cytotoxic agent.

04:21 PM Abstract No. 392 Trans-pulmonary artery selective chemotherapy delivery to lung using a double balloon-occlusion catheter: feasibility study in swine

To assess the feasibility of selective delivery of chemotherapy in lung using a double balloon occlusion catheter in subsegmental pulmonary arteries (PA) to increase tissue drug concentrations relative to intravenous (IV) administration. Four adult swine were used in this IACUC approved protocol. Via transjugular access, a 6F double balloon-occlusion catheter (RenovoRx Rc-120, Los Altos, CA) was used to isolate a subsegmental branch of the left lower lobe PA in three swine. 5000 IU heparin was given IV. Gemcitabine at 1g/m2 was administered under flow isolation over 20 minutes using an infusion pump (150 max PSI). Gemcitabine at 1g/m2 was administered IV over 20 minutes in a control animal. Peripheral blood was collected during infusion to test systemic drug concentrations. After drug infusion, 6cc methylene blue was infused via the same technique to stain perfused lung tissue. Animals were sacrificed and stained lung was harvested for gemcitabine concentrations. Selective delivery of gemcitabine to subsegmental PA under double balloon occlusion was feasible in all animals. No PA injury occurred and there were no arrythmias. By inspection, no pulmonary hemorrhage or overt injury was seen. Dense methylene blue staining was observed in the parenchyma of animals treated with selective PA delivery up to 3cm around the isolated segment, whereas no discernible blue stain was seen in the animal with IV delivery. Tissue analysis revealed approximately 100x greater tissue gemcitabine levels in animals treated via PA compared to IV (1,272.83 vs. 13.40 mcg/g tissue, T-test, p<0.02). Systemic drug concentrations varied widely from 10%-100% of IV dosing. Selective delivery of chemotherapy to lung via double balloon-occlusion isolation of pulmonary arteries is feasible and led to significantly greater tissue drug concentrations compared with IV administration. Further investigation will investigate the variability in systemic levels to characterize the pharmacokinetic profile for optimized delivery. If successful, this strategy may be promising for treatment of lung cancers not amenable to surgical or ablative techniques.

Promising Chitosan-Coated Alginate-Tween 80 Nanoparticles as Rifampicin Coadministered Ascorbic Acid Delivery Carrier Against Mycobacterium tuberculosis.

The aim of this study was to design a nanocarrier system for inhalation delivery of rifampicin (RIF) in combination with ascorbic acid (ASC), namely constituted of sodium alginate coated with chitosan and Tween 80 (RIF/ASC NPs) as a platform for the treatment of pulmonary tuberculosis infection. A Box-Behnken experimental design and response surface methodology (RSM) were applied to elucidate and evaluate the effects of several factors on the nanoparticle properties. On the other hand, it was found that RIF/ASC NPs were less cytotoxic than the free RIF, showing a significantly improved activity against nine clinical strains of Mycobacterium tuberculosis (M. tb) in comparison with the free drug. RIF/ASC NPs had an average particle size of 324.0 ± 40.7nm, a polydispersity index of 0.226 ± 0.030, and a zeta potential of - 28.52 ± 0.47mV and the surface was hydrophilic. The addition of sucrose (1% w/v) to the nanosuspension resulted in the formation of a solid pellet easily redispersible after lyophilization. RIF/ASC NPs were found to be stable at different physiological pH values. In summary, findings of this work highlight the potential of the RIF/ASC NP-based formulation development herein to deliver RIF in combination with ASC through pulmonary route by exploring a non-invasive route of administration of this antibiotic, increasing the local drug concentrations in lung tissues, the primary infection site, as well as reducing the risk of systemic toxicity and hence improving the patient compliance.

Rate of Drug Coating Dissolution Determines In-Tissue Drug Retention and Durability of Biological Efficacy.

Two different drug-coated balloons (DCBs) possessing different coating formulations were compared for rate of coating dissolution in vitro, in addition to tissue drug concentration and histological responses of treated vascular tissue in vivo, to determine if the rate of drug bioavailability to vascular tissue can impact the degree and duration of the observed pharmacological response to locally delivered drug. In vitro dissolution comparison demonstrated that a urea/paclitaxel-based coating formulation (IN.PACT™ Admiral™) released drug from solid to soluble phase at a slower and constant rate, yielding approximately 7% solubilized drug in 24 h. In contrast, a coating formulated from polysorbate/sorbitol/paclitaxel (Lutonix™) released 51% of solid phase drug to soluble phase in 1 h of dissolution with the remainder solubilizing in 24 h. In vivo evaluation of tissue drug concentration of both products showed significantly different tissue pharmacokinetic profile, with a higher concentration of paclitaxel in tissue at 90 days with a urea-based formulation excipient. Histological comparison of smooth muscle cell loss in response to drug exposure revealed contrasting trends of smooth muscle cell loss from 28 to 90 days with significantly higher response to drug observed at 90 days with the urea-based formulation. Rapid dissolution of drug from the polysorbate/sorbitol coating formulation was associated with an early increase in local cellular response to drug which diminished over 90 days with clearance of local drug from tissue. Sustained long-term drug-in-tissue concentration associated with the urea-based formulation demonstrated sustained pharmacological activity at 90 days, suggesting that slow coating dissolution provides a sustainable long-term tissue response.