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Pharmaceutical Research
Journal Prestige (SJR): 1.077
Citation Impact (citeScore): 3
Number of Followers: 158  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1573-904X - ISSN (Online) 0724-8741
Published by Springer-Verlag Homepage  [2352 journals]
  • Impact of a Heat Shock Protein Impurity on the Immunogenicity of
           Biotherapeutic Monoclonal Antibodies
    • Authors: Shraddha S. Rane; Rebecca J. Dearman; Ian Kimber; Shahid Uddin; Stephen Bishop; Maryam Shah; Adrian Podmore; Alain Pluen; Jeremy P. Derrick
      Abstract: Purpose Anti-drug antibodies can impair the efficacy of therapeutic proteins and, in some circumstances, induce adverse health effects. Immunogenicity can be promoted by aggregation; here we examined the ability of recombinant mouse heat shock protein 70 (rmHSP70) - a common host cell impurity - to modulate the immune responses to aggregates of two therapeutic mAbs in mice. Methods Heat and shaking stress methods were used to generate aggregates in the sub-micron size range from two human mAbs, and immunogenicity assessed by intraperitoneal exposure in BALB/c mice. Results rmHSP70 was shown to bind preferentially to aggregates of both mAbs, but not to the native, monomeric proteins. Aggregates supplemented with 0.1% rmHSP70 induced significantly enhanced IgG2a antibody responses compared with aggregates alone but the effect was not observed for monomeric mAbs. Dendritic cells pulsed with mAb aggregate showed enhanced IFNγ production on co-culture with T cells in the presence of rmHSP70. Conclusion The results indicate a Th1-skewing of the immune response by aggregates and show that murine rmHSP70 selectively modulates the immune response to mAb aggregates, but not monomer. These data suggest that heat shock protein impurities can selectively accumulate by binding to mAb aggregates and thus influence immunogenic responses to therapeutic proteins.
      PubDate: 2019-02-15
      DOI: 10.1007/s11095-019-2586-7
      Issue No: Vol. 36, No. 4 (2019)
  • Evaluation of the Immunomodulatory Effects of All-Trans Retinoic Acid
           Solid Lipid Nanoparticles and Human Mesenchymal Stem Cells in an A549
           Epithelial Cell Line Model
    • Authors: Christina M. Payne; Liam P. Burke; Brenton Cavanagh; Daniel O’Toole; Sally-Ann Cryan; Helena M. Kelly
      Abstract: Purpose To investigate two potential strategies aimed at targeting the inflammatory pathogenesis of COPD: a small molecule, all trans retinoic acid (atRA) and human mesenchymal stem cells (hMSCs). Methods atRA was formulated into solid lipid nanoparticles (SLNs) via the emulsification-ultrasonication method, and these SLNs were characterised physicochemically. Assessment of the immunomodulatory effects of atRA-SLNs on A549 cells in vitro was determined using ELISA. hMSCs were suspended in a previously developed methylcellulose, collagen and beta-glycerophosphate hydrogel prior to investigating their immunomodulatory effects in vitro. Results SLNs provided significant encapsulation of atRA and also sustained its release over 72 h. A549 cells were viable following the addition of atRA SLNs and showed a reduction in IL-6 and IL-8 levels. A549 cells also remained viable following addition of the hMSC/hydrogel formulation – however, this formulation resulted in increased levels of IL-6 and IL-8, indicating a potentially pro-inflammatory effect. Conclusion Both atRA SLNs and hMSCs show potential for modulating the environment in inflammatory disease, though through different mechanisms and leading to different outcomes – despite both being explored as strategies for use in inflammatory disease. atRA shows promise by acting in a directly anti-inflammatory manner, whereas further research into the exact mechanisms and behaviours of hMSCs in inflammatory diseases is required.
      PubDate: 2019-02-13
      DOI: 10.1007/s11095-019-2583-x
      Issue No: Vol. 36, No. 4 (2019)
  • Elucidating the Mechanism of Absorption of Fast-Acting Insulin Aspart: The
           Role of Niacinamide
    • Authors: Jonas Kildegaard; Stephen T. Buckley; Rasmus H. Nielsen; Gro K. Povlsen; Torben Seested; Ulla Ribel; Helle B. Olsen; Svend Ludvigsen; Claus B. Jeppesen; Hanne H. F. Refsgaard; Kristian M. Bendtsen; Niels R. Kristensen; Susanne Hostrup; Jeppe Sturis
      Abstract: Purpose Fast-acting insulin aspart (faster aspart) is a novel formulation of insulin aspart containing two additional excipients: niacinamide, to increase early absorption, and L-arginine, to optimize stability. The aim of this study was to evaluate the impact of niacinamide on insulin aspart absorption and to investigate the mechanism of action underlying the accelerated absorption. Methods The impact of niacinamide was assessed in pharmacokinetic analyses in pigs and humans, small angle X-ray scattering experiments, trans-endothelial transport assays, vascular tension measurements, and subcutaneous blood flow imaging. Results Niacinamide increased the rate of early insulin aspart absorption in pigs, and pharmacokinetic modelling revealed this effect to be most pronounced up to ~30–40 min after injection in humans. Niacinamide increased the relative monomer fraction of insulin aspart by ~35%, and the apparent permeability of insulin aspart across an endothelial cell barrier by ~27%. Niacinamide also induced a concentration-dependent vasorelaxation of porcine arteries, and increased skin perfusion in pigs. Conclusion Niacinamide mediates the acceleration of initial insulin aspart absorption, and the mechanism of action appears to be multifaceted. Niacinamide increases the initial abundance of insulin aspart monomers and transport of insulin aspart after subcutaneous administration, and also mediates a transient, local vasodilatory effect.
      PubDate: 2019-02-11
      DOI: 10.1007/s11095-019-2578-7
      Issue No: Vol. 36, No. 3 (2019)
  • Analyzing the Mechanisms Behind Macrolide Antibiotic-Induced Liver Injury
           Using Quantitative Systems Toxicology Modeling
    • Authors: Jeffrey L. Woodhead; Kyunghee Yang; David Oldach; Chris MacLauchlin; Prabhavathi Fernandes; Paul B. Watkins; Scott Q. Siler; Brett A. Howell
      Abstract: Purpose Macrolide antibiotics are commonly prescribed treatments for drug-resistant bacterial infections; however, many macrolides have been shown to cause liver enzyme elevations and one macrolide, telithromycin, has been pulled from the market by its provider due to liver toxicity. This work seeks to assess the mechanisms responsible for the toxicity of macrolide antibiotics. Methods Five macrolides were assessed in in vitro systems designed to test for bile acid transporter inhibition, mitochondrial dysfunction, and oxidative stress. The macrolides were then represented in DILIsym, a quantitative systems pharmacology (QST) model of drug-induced liver injury, placing the in vitro results in context with each compound’s predicted liver exposure and known biochemistry. Results DILIsym results suggest that solithromycin and clarithromycin toxicity is primarily due to inhibition of the mitochondrial electron transport chain (ETC) while erythromycin toxicity is primarily due to bile acid transporter inhibition. Telithromycin and azithromycin toxicity was not predicted by DILIsym and may be caused by mechanisms not currently incorporated into DILIsym or by unknown metabolite effects. Conclusions The mechanisms responsible for toxicity can be significantly different within a class of drugs, despite the structural similarity among the drugs. QST modeling can provide valuable insight into the nature of these mechanistic differences.
      PubDate: 2019-02-07
      DOI: 10.1007/s11095-019-2582-y
      Issue No: Vol. 36, No. 3 (2019)
  • The Binding of Human IgG to Minipig FcγRs – Implications for
           Preclinical Assessment of Therapeutic Antibodies
    • Authors: Jerome Egli; Tilman Schlothauer; Christian Spick; Stefan Seeber; Thomas Singer; Alex Odermatt; Antonio Iglesias
      Abstract: Purpose The Göttingen minipig is a relevant non-rodent species for regulatory toxicological studies. Yet, its use with therapeutic antibodies has been limited by the unknown binding properties of human immunoglobulins (huIgG) to porcine Fc gamma receptors (poFcγR) influencing safety and efficacy readouts. Therefore, knowing IgG-FcγR interactions in the animal model is a prerequisite for the use of minipigs in preclinical safety and efficacy studies with therapeutic antibodies. Methods Here, we describe the cloning and expression of poFcγRs and their interactions with free and complexed human therapeutic IgG1 by surface plasmon resonance and flow cytometry. Results We show here that poFcγRIa, poFcγRIIa, and poFcγRIIb bind huIgG1 antibodies with comparable affinities as corresponding huFcγRs. Importantly, poFcγRs bind huIgG immune complexes with high avidity, thus probably allowing human-like effector functions. However, poFcγRIIIa binds poIgG1a but not to huIgG1. Conclusions The lack of binding of poFcγRIIIa to huIgG1 might cause underestimation of FcγRIIIa-mediated efficacy or toxicity as mediated by porcine natural killer cells. Therefore, the suitability of minipigs in preclinical studies with human therapeutic antibodies has to be assessed case by case. Our results facilitate the use of Göttingen minipigs for assessment of human therapeutic antibodies in preclinical studies.
      PubDate: 2019-02-05
      DOI: 10.1007/s11095-019-2574-y
      Issue No: Vol. 36, No. 3 (2019)
  • Dosage Optimization Based on Population Pharmacokinetic Analysis of
           Tacrolimus in Chinese Patients with Nephrotic Syndrome
    • Authors: Tong Lu; Xu Zhu; Shansen Xu; Mingming Zhao; Xueshi Huang; Zhanyou Wang; Limei Zhao
      Abstract: Purpose The objective of this study was to merge genetic and non-genetic factors of tacrolimus pharmacokinetics to establish a more stable population pharmacokinetic model for individualized dosage regimen in Chinese nephrotic syndrome patients. Methods Nephrotic syndrome patients (>16 years old) treated with tacrolimus were included in the study. The population pharmacokinetic approach was analyzed using NONMEM version 7.3.0 software. Monte Carlo simulations were performed to optimize the dosage according to the population pharmacokinetic parameters of tacrolimus. Results The mean apparent clearance (CL/F) of tacrolimus was 13.4 L/h, with an inter-individual variability of 22.4%. The CL/F of tacrolimus in Wuzhi tablets co-administration and CYP3A5 non-expresser groups were 19.3% and 19.1% lower than that of the non-Wuzhi tablets and CYP3A5 expresser groups, respectively. The NR1I2 rs2276707 TT variant carriers had 1.17-fold CL/F compared to the CC/CT variant carriers. Monte Carlo simulation showed that the nephrotic syndrome patients that were CYP3A5 non-expressers or co-administered Wuzhi tablets received 50% or 33.3% lower dose of tacrolimus to reach the target concentration. In contrast, the NR1I2 rs227707 TT genotype carriers were administered a 33.3% higher dose of tacrolimus than the NR1I2 rs227707 CC/CT genotype carriers. Conclusions A new population pharmacokinetic model was established to describe the pharmacokinetics of tacrolimus in nephrotic syndrome patients, which can be used to select rational dosage regimens to achieve a desirable whole-blood concentration.
      PubDate: 2019-02-04
      DOI: 10.1007/s11095-019-2579-6
      Issue No: Vol. 36, No. 3 (2019)
  • Pharmacokinetics, Tissue Distribution and Excretion of Ag 2 S Quantum Dots
           in Mice and Rats: the Effects of Injection Dose, Particle Size and Surface
    • Authors: Jaber Javidi; Azadeh Haeri; Fatemeh Nowroozi; Simin Dadashzadeh
      Abstract: Purpose We systematically investigated the effects of injection dose, particle size and surface charge on the pharmacokinetics, tissue distribution and excretion of Ag2S quantum dots (Qds) in rats and mice. Methods Three different doses of Ag2S Qds with similar size and composition were administrated to rats and mice. The effect of size and surface charge was investigated with the injection of three sizes (5, 15 and 25 nm) of Ag2S Qds possessing similar surface charge, as well as 5 nm Qds with a positive surface charge. Results Results indicated that pharmacokinetics and biodistribution of Ag2S Qds were strongly dose, particle size and surface charge dependent. By increasing the dose from 0.5 to 4.0 mg/kg, mean residence time (MRT) and apparent volume of distribution at steady state (Vss) were increased while clearance (CL) was decreased. Qds with a negative surface charge had significantly larger MRT and Vss values than positively charged particles, but their CL was about 50% lower than that of positively charged ones. By increasing Qds size from 5 to 25 nm, CL was increased while MRT and AUC were decreased. Conclusions This study establishes comprehensive principles for the rational design and tailoring of Ag2S Qds for biomedical applications. Graphical The effects of injection dose, particle size and surface charge on pharmacokinetics and tissue distribution of Ag2S Qds after intravenous injection into rats and mice were investigated.
      PubDate: 2019-02-04
      DOI: 10.1007/s11095-019-2571-1
      Issue No: Vol. 36, No. 3 (2019)
  • In vitro Pharmacokinetic Cell Culture System that Simulates Physiologic
           Drug and Nanoparticle Exposure to Macrophages
    • Authors: Hilliard L. Kutscher; Gene D. Morse; Paras N. Prasad; Jessica L. Reynolds
      Abstract: Purpose An in vitro dynamic pharmacokinetic (PK) cell culture system was developed to more precisely simulate physiologic nanoparticle/drug exposure. Methods A dynamic PK cell culture system was developed to more closely reflect physiologic nanoparticle/drug concentrations that are changing with time. Macrophages were cultured in standard static and PK cell culture systems with rifampin (RIF; 5 μg/ml) or β-glucan, chitosan coated, poly(lactic-co-glycolic) acid (GLU-CS-PLGA) nanoparticles (RIF equivalent 5 μg/ml) for 6 h. Intracellular RIF concentrations were measured by UPLC/MS. Antimicrobial activity against M. smegmatis was tested in both PK and static systems. Results The dynamic PK cell culture system mimics a one-compartment elimination pharmacokinetic profile to properly mimic in vivo extracellular exposure. GLU-CS-PLGA nanoparticles increased intracellular RIF concentration by 37% compared to free drug in the dynamic cell culture system. GLU-CS-PLGA nanoparticles decreased M. smegmatis colony forming units compared to free drug in the dynamic cell culture system. Conclusions The PK cell culture system developed herein enables more precise simulation of human PK exposure (i.e., drug dosing and drug elimination curves) based on previously obtained PK parameters.
      PubDate: 2019-02-01
      DOI: 10.1007/s11095-019-2576-9
      Issue No: Vol. 36, No. 3 (2019)
  • Particle Surface Roughness Improves Colloidal Stability of Pressurized
           Pharmaceutical Suspensions
    • Authors: Hui Wang; David S. Nobes; Reinhard Vehring
      Abstract: Purpose The effects of particle size and particle surface roughness on the colloidal stability of pressurized pharmaceutical suspensions were investigated using monodisperse spray-dried particles. Methods The colloidal stability of multiple suspensions in the propellant HFA227ea was characterized using a shadowgraphic imaging technique and quantitatively compared using an instability index. Model suspensions of monodisperse spray-dried trehalose particles of narrow distributions (GSD < 1.2) and different sizes (MMAD = 5.98 μm, 10.1 μm, 15.5 μm) were measured first to study the dependence of colloidal stability on particle size. Particles with different surface rugosity were then designed by adding different fractions of trileucine, a shell former, and their suspension stability measured to further study the effects of surface roughness on the colloidal stability of pressurized suspensions. Results The colloidal stability significantly improved (p < 0.001) from the suspension with 15.5 μm-particles to the suspension with 5.98 μm-particles as quantified by the decreased instability index from 0.63 ± 0.04 to 0.07 ± 0.01, demonstrating a strongly size-dependent colloidal stability. No significant improvement of suspension stability (p > 0.1) was observed at low trileucine fraction at 0.4 % where particles remained relatively smooth until the surface rugosity of the particles was improved by the higher trileucine fractions at 1.0 % and 5.0 %, which was indicated by the substantially decreased instability index from 0.27 ± 0.02 for the suspensions with trehalose model particles to 0.18 ± 0.01 (p < 0.01) and 0.03 ± 0.01 (p < 0.002) respectively. Conclusions Surface modification of particles by adding shell formers like trileucine to the feed solutions of spray drying was demonstrated to be a promising method of improving the colloidal stability of pharmaceutical suspensions in pressurized metered dose inhalers.
      PubDate: 2019-01-30
      DOI: 10.1007/s11095-019-2572-0
      Issue No: Vol. 36, No. 3 (2019)
  • 3D Printing of Pharmaceutical and Medical Applications: a New Era
    • Authors: Dionysios Douroumis
      PubDate: 2019-01-25
      DOI: 10.1007/s11095-019-2575-x
      Issue No: Vol. 36, No. 3 (2019)
  • A Population Dynamic Energy Budget-Based Tumor Growth Inhibition Model for
           Etoposide Effects on Wistar Rats
    • Authors: E. M. Tosca; M. C. Pigatto; T. Dalla Costa; P. Magni
      Abstract: Purpose This work aimed to develop a population PK/PD tumor-in-host model able to describe etoposide effects on both tumor cells and host in Walker-256 tumor-bearing rats. Methods Etoposide was investigated on thirty-eight Wistar rats randomized in five arms: two groups of tumor-free animals receiving either placebo or etoposide (10 mg/kg bolus for 4 days) and three groups of tumor-bearing animals receiving either placebo or etoposide (5 or 10 mg/kg bolus for 8 or 4 days, respectively). To analyze experimental data, a tumor-in-host growth inhibition (TGI) model, based on the Dynamic Energy Budget (DEB) theory, was developed. Total plasma and free-interstitial tumor etoposide concentrations were assessed as driver of tumor kinetics. Results The model simultaneously describes tumor and host growths, etoposide antitumor effect as well as cachexia phenomena related to both the tumor and the drug treatment. The schedule-dependent inhibitory effect of etoposide is also well captured when the intratumoral drug concentration is considered as the driver of the tumor kinetics. Conclusions The DEB-based TGI model capabilities, up to now assessed only in mice, are fully confirmed in this study involving rats. Results suggest that well designed experiments combined with a mechanistic modeling approach could be extremely useful to understand drug effects and to describe all the dynamics characterizing in vivo tumor growth studies.
      PubDate: 2019-01-11
      DOI: 10.1007/s11095-019-2568-9
      Issue No: Vol. 36, No. 3 (2019)
  • Knockdown of Orphan Transporter SLC22A18 Impairs Lipid Metabolism and
           Increases Invasiveness of HepG2 Cells
    • Authors: Shingo Ito; Gentaro Honda; Yu Fujino; Seiryo Ogata; Mio Hirayama-Kurogi; Sumio Ohtsuki
      Abstract: Purpose The aim of this work is to investigate the roles of solute carrier family 22 member 18 (SLC22A18) in lipid metabolism and in establishing the tumor phenotype of HepG2 cells. Methods SLC22A18-knockdown HepG2 cells were established by stable transfection with shRNA. Protein expression levels were measured by quantitative proteomics and Western blot analysis. Cell growth was examined by cell counting kit. Accumulation of triglyceride-rich lipid droplets was measured by Oil-Red O staining. Cell migration and invasion were examined by Transwell assays. Results SLC22A18-knockdown HepG2 cells accumulated triglyceride-rich lipid droplets and showed decreased expression levels of lysosomal/autophagic proteins, suggesting that lipid degradation is suppressed. Growth of HepG2 cells was decreased by SLC22A18 knockdown, but was restored by free fatty acid supplementation. In addition, SLC22A18 knockdown decreased the expression of insulin-like growth factor-binding protein 1 (IGFBP-1) and increased the invasion ability of HepG2 cells. Exogenous IGFBP-1 blocked the increase of invasion activity induced by SLC22A18 knockdown. Conclusion Our results suggest that suppression of SLC22A18 decreased the supply of intracellular free fatty acids from triglyceride-rich lipid droplets by impairing the lysosomal/autophagy degradation pathway and reduced the invasive activity of HepG2 cells by decreasing IGFBP-1 expression.
      PubDate: 2019-01-11
      DOI: 10.1007/s11095-018-2565-4
      Issue No: Vol. 36, No. 3 (2019)
  • Application of a Quality-By-Design Approach to Optimise Lipid-Polymer
           Hybrid Nanoparticles Loaded with a Splice-Correction Antisense
           Oligonucleotide: Maximising Loading and Intracellular Delivery
    • Authors: Kaushik Thanki; Simon Papai; Abhijeet Lokras; Fabrice Rose; Emily Falkenberg; Henrik Franzyk; Camilla Foged
      Abstract: Background Antisense oligonucleotides (ASOs) are promising therapeutics for specific modulation of cellular RNA function. However, ASO efficacy is compromised by inefficient intracellular delivery. Lipid-polymer hybrid nanoparticles (LPNs) are attractive mediators of intracellular ASO delivery due to favorable colloidal stability and sustained release properties. Methods LPNs composed of cationic lipidoid 5 (L5) and poly(DL-lactic-co-glycolic acid) were studied for delivery of an ASO mediating splice correction of a luciferase gene transcript (Luc-ASO). Specific purposes were: (i) to increase the mechanistic understanding of factors determining the loading of ASO in LPNs, and (ii) to optimise the LPNs and customise them for Luc-ASO delivery in HeLa pLuc/705 cells containing an aberrant luciferase gene by using a quality-by-design approach. Critical formulation variables were linked to critical quality attributes (CQAs) using risk assessment and design of experiments, followed by delineation of an optimal operating space (OOS). Results A series of CQAs were identified based on the quality target product profile. The L5 content and L5:Luc-ASO ratio (w/w) were determined as critical formulation variables, which were optimised systematically. The optimised Luc-ASO-loaded LPNs, defined from the OOS, displayed high loading and mediated splice correction at well-tolerated, lower doses as compared to those required for reference L5-based lipoplexes, L5-modified stable nucleic acid lipid nanoparticles or LPNs modified with dioleoyltrimethylammonium propane (conventional cationic lipid). Conclusions The optimal Luc-ASO-loaded LPNs represent a robust formulation that mediates efficient intracellular delivery of Luc-ASO. This opens new avenues for further development of LPNs as a broadly applicable technology platform for delivering nucleic acid cargos intracellularly.
      PubDate: 2019-01-09
      DOI: 10.1007/s11095-018-2566-3
      Issue No: Vol. 36, No. 3 (2019)
  • Correction to: Creation of Straight-Chain Cationic Polysaccharide-Based
           Bile Salt Sequestrants Made from Euglenoid β-1,3-Glucan as Potential
           Antidiabetic Agents
    • Authors: Motonari Shibakami; Kazuhiko Shibata; Akira Akashi; Nobuteru Onaka; Jun Takezaki; Gen Tsubouchi; Hiroaki Yoshikawa
      Abstract: The corresponding author (Motonari Shibakami) inadvertently failed to include his ORCID ID: In the published article.
      PubDate: 2019-01-02
      DOI: 10.1007/s11095-018-2559-2
      Issue No: Vol. 36, No. 2 (2019)
  • Editorial to Theme Issue on Cell Based Therapeutics
    • PubDate: 2019-01-23
      DOI: 10.1007/s11095-019-2573-z
  • Review of Biomarkers in Ocular Matrices: Challenges and Opportunities
    • Abstract: Biomarkers provide a powerful and dynamic approach to improve our understanding of the mechanisms underlying ocular diseases with applications in diagnosis, disease modulation or for predicting and monitoring of clinical response to treatment. Defined as measurable indicator of normal or pathological processes, biomarker evaluation has been used extensively in drug development within clinical settings to better comprehend effectiveness of treatment in ocular diseases. Biomarkers in the eye have the advantage of access to multiple ocular matrices via minimally invasive methods. Repeat sampling for biomarker assessment has enabled reproducible objective measures of disease process or biological responses to a drug treatment. This review describes the usage of biomarkers with respect to four commonly sampled ocular matrices in clinic: tears, conjunctiva, aqueous humor and vitreous. Issues that affect the evaluation of biomarkers are discussed along with opportunities to leverage biomarkers such that ultimately, they can be used for customized targeted therapy.
      PubDate: 2019-01-23
      DOI: 10.1007/s11095-019-2569-8
  • Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease
    • Abstract: Inherited retinal diseases (IRDs) are a group of rare, heterogenous eye disorders caused by gene mutations that result in degeneration of the retina. There are currently limited treatment options for IRDs; however, retinal gene therapy holds great promise for the treatment of different forms of inherited blindness. One such IRD for which gene therapy has shown positive initial results is choroideremia, a rare, X-linked degenerative disorder of the retina and choroid. Mutation of the CHM gene leads to an absence of functional Rab escort protein 1 (REP1), which causes retinal pigment epithelium cell death and photoreceptor degeneration. The condition presents in childhood as night blindness, followed by progressive constriction of visual fields, generally leading to vision loss in early adulthood and total blindness thereafter. A recently developed adeno-associated virus-2 (AAV2) vector construct encoding REP1 (AAV2-REP1) has been shown to deliver a functional version of the CHM gene into the retinal pigment epithelium and photoreceptor cells. Phase 1 and 2 studies of AAV2-REP1 in patients with choroideremia have produced encouraging results, suggesting that it is possible not only to slow or stop the decline in vision following treatment with AAV2-REP1, but also to improve visual acuity in some patients.
      PubDate: 2019-01-07
      DOI: 10.1007/s11095-018-2564-5
  • Machine Learning Models for the Prediction of Chemotherapy-Induced
           Peripheral Neuropathy
    • Abstract: Purpose Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse side effect of cancer chemotherapy that can be life debilitating and cause extreme pain. The multifactorial and poorly understood mechanisms of toxicity have impeded the identification of novel treatment strategies. Computational models of drug neurotoxicity could be implemented in early drug discovery to screen for high-risk compounds and select safer drug candidates for further development. Methods Quantitative-structure toxicity relationship (QSTR) models were developed to predict the incidence of PN. A manually curated library of 95 approved drugs were used to develop the model. Molecular descriptors sensitive to the incidence of PN were identified to provide insights into structural modifications to reduce neurotoxicity. The incidence of PN was predicted for 60 antineoplastic drug candidates currently under clinical investigation. Results The number of aromatic nitrogens was identified as the most important molecular descriptor. The chemical transformation of aromatic nitrogens to carbons reduced the predicted PN incidence of bortezomib from 32.3% to 21.1%. Antineoplastic drug candidates were categorized into three groups (high, medium, low) based on their predicted PN incidence. Conclusions QSTR models were developed to link physicochemical descriptors of compounds with PN incidence, which can be utilized during drug candidate selection to reduce neurotoxicity.
      PubDate: 2019-01-07
      DOI: 10.1007/s11095-018-2562-7
  • Ocular Pharmacokinetics of a Topical Ophthalmic Nanomicellar Solution of
           Cyclosporine (Cequa®) for Dry Eye Disease
    • Abstract: Cequa®, a unique and first-in-class preservative free cyclosporine-A (CsA) nanomicellar topical formulation was recently approved by US FDA for treatment of dry eye disease or keratoconjuntivitis sicca (KCS). Being highly hydrophobic, CsA is currently available as an oil based emulsion, which has its own shortcomings. Developing an aqueous and clear formulation of CsA is imperative yet a challenging need in the quest for a safe and better drug product. In this regard, a novel, clear, aqueous nanomicellar solution of CsA was developed which has the potential to deliver therapeutic concentrations of CsA with minimal discomfort to patients. Highly promising pre-clinical results of Cequa® (OTX-101), has led to its advancement to the clinical trials. Phase III clinical trials have demonstrated that OTX-101 is highly effective, safe, and has a rapid onset of action in treating KCS. This review presents a comprehensive insight on formulation development, preclinical and clinical pharmacokinetic results of Cequa®. Additionally, the translational development of Cequa® from the laboratory benchtop to patient bedside has been discussed.
      PubDate: 2019-01-07
      DOI: 10.1007/s11095-018-2556-5
  • Impact of Older Age on the Exposure of Paclitaxel: a Population
           Pharmacokinetic Study
    • Abstract: Purpose Limited available data suggest that older patients are more prone to develop paclitaxel-induced toxicity than their younger peers. It remains unclear whether this is related to age-dependent pharmacokinetics (PK) of paclitaxel. Primary objective of this study was to determine the influence of older age on the PK of paclitaxel. Methods PK data of patients aged ≥70 years who received paclitaxel intravenously at the Netherlands Cancer Institute (NKI) and the Radboud University Medical Center between September 2012 and May 2017 were collected. These prospectively collected data were pooled with previously published databases from multiple clinical trials conducted at the NKI and Erasmus MC Cancer Institute. A previously developed 3-compartment population PK model with saturable distribution and elimination was used to describe paclitaxel plasma concentration-time data. Hereafter, influence of age on paclitaxel PK was assessed in a previously established full covariate model. Results In total, paclitaxel PK data from 684 patients were available, consisting of 166 patients ≥70 years (24%). Median age of the cohort was 61 years (range 18 to 84 years). The impact of age, either treated as a continuous or dichotomous covariate (<70 versus ≥70 years), on the elimination of paclitaxel was only marginal but statistically significant (both p < 0.001 with no clinically relevant decrease in interindividual variability). For a typical patient, maximal elimination capacity decreased by only 5% for a 10-year increment of age. Conclusion In this extensive multi-center dataset, which included a considerable number of older patients, older age had no clinically relevant impact on paclitaxel PK.
      PubDate: 2019-01-07
      DOI: 10.1007/s11095-018-2563-6
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