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AAPS Journal

Xu Steven Xu, Min Yuan, Haitao Yang, Yan Feng, Jinfeng Xu, Jose Pinheiro
Covariate analysis based on population pharmacokinetics (PPK) is used to identify clinically relevant factors. The likelihood ratio test (LRT) based on nonlinear mixed effect model fits is currently recommended for covariate identification, whereas individual empirical Bayesian estimates (EBEs) are considered unreliable due to the presence of shrinkage. The objectives of this research were to investigate the type I error for LRT and EBE approaches, to confirm the similarity of power between the LRT and EBE approaches from a previous report and to explore the influence of shrinkage on LRT and EBE inferences...
October 19, 2016: AAPS Journal
Sam Maher, Mekki Medani, Nestor N Carballeira, Desmond C Winter, Alan W Baird, David J Brayden
Intestinal permeation enhancers (PEs) offer an attractive strategy to enable oral peptide administration. However, optimal presentation of peptide and PE from solid-dosage forms is offset by slow dissolution rates in the small intestine, which reduces the likelihood that the PE can reach the threshold concentration for sufficient permeability enhancement. The purpose of this study was to design a PE-based liquid dispersion that can improve intestinal permeation of macromolecules across Caco-2 monolayers and isolated rat/human intestinal mucosae mounted in Ussing chambers...
October 13, 2016: AAPS Journal
Helena Edlund, Casper Steenholdt, Mark A Ainsworth, Eva Goebgen, Jørn Brynskov, Ole Ø Thomsen, Wilhelm Huisinga, Charlotte Kloft
Antibodies (Abs) against infliximab (IFX) increase IFX clearance and can result in treatment failure and acute hypersensitivity reactions. However, interpretation of their clinical value is complicated by individual differences in Ab responses and methods used for quantification. The increase in IFX clearance imposed by anti-IFX Abs has generally been evaluated using a binary classification, i.e., positive or negative. This analysis aimed to investigate if anti-IFX Ab concentrations provide a more adequate prediction of alterations in clearance...
October 13, 2016: AAPS Journal
Saloumeh Kadkhodayan Fischer, Melissa Cheu, Kun Peng, John Lowe, James Araujo, Elaine Murray, Dana McClintock, John Matthews, Patricia Siguenza, An Song
Host cell proteins are manufacturing process-related impurities that may co-purify with the product despite extensive efforts to optimize the purification process. The risks associated with these impurities can vary and may be patient and/or therapeutic dependent. Therefore, it is critical to monitor and control the levels of these impurities in products and their potential impact on safety and efficacy. Lebrikizumab is a humanized immunoglobulin G4 monoclonal antibody (mAb) that binds specifically to soluble interleukin 13...
October 13, 2016: AAPS Journal
Miguel Montenegro-Nicolini, Víctor Miranda, Javier O Morales
Peptides and proteins represent a promissory group of molecules used by the pharmaceutical industry for drug therapy with great potential for development. However, the administration of these molecules presents a series of difficulties, making necessary the exploration of new alternatives like the buccal route of administration to improve drug therapy compliance. Although drop-on demand printers have been explored for small molecule drugs with promising results, the development of delivery systems for peptides and proteins through inkjet printing has seen little development...
October 13, 2016: AAPS Journal
Marla C Dubinsky, Becky L Phan, Namita Singh, Shervin Rabizadeh, Diane R Mould
Standard of care (SOC; combination of 5-10 mg/kg and an interval every 6-8 weeks) dosing of infliximab (IFX) is associated with significant loss of response. Dashboards using covariates that influence IFX pharmacokinetics (PK) may be a more precise way of optimizing anti-TNF dosing. We tested a prototype dashboard to compare forecasted dosing regimens with actual administered regimens and SOC. Fifty IBD patients completing IFX induction were monitored during maintenance (weeks 14-54). Clinical and laboratory data were collected at each infusion; serum was analyzed for IFX concentrations and anti-drug antibodies (ADA) at weeks 14 and 54 (Prometheus Labs, San Diego)...
October 13, 2016: AAPS Journal
Yi Tsong, Qi Xia, Yu-Ting Weng
No abstract text is available yet for this article.
October 5, 2016: AAPS Journal
Richard Burdick, Todd Coffey, Hiten Gutka, Gyöngyi Gratzl, Hugh D Conlon, Chi-Ting Huang, Michael Boyne, Henriette Kuehne
Protein therapeutics have unique critical quality attributes (CQAs) that define their purity, potency, and safety. The analytical methods used to assess CQAs must be able to distinguish clinically meaningful differences in comparator products, and the most important CQAs should be evaluated with the most statistical rigor. High-risk CQA measurements assess the most important attributes that directly impact the clinical mechanism of action or have known implications for safety, while the moderate- to low-risk characteristics may have a lower direct impact and thereby may have a broader range to establish similarity...
October 5, 2016: AAPS Journal
Shilong Zhong, Weichao Han, Chuqi Hou, Junjin Liu, Lili Wu, Menghua Liu, Zhi Liang, Haoming Lin, Lili Zhou, Shuwen Liu, Lan Tang
Cytochrome P450 (CYPs) and UDP-glucuronosyltransferases (UGTs) play important roles in the metabolism of exogenous and endogenous compounds. The gene transcription of CYPs and UGTs can be enhanced or reduced by transcription factors (TFs). This study aims to explore novel TFs involved in the regulatory network of human hepatic UGTs/CYPs. Correlations between the transcription levels of 683 key TFs and CYPs/UGTs in three different human liver expression profiles (n = 640) were calculated first. Supervised weighted correlation network analysis (sWGCNA) was employed to define hub genes among the selected TFs...
September 28, 2016: AAPS Journal
Tim Cardilin, Joachim Almquist, Mats Jirstrand, Alexandre Sostelly, Christiane Amendt, Samer El Bawab, Johan Gabrielsson
Combination therapies are widely accepted as a cornerstone for treatment of different cancer types. A tumor growth inhibition (TGI) model is developed for combinations of cetuximab and cisplatin obtained from xenograft mice. Unlike traditional TGI models, both natural cell growth and cell death are considered explicitly. The growth rate was estimated to 0.006 h(-1) and the natural cell death to 0.0039 h(-1) resulting in a tumor doubling time of 14 days. The tumor static concentrations (TSC) are predicted for each individual compound...
September 28, 2016: AAPS Journal
Siddharth Sukumaran, Crystal Zhang, Douglas D Leipold, Ola M Saad, Keyang Xu, Kapil Gadkar, Divya Samineni, Bei Wang, Marija Milojic-Blair, Montserrat Carrasco-Triguero, Bonnee Rubinfeld, Paul Fielder, Kedan Lin, Saroja Ramanujan
Antibody drug conjugates (ADC), in which small molecule cytotoxic agents are non-specifically linked to antibodies, can enable targeted delivery of chemotherapeutics to tumor cells. ADCs are often produced and administered as a mixture of conjugated antibodies with different drug to antibody ratios (DAR) resulting in complex and heterogeneous disposition kinetics. We developed a mechanism-based platform model that can describe and predict the complex pharmacokinetic (PK) behavior of ADCs with protease-cleavable valine-citrulline (VC) linker linked to Monomethylmonomethyl auristatin F/E by incorporating known mechanisms of ADC disposition...
September 27, 2016: AAPS Journal
Thaigarajan Parumasivam, Sharon S Y Leung, Patricia Tang, Citterio Mauro, Warwick Britton, Hak-Kim Chan
The routine of loading multiple capsules for delivery of high-dose antibiotics is time consuming, which may reduce patient adherence to inhaled treatment. To overcome this limitation, an investigation was carried out using four modified versions of the Aerolizer® that accommodate a size 0 capsule for delivery of high payload formulations. In some prototypes, four piercing pins of 0.6 mm each were replaced with a single centrally located 1.2-mm pin and one-third reduced air inlet of the original design. The performance of these inhalers was evaluated using spray-dried antibiotic powders with distinct morphologies: spherical particles with a highly corrugated surface (colistin and tobramycin) and needle-like particles (rifapentine)...
September 27, 2016: AAPS Journal
Sheetal D'Mello, Keerthi Atluri, Sean M Geary, Liu Hong, Satheesh Elangovan, Aliasger K Salem
Gene delivery to bone is a potential therapeutic strategy for directed, sustained, and regulated protein expression. Tissue engineering strategies for bone regeneration include delivery of proteins, genes (viral and non-viral-mediated delivery), and/or cells to the bone defect site. In addition, biomimetic scaffolds and scaffolds incorporating bone anabolic agents greatly enhance the bone repair process. Regional gene therapy has the potential of enhancing bone defect healing and bone regeneration by delivering osteogenic genes locally to the osseous lesions, thereby reducing systemic toxicity and the need for using supraphysiological dosages of therapeutic proteins...
September 21, 2016: AAPS Journal
Min Li, Sanna Sander, John Duan, Susan Rosencrance, Sarah Pope Miksinski, Lawrence Yu, Paul Seo, Bhagwant Rege
This review presents scientific and regulatory considerations for the development of solid oral modified release (MR) drug products. It includes a rationale for patient-focused development based on Quality-by-Design (QbD) principles. Product and process understanding of MR products includes identification and risk-based evaluation of critical material attributes (CMAs), critical process parameters (CPPs), and their impact on critical quality attributes (CQAs) that affect the clinical performance. The use of various biopharmaceutics tools that link the CQAs to a predictable and reproducible clinical performance for patient benefit is emphasized...
September 20, 2016: AAPS Journal
A M Novakovic, E H J Krekels, A Munafo, S Ueckert, M O Karlsson
In this study, we report the development of the first item response theory (IRT) model within a pharmacometrics framework to characterize the disease progression in multiple sclerosis (MS), as measured by Expanded Disability Status Score (EDSS). Data were collected quarterly from a 96-week phase III clinical study by a blinder rater, involving 104,206 item-level observations from 1319 patients with relapsing-remitting MS (RRMS), treated with placebo or cladribine. Observed scores for each EDSS item were modeled describing the probability of a given score as a function of patients' (unobserved) disability using a logistic model...
September 15, 2016: AAPS Journal
Shereen Yousef, Yousuf Mohammed, Sarika Namjoshi, Jeffrey Grice, Wedad Sakran, Michael Roberts
We sought to understand when and how hydration enhances the percutaneous absorption of salicylate esters. Human epidermal membrane fluxes and stratum corneum solubilities of neat and diluted solutions of three esters were determined under hydrated and dehydrated conditions. Hydration doubled the human epidermal flux seen for methyl and ethyl salicylate under dehydrated conditions and increased the flux of neat glycol salicylate 10-fold. Mechanistic analyses showed that this hydration-induced enhancement arises mainly from an increase in the stratum corneum diffusivity of the three esters...
September 15, 2016: AAPS Journal
Songyan Zheng, Aastha Puri, Jinjiang Li, Archana Jaiswal, Monica Adams
Micro-flow imaging (MFI) has been used for formulation development for analyzing sub-visible particles. Archimedes, a novel technique for analyzing sub-micron particles, has been considered as an orthogonal method to currently existing techniques. This study utilized these two techniques to investigate the effectiveness of polysorbate (PS-80) in mitigating the particle formation of a therapeutic protein formulation stored in silicone oil-coated pre-filled syringes. The results indicated that PS-80 prevented the formation of both protein and silicone oil particles...
September 12, 2016: AAPS Journal
Jennifer H Grossman, Rachael M Crist, Jeffrey D Clogston
The vast majority of drug product candidates in early development fail to progress to clinics. This is true for products containing nanomaterials just as for other types of pharmaceuticals. Early development pathways should therefore place high priority on experiments that help candidates fail faster and less expensively. Nanomedicines fail for many reasons, but some are more avoidable than others. Some of the points of failure are not considerations in the development of small molecules or biopharmaceuticals, and so may be unexpected, even to those with previous experience bringing drug products to the clinic...
September 9, 2016: AAPS Journal
Greg Troiano, Jim Nolan, Donald Parsons, Christina Van Geen Hoven, Stephen Zale
The translation of nanomedicines from concepts to commercial products has not reached its full potential, in part because of the technical and regulatory challenges associated with chemistry, manufacturing, and controls (CMC) development of such complex products. It is critical to take a quality by design (QbD) approach to developing nanomedicines-using a risk-based approach to identifying and classifying product attributes and process parameters and ultimately developing a deep understanding of the products, processes, and platform...
September 8, 2016: AAPS Journal
Robert R Smith, Umang V Shah, Jose V Parambil, Daniel J Burnett, Frank Thielmann, Jerry Y Y Heng
The aim of this work was to assess the effect of different crystalline polymorphism on surface energetics of D-mannitol using finite dilution inverse gas chromatography (FD-IGC). Pure α, β and δ polymorphs were prepared via solution crystallisation and characterised by powder X-ray diffraction (P-XRD). The dispersive surface energies were found to range from 43 to 34 mJ/m(2), 50 to 41 mJ/m(2), and 48 to 38 mJ/m(2) , for α, β, and δ, respectively, for surface coverage ranging from 0.006 to 0.095. A deconvolution modelling approach was employed to establish their energy sites...
September 8, 2016: AAPS Journal
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