1,510 results match your criteria The AAPS Journal [Journal]


Moringa Isothiocyanate Activates Nrf2: Potential Role in Diabetic Nephropathy.

AAPS J 2019 Feb 19;21(2):31. Epub 2019 Feb 19.

Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 228, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA.

Moringa isothiocyanate (MIC-1) is the main active isothiocyanate found in Moringa oleifera, a plant consumed as diet and traditional herbal medicine. Compared to sulforaphane (SFN), MICs are less studied and most work have focused on its anti-inflammatory activity. The purpose of this study is to better understand the Nrf2-ARE antioxidant activity of MIC-1 and its potential in diabetic nephropathy. Read More

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http://dx.doi.org/10.1208/s12248-019-0301-6DOI Listing
February 2019

Activation of Protein Kinase A Stimulates SUMOylation, Expression, and Transport Activity of Organic Anion Transporter 3.

AAPS J 2019 Feb 13;21(2):30. Epub 2019 Feb 13.

Department of Pharmaceutics, Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, New Jersey, 08854, USA.

Organic anion transporter 3 (OAT3) plays a vital role in removing a broad variety of anionic drugs from kidney, thus avoiding their possible toxicity in the body. We earlier established that activation of protein kinase C (PKC) enhances OAT3 ubiquitination, which promotes OAT3 internalization from the cell plasma membrane to intracellular endosomes and consequent degradation. As a result, OAT3 expression and transport activity are reduced. Read More

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http://dx.doi.org/10.1208/s12248-019-0303-4DOI Listing
February 2019

Dissolution and Translational Modeling Strategies Toward Establishing an In Vitro-In Vivo Link-a Workshop Summary Report.

AAPS J 2019 Feb 11;21(2):29. Epub 2019 Feb 11.

Pharmaceutical Sciences, Merck & Co., Inc., 770 Sumneytown Pike, WP75B-210, West Point, Pennsylvania, 19486-0004, USA.

This publication summarizes the proceedings of day 2 of a 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." Patient-centric drug product development from a drug product quality perspective necessitates the establishment of clinically relevant drug product specifications via an in vitro-in vivo link. Modeling and simulation offer a path to establish this link; in this regard, physiologically based modeling has been implemented successfully to support regulatory decision-making and drug product labeling. Read More

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http://dx.doi.org/10.1208/s12248-019-0298-xDOI Listing
February 2019

Incurred Sample Reanalysis: Time to Change the Sample Size Calculation?

AAPS J 2019 Feb 11;21(2):28. Epub 2019 Feb 11.

Pharmacokinetics Department, Pharmaceutical Research Institute, 8 Rydygiera Street, 01-793, Warsaw, Poland.

Reliable results of pharmacokinetic and toxicokinetic studies are vital for correct decision making during drug discovery and development. Thus, ensuring high quality of bioanalytical methods is of critical importance. Incurred sample reanalysis (ISR)-one of the tools used to validate a method-is included in the bioanalytical regulatory recommendations. Read More

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http://dx.doi.org/10.1208/s12248-019-0293-2DOI Listing
February 2019

Estimation of Solid Tumor Doubling Times from Progression-Free Survival Plots Using a Novel Statistical Approach.

AAPS J 2019 Feb 8;21(2):27. Epub 2019 Feb 8.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Kapoor Hall, Buffalo, New York, 14214, USA.

Tumor doubling time can significantly affect the outcome of anticancer therapy, but it is very challenging to determine. Here, we present a statistical approach that extracts doubling times from progression-free survival (PFS) plots, which inherently contains information regarding the growth of solid tumors. Twelve cancers were investigated and multiple PFS plots were evaluated for each type. Read More

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http://dx.doi.org/10.1208/s12248-019-0302-5DOI Listing
February 2019
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Multiplexed Gene Expression as a Characterization of Bioactivity for Interferon Beta (IFN-β) Biosimilar Candidates: Impact of Innate Immune Response Modulating Impurities (IIRMIs).

AAPS J 2019 Feb 8;21(2):26. Epub 2019 Feb 8.

Laboratory of Immunology, Division of Biotechnology Review and Research III, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Building 52-Room 2112, 10903 New Hampshire Av., Silver Spring, Maryland, 20993, USA.

Recombinant human interferon-β (rhIFN-β) therapy is the first-line treatment in relapsing-remitting forms of multiple sclerosis (MS). The mechanism of action underlying its therapeutic activity is only partially understood as IFN-βs induce the expression of over 1000 genes modifying multiple immune pathways. Currently, assessment of potency for IFN-β products is based on their antiviral effect, which is not linked to its therapeutic effect. Read More

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http://dx.doi.org/10.1208/s12248-019-0300-7DOI Listing
February 2019
1 Read

Development of a New Inhaler for High-Efficiency Dispersion of Spray-Dried Powders Using Computational Fluid Dynamics (CFD) Modeling.

AAPS J 2019 Feb 7;21(2):25. Epub 2019 Feb 7.

Department of Mechanical and Nuclear Engineering, Virginia Commonwealth University, 401 West Main Street, P. O. Box 843015, Richmond, Virginia, 23284, USA.

Computational fluid dynamics (CFD) modeling offers a powerful tool for the development of drug delivery devices using a first principles approach but has been underutilized in the development of pharmaceutical inhalers. The objective of this study was to develop quantitative correlations for predicting the aerosolization behavior of a newly proposed dry powder inhaler (DPI). The dose aerosolization and containment (DAC) unit DPI utilizes inlet and outlet air orifices designed to maximize the dispersion of spray-dried powders, typically with low air volumes (~ 10 mL) and relatively low airflow rates (~ 3 L/min). Read More

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February 2019
1 Read

Systemic Bioequivalence Is Unlikely to Equal Target Site Bioequivalence for Nanotechnology Oncologic Products.

AAPS J 2019 Feb 1;21(2):24. Epub 2019 Feb 1.

Institute of Quantitative Systems Pharmacology, 1815 Aston Avenue, suite 107, Carlsbad, California, 92008, USA.

Approval of generic drugs by the US Food and Drug Administration (FDA) requires the product to be pharmaceutically equivalent to the reference listed drug (RLD) and demonstrate bioequivalence (BE) in effectiveness when administered to patients under the conditions in the RLD product labeling. Effectiveness is determined by drug exposure at the target sites. However, since such measurement is usually unavailable, systemic exposure is assumed to equal target site exposure and systemic BE to equal target site BE. Read More

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http://dx.doi.org/10.1208/s12248-019-0296-zDOI Listing
February 2019
1 Read

Translational Framework Predicting Tumour Response in Gemcitabine-Treated Patients with Advanced Pancreatic and Ovarian Cancer from Xenograft Studies.

AAPS J 2019 Jan 31;21(2):23. Epub 2019 Jan 31.

Pharmacometrics & Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and Nutrition, University of Navarra, 31080, Pamplona, Spain.

The aim of this evaluation was to predict tumour response to gemcitabine in patients with advanced pancreas or ovarian cancer using pre-clinical data obtained from xenograft tumour-bearing mice. The approach consisted of building a translational model combining pre-clinical pharmacokinetic-pharmacodynamic (PKPD) models and parameters, with dosing paradigms used in the clinics along with clinical PK models to derive tumour profiles in humans driving overall survival. Tumour growth inhibition simulations were performed using drug effect parameters obtained from mice, system parameters obtained from mice after appropriate scaling, patient PK models for gemcitabine and carboplatin, and the standard dosing schedules given in the clinical scenario for both types of cancers. Read More

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http://dx.doi.org/10.1208/s12248-018-0291-9DOI Listing
January 2019

Predicting Overall Survival and Progression-Free Survival Using Tumor Dynamics in Advanced Breast Cancer Patients.

AAPS J 2019 Jan 30;21(2):22. Epub 2019 Jan 30.

Clinical Pharmacology, Global Product Development, Pfizer, 10555 Science Center Dr., San Diego, California, 92121, USA.

Prediction of survival endpoints, e.g., overall survival (OS) and progression-free survival (PFS), based on early observations, i. Read More

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http://dx.doi.org/10.1208/s12248-018-0290-xDOI Listing
January 2019
1 Read

Dissolution Testing in Drug Product Development: Workshop Summary Report.

AAPS J 2019 Jan 28;21(2):21. Epub 2019 Jan 28.

Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, 20993, USA.

This publication summarizes the proceedings and key outcomes of the first day ("Day 1") of the 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." The overall aims of the workshop were to foster a productive dialog between industry and regulatory agencies and to discuss current strategies toward the development and implementation of clinically relevant dissolution specifications as an integral part of enhanced drug product understanding and effective drug product life-cycle management. The Day 1 podium presentations covered existing challenges and concerns for implementing highly valuable, yet often unique and novel experimental dissolution setups as quality control tools. Read More

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January 2019
7 Reads

Quantitative Prediction of Human Hepatic Clearance for P450 and Non-P450 Substrates from In Vivo Monkey Pharmacokinetics Study and In Vitro Metabolic Stability Tests Using Hepatocytes.

AAPS J 2019 Jan 23;21(2):20. Epub 2019 Jan 23.

Preclinical Research Unit, Sumitomo Dainippon Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana-ku, Osaka, 554-0022, Japan.

Accurate prediction of human pharmacokinetics for drugs remains challenging, especially for non-cytochrome P450 (P450) substrates. Hepatocytes might be suitable for predicting hepatic intrinsic clearance (CL) of new chemical entities, because they can be applied to various compounds regardless of the metabolic enzymes. However, it was reported that hepatic CL is underestimated in hepatocytes. Read More

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http://dx.doi.org/10.1208/s12248-019-0294-1DOI Listing
January 2019
1 Read

PBPK Absorption Modeling: Establishing the In Vitro-In Vivo Link-Industry Perspective.

AAPS J 2019 Jan 23;21(2):19. Epub 2019 Jan 23.

Biopharmaceutics and Specialty Dosage Forms, Pharmaceutical Sciences, Merck & Co., Inc., 770 Sumneytown Pike, WP75B-210, West Point, Pennsylvania, 19486-0004, USA.

The establishment of an in vitro-in vivo correlation (IVIVC) is considered the gold standard to establish in vivo relevance of a dissolution method and to utilize dissolution data in the context of regulatory bioequivalence questions, including the development of dissolution specifications. However, several recent publications, including industry surveys and reviews from regulatory agencies, have indicated a low success rate for IVIVCs, especially for immediate-release formulations. In recent years, the use of physiologically based pharmacokinetics (PBPK) and absorption modeling, as a tool to facilitate formulation development, has been attracting increased attention. Read More

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http://dx.doi.org/10.1208/s12248-019-0292-3DOI Listing
January 2019
3 Reads

Tumor-Targeted Chemoimmunotherapy with Immune-Checkpoint Blockade for Enhanced Anti-Melanoma Efficacy.

AAPS J 2019 Jan 11;21(2):18. Epub 2019 Jan 11.

Key Laboratory of Drug Targeting, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Section 3, Southern Renmin Road, Chengdu, 610041, People's Republic of China.

Chemoimmunotherapy with chemotherapeutics and immunoadjuvant inhibits tumor growth by activating cytotoxic T cells. However, this process also upregulates the expression of PD-1/PD-L1 and consequently leads to immune suppression. To maximize the anti-tumor immune responses and alleviate immunosuppression, PD-L1 antibody was combined with paclitaxel (PTX) and the immunoadjuvant α-galactosylceramide (αGC), which were coencapsulated into pH-sensitive TH peptide-modified liposomes (PTX/αGC/TH-Lip) to treat melanoma and lung metastasis. Read More

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http://link.springer.com/10.1208/s12248-018-0289-3
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January 2019
7 Reads

What Does it Take to Make Model-Informed Precision Dosing Common Practice? Report from the 1st Asian Symposium on Precision Dosing.

AAPS J 2019 Jan 9;21(2):17. Epub 2019 Jan 9.

Department of Pharmacology and Clinical Pharmacology, Pharmacogenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea.

Model-informed precision dosing (MIPD) is modeling and simulation in healthcare to predict the drug dose for a given patient based on their individual characteristics that is most likely to improve efficacy and/or lower toxicity in comparison to traditional dosing. This paper describes the background and status of MIPD and the activities at the 1st Asian Symposium of Precision Dosing. The theme of the meeting was the question, "What does it take to make MIPD common practice?" Formal presentations highlighted the distinction between genetic and non-genetic sources of variability in drug exposure and response, the use of modeling and simulation as decision support tools, and the facilitators to MIPD implementation. Read More

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http://link.springer.com/10.1208/s12248-018-0286-6
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http://dx.doi.org/10.1208/s12248-018-0286-6DOI Listing
January 2019
9 Reads

Survival Prolongation Index as a Novel Metric to Assess Anti-Tumor Activity in Xenograft Models.

AAPS J 2019 Jan 9;21(2):16. Epub 2019 Jan 9.

Translation Modeling and Simulation, DMPK, Takeda Pharmaceuticals, 35 Landsdowne St, Cambridge, Massachusetts, 02139, USA.

A single efficacy metric quantifying anti-tumor activity in xenograft models is useful in evaluating different tumors' drug sensitivity and dose-response of an anti-tumor agent. Commonly used metrics include the ratio of tumor volume in treated vs. control mice (T/C), tumor growth inhibition (TGI), ratio of area under the curve (AUC), and growth rate inhibition (GRI). Read More

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http://dx.doi.org/10.1208/s12248-018-0284-8DOI Listing
January 2019
1 Read

Sorafenib N-Oxide Is an Inhibitor of Human Hepatic CYP3A4.

AAPS J 2019 Jan 9;21(2):15. Epub 2019 Jan 9.

Pharmacogenomics and Drug Development Group, Discipline of Pharmacology, School of Medical Sciences, Sydney Medical School, University of Sydney, Sydney, NSW, 2006, Australia.

The multi-kinase inhibitor sorafenib (SOR) is clinically important in the treatment of hepatocellular and renal cancers and undergoes CYP3A4-dependent oxidation in liver to the pharmacologically active N-oxide metabolite (SNO). There have been reports that kinase inhibitors such as SOR may precipitate pharmacokinetic interactions with coadministered drugs that compete for CYP3A4-mediated biotransformation, but these occur non-uniformly in patients. Clinical evidence also indicates that SNO accumulates in serum of some patients during prolonged SOR therapy. Read More

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http://link.springer.com/10.1208/s12248-018-0262-1
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January 2019
4 Reads

Cellular Uptake of MCT1 Inhibitors AR-C155858 and AZD3965 and Their Effects on MCT-Mediated Transport of L-Lactate in Murine 4T1 Breast Tumor Cancer Cells.

AAPS J 2019 Jan 7;21(2):13. Epub 2019 Jan 7.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 352 Kapoor Hall, Buffalo, NY, 14214, USA.

AR-C155858 and AZD3965, pyrrole pyrimidine derivatives, represent potent monocarboxylate transporter 1 (MCT1) inhibitors, with potential immunomodulatory and chemotherapeutic properties. Currently, there is limited information on the inhibitory properties of this new class of MCT1 inhibitors. The purpose of this study was to characterize the concentration- and time-dependent inhibition of L-lactate transport and the membrane permeability properties of AR-C155858 and AZD3965 in the murine 4T1 breast tumor cells that express MCT1. Read More

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http://link.springer.com/10.1208/s12248-018-0279-5
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January 2019
2 Reads

Scientific Considerations for the Review and Approval of First Generic Mometasone Furoate Nasal Suspension Spray in the United States from the Bioequivalence Perspective.

AAPS J 2019 Jan 7;21(2):14. Epub 2019 Jan 7.

Office of Generic Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA.

In 2016, the US Food and Drug Administration (FDA) approved the first Abbreviated New Drug Application for Mometasone Furoate Nasal Suspension Spray. To establish the bioequivalence of this generic nasal suspension spray with the reference listed drug product (RLD), Nasonex®, a "weight-of-evidence" approach was utilized by the applicant that included formulation and device similarities, equivalent in vitro performance, equivalent systemic exposure, and equivalent local delivery. In addition to these testing for comprehensive evaluation of the drug product, FDA also considered supportive data generated by a novel in vitro method, Morphologically-Directed Raman Spectroscopy (MDRS), to characterize the particle size distribution (PSD) of active pharmaceutical ingredient (API) in the drug product. Read More

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http://link.springer.com/10.1208/s12248-018-0283-9
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http://dx.doi.org/10.1208/s12248-018-0283-9DOI Listing
January 2019
3 Reads

Evaluation of a Particulate Breast Cancer Vaccine Delivered via Skin.

AAPS J 2019 Jan 2;21(2):12. Epub 2019 Jan 2.

Vaccine Nanotechnology Laboratory, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Mercer University, Atlanta, Georgia, 30341, USA.

Breast cancer impacts female population globally and is the second most common cancer for females. With various limitations and adverse effects of current therapies, several immunotherapies are being explored. Development of an effective breast cancer vaccine can be a groundbreaking immunotherapeutic approach. Read More

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http://dx.doi.org/10.1208/s12248-018-0285-7DOI Listing
January 2019
1 Read

Covariates in Pharmacometric Repeated Time-to-Event Models: Old and New (Pre)Selection Tools.

AAPS J 2018 Dec 18;21(1):11. Epub 2018 Dec 18.

Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Room number 0.2.11, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.

During covariate modeling in pharmacometrics, computational time can be reduced by using a fast preselection tool to identify a subset of promising covariates that are to be tested with the more computationally demanding likelihood ratio test (LRT), which is considered to be the standard for covariate selection. There is however a lack of knowledge on best practices for covariate (pre)selection in pharmacometric repeated time-to-event (RTTE) models. Therefore, we aimed to systematically evaluate the performance of three covariate (pre)selection tools for RTTE models: the likelihood ratio test (LRT), the empirical Bayes estimates (EBE) test, and a novel Schoenfeld-like residual test. Read More

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http://dx.doi.org/10.1208/s12248-018-0278-6DOI Listing
December 2018
1 Read

Golimumab Dried Blood Spot Analysis (GOUDA): a Prospective Trial Showing Excellent Correlation with Venepuncture Samples and More Detailed Pharmacokinetic Information.

AAPS J 2018 Dec 18;21(1):10. Epub 2018 Dec 18.

Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven, Leuven, Belgium.

Development of a dried blood spot (DBS) method for golimumab will facilitate sample collection in a study setting and will give a more complete insight in the total drug exposure (area under the curve, AUC). We established a DBS method and assessed its robustness, user-friendliness and clinical usefulness in 10 patients with ulcerative colitis during golimumab induction and maintenance regimens. DBS was obtained through spotting of golimumab spiked in whole citrated blood to a filter paper. Read More

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http://dx.doi.org/10.1208/s12248-018-0282-xDOI Listing
December 2018
2 Reads

Measurement of IL-17AA and IL-17FF as Pharmacodynamic Biomarkers to Demonstrate Target Engagement in the Phase I Study of MCAF5352A.

AAPS J 2018 Dec 13;21(1). Epub 2018 Dec 13.

Department of OMNI Biomarker Development, Genentech Inc, South San Francisco, California, USA.

The interleukin (IL)-17 pathway has been implicated in the pathophysiology of many autoimmune diseases. MCAF5352A is a humanized monoclonal antibody which targets both IL-17A and IL-17F, thereby inhibiting the activity of IL-17 dimers (IL-17AA, IL-17AF, and IL-17FF). The pharmacokinetic profile of MCAF5352A has been characterized in both a Phase Ia single ascending dose study and a Phase Ib multiple ascending dose study. Read More

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http://dx.doi.org/10.1208/s12248-018-0280-zDOI Listing
December 2018
1 Read

PBPK and its Virtual Populations: the Impact of Physiology on Pediatric Pharmacokinetic Predictions of Tramadol.

AAPS J 2018 Nov 29;21(1). Epub 2018 Nov 29.

Faculty of Pharmaceutical Sciences, Laboratory of Medical Biochemistry and Clinical Analysis, Ottergemsesteenweg 460, 9000, Ghent, Belgium.

In pediatric PBPK models, age-related changes in the body are known to occur. Given the sparsity of and the variability associated with relevant physiological parameters, different PBPK software providers may vary in their system's data. In this work, three commercially available PBPK software packages (PK-Sim®, Simcyp®, and Gastroplus®) were investigated regarding their differences in system-related information, possibly affecting clearance prediction. Read More

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http://dx.doi.org/10.1208/s12248-018-0277-7DOI Listing
November 2018
3 Reads

The Assessment of Quality Attributes for Biosimilars: a Statistical Perspective on Current Practice and a Proposal.

AAPS J 2018 Nov 27;21(1). Epub 2018 Nov 27.

Novartis Pharma AG, 4056, Basel, Switzerland.

Establishing comparability of the originator and its biosimilar at the structural and functional level, by analyzing so-called quality attributes, is an important step in biosimilar development. The statistical assessment of quality attributes is currently in the focus of attention because both the FDA and the EMA are working on regulatory documents for advising companies on the use of statistical approaches for strengthening their comparability claim. In this paper, we first discuss "comparable" and "not comparable" settings and propose a shift away from the usual comparison of the mean values: we argue that two products can be considered comparable if the range of the originator fully covers the range of the biosimilar. Read More

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November 2018
5 Reads

Overlooked Issues on Pharmacokinetics Data Interpretation of Protein Drugs-a Case Example of Erythropoietin.

AAPS J 2018 Nov 26;21(1). Epub 2018 Nov 26.

Department of Pediatrics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, USA.

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November 2018
2 Reads

Effect of the Plasticizer DEHP in Blood Collection Bags on Human Plasma Fraction Unbound Determination for Alpha-1-Acid Glycoprotein (AAG) Binding Drugs.

AAPS J 2018 Nov 16;21(1). Epub 2018 Nov 16.

Q2 Solutions, Bioanalytical and ADME Labs, 5225 Exploration Drive, Indianapolis, Indiana, 46241, USA.

Fraction unbound (f) is a critical drug distribution parameter commonly utilized for modeling efficacious dosage and safety margin predictions. An over-estimation of f for 13 chemically diverse small molecule drugs primarily bound to alpha-1-acid glycoprotein (AAG) in human plasma was discovered when in vitro results from our screening lab were compared to literature values. Di-(2-ethylhexyl) phthalate (DEHP), a plasticizer known to be used in the manufacture of blood collection bags, was extracted from plasma obtained through three common techniques that allowed contact with DEHP, and drug f values in plasma from each collection method were estimated using the HTDialysis protein binding methodology. Read More

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November 2018
14 Reads

Approaches to Resolve False Reporting in Neutralizing Antibody Assays Caused by Reagent Leaching from Affinity Capture Elution Solid Phase.

AAPS J 2018 Nov 6;21(1). Epub 2018 Nov 6.

Pfizer Worldwide Research & Development, Biomedicine Design, 1 Burtt Rd., Andover, Massachusetts, 01810, USA.

Insufficient drug tolerance presents a major challenge in the development of neutralizing antibody (NAb) assays for biotherapeutics. Sample pre-treatment using solid-phase extraction with acid dissociation (SPEAD) is widely reported to improve drug tolerance. In this paper, a case study is presented in which SPEAD was used in conjunction with a competitive ligand binding NAb assay format. Read More

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November 2018
11 Reads

In Vitro and In Vivo Efficacy of the Monocarboxylate Transporter 1 Inhibitor AR-C155858 in the Murine 4T1 Breast Cancer Tumor Model.

AAPS J 2018 Nov 5;21(1). Epub 2018 Nov 5.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 352 Kapoor Hall, Buffalo, New York, 14214, USA.

Monocarboxylate transporter 1 (MCT1), also known as a L-lactate transporter, is a potential therapeutic target in cancer. The objectives of this study were to evaluate efficacy and assess concentration-effect relationships of AR-C155858 (a selective and potent MCT1 inhibitor) in murine 4T1 breast cancer cells and in the 4T1 tumor xenograft model. Western blotting of 4T1 cells demonstrated triple negative breast cancer (TNBC) characteristics and overexpression of MCT1 and CD147 (a MCT1 accessory protein), but absence of MCT4 expression. Read More

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http://dx.doi.org/10.1208/s12248-018-0261-2DOI Listing
November 2018
2 Reads

Population Pharmacokinetics of AL-335 and Its Two Main Metabolites (ALS-022399, ALS-022227) in Monotherapy and in Combination with Odalasvir and/or Simeprevir.

AAPS J 2018 Oct 24;21(1). Epub 2018 Oct 24.

Janssen Research and Development, Global Clinical Pharmacology, Turnhoutseweg 30, B-2340, Beerse, Belgium.

The aim of the current study was to characterize the time course of plasma concentrations of AL-335 and its main metabolites (ALS-022399 and ALS-022227) after oral administration in healthy and hepatitis C virus (HCV)-infected subjects, in monotherapy as well as in combination with simeprevir and/or odalasvir. AL-335, ALS-022399, and ALS-022227 plasma concentrations from subjects receiving 800 mg of AL-335 orally once daily (qd) as monotherapy or in combination were pooled and analyzed using a nonlinear mixed effect modeling approach. The typical values (between subject variability) of AL-335 and ALS-022399 apparent linear clearances were 3300 L/h (33. Read More

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http://dx.doi.org/10.1208/s12248-018-0272-zDOI Listing
October 2018
2 Reads

Characterizing the Pharmacokinetic Interaction Between Simeprevir and Odalasvir in Healthy Volunteers Using a Population Modeling Approach.

AAPS J 2018 Oct 22;20(6):111. Epub 2018 Oct 22.

Janssen Research and Development, Global Clinical Pharmacology, Turnhoutseweg 30, B-2340, Beerse, Belgium.

The aim of this study was to characterize the pharmacokinetic drug-drug interaction (DDI) between simeprevir (NS3/4A protease inhibitor) and odalasvir (NS5A inhibitor) after oral administration to support the design and dose selection of clinical studies with this combination for the treatment of chronic hepatitis C infection (HCV). Simeprevir and odalasvir plasma concentrations from 30 healthy subjects receiving these drugs in monotherapy as well as in combination were pooled and analyzed using a population pharmacokinetic modeling approach. Previous pharmacokinetic models developed to characterize the pharmacokinetics for each drug were used as starting point. Read More

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http://dx.doi.org/10.1208/s12248-018-0271-0DOI Listing
October 2018
6 Reads

Conjugation to Ascorbic Acid Enhances Brain Availability of Losartan Carboxylic Acid and Protects Against Parkinsonism in Rats.

AAPS J 2018 Oct 22;20(6):110. Epub 2018 Oct 22.

Drug Development and Analysis Lab., School of Pharmaceutical Sciences, Siksha O Anusandhan Deemed to be University, Ghatikia, Kalinganagar, Bhubaneswar, Odisha, 751029, India.

Identification of renin-angiotensin system in the interplay of hypertension and neurodegeneration has paved the way for the repurposing of antihypertensive drugs against Parkinsonism. Losartan carboxylic acid (LCA), the potent AT1 blocker metabolite of losartan, suffers from poor bioavailability and brain access. Since ascorbate transporters have earlier shown enough flexibility as carriers, we have conjugated losartan carboxylic acid to ascorbic acid with the aim of achieving higher oral/brain availability. Read More

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http://dx.doi.org/10.1208/s12248-018-0270-1DOI Listing
October 2018
3 Reads

Risk-Based Comparability Assessment for Monoclonal Antibodies During Drug Development: A Clinical Pharmacology Perspective.

AAPS J 2018 Oct 15;20(6):109. Epub 2018 Oct 15.

Global Clinical Pharmacology, Janssen Research & Development, LLC, 1400 McKean Road, Spring House, Pennsylvania, 19477, USA.

Due to complexities in the structure, function, and manufacturing process of antibody-based therapeutic proteins, comparability assessment for supporting manufacturing changes can sometimes be a challenging task. Regulatory guidance recommends a hierarchical risk-based approach, starting with Chemistry, Manufacturing, and Controls (CMC) analytical characterizations, followed by non-clinical and/or clinical studies to ensure that any potential changes in quality attributes have no adverse impact on efficacy and safety of the product. This review focuses on the changes in quality attributes which may potentially affect the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of a monoclonal antibody (mAb) product, and provides general guidelines in designing non-clinical and clinical PK/PD studies to help support comparability assessments. Read More

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http://link.springer.com/10.1208/s12248-018-0268-8
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http://dx.doi.org/10.1208/s12248-018-0268-8DOI Listing
October 2018
13 Reads

Nanoparticle-Based Delivery of CRISPR/Cas9 Genome-Editing Therapeutics.

AAPS J 2018 Oct 10;20(6):108. Epub 2018 Oct 10.

Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, Iowa, 52242, USA.

The recent progress in harnessing the efficient and precise method of DNA editing provided by CRISPR/Cas9 is one of the most promising major advances in the field of gene therapy. However, the development of safe and optimally efficient delivery systems for CRISPR/Cas9 elements capable of achieving specific targeting of gene therapy to the location of interest without off-target effects is a primary challenge for clinical therapeutics. Nanoparticles (NPs) provide a promising means to meet such challenges. Read More

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http://link.springer.com/10.1208/s12248-018-0267-9
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http://dx.doi.org/10.1208/s12248-018-0267-9DOI Listing
October 2018
11 Reads

Tissue Physiology of Cynomolgus Monkeys: Cross-Species Comparison and Implications for Translational Pharmacology.

AAPS J 2018 Oct 8;20(6):107. Epub 2018 Oct 8.

Preclinical and Translational Pharmacokinetics, Genentech Research and Early Development, South San Francisco, California, 94080, USA.

We previously performed a comparative assessment of tissue-level vascular physiological parameters in mice and rats, two of the most commonly utilized species in translational drug development. The present work extends this effort to non-human primates by measuring tissue- and organ-level vascular volumes (V), interstitial volumes (V), and blood flow rates (Q) in cynomolgus monkeys. These measurements were accomplished by red blood cell labeling, extracellular marker infusion, and rubidium chloride bolus distribution, respectively, the same methods used in previous rodent measurements. Read More

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http://dx.doi.org/10.1208/s12248-018-0264-zDOI Listing
October 2018
2 Reads

Reverse Engineering the 1-Month Lupron Depot®.

AAPS J 2018 Oct 2;20(6):105. Epub 2018 Oct 2.

Department of Pharmaceutical Sciences, The Biointerfaces Institute, University of Michigan, 2800 Plymouth Rd., Ann Arbor, Michigan, 48109, USA.

The 1-month Lupron Depot® (LD) encapsulating water-soluble leuprolide in poly(lactic-co-glycolic acid) (PLGA) microspheres is a benchmark product upon which modern long-acting release products are often compared. Despite expiration of patent coverage, no generic product for the LD has been approved in the USA, likely due to the complexity of components and manufacturing processes involved in the product. Here, we describe the reverse engineering of the LD composition and important product attributes. Read More

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http://link.springer.com/10.1208/s12248-018-0253-2
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http://dx.doi.org/10.1208/s12248-018-0253-2DOI Listing
October 2018
13 Reads
3.800 Impact Factor

A Gyrolab Assay for the Quantitation of Free Complement Protein C5a in Human Plasma.

AAPS J 2018 Oct 2;20(6):106. Epub 2018 Oct 2.

Bioanalytical Development, Alexion Pharmaceuticals Inc., 100 College Ave, New Haven, Connecticut, USA.

Complement protein C5a is recognized as an important component of the alternative complement pathway. Its role is prominent enough to garner interest not only as a biomarker, but also as a potential therapeutic target. Bioanalytical challenges have been posed in proper quantitation of free C5a due to interference from its precursor, C5. Read More

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http://link.springer.com/10.1208/s12248-018-0266-x
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http://dx.doi.org/10.1208/s12248-018-0266-xDOI Listing
October 2018
22 Reads

Correction to: Reflections on FDA Draft Guidance for Products Containing Nanomaterials: Is the Abbreviated New Drug Application (ANDA) a Suitable Pathway for Nanomedicines?

AAPS J 2018 09 25;20(6):104. Epub 2018 Sep 25.

Non-Biological Complex Drugs, Vifor Pharma Ltd., Flughofstrasse 61, 8152, Opfikon, Switzerland.

In the published article the given name and the family name for each author is listed in the incorrect order and therefore cited incorrectly. The correct order (given name followed by family name) of names is listed above. Read More

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http://link.springer.com/10.1208/s12248-018-0265-y
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http://dx.doi.org/10.1208/s12248-018-0265-yDOI Listing
September 2018
3 Reads

The Properties of Cysteine-Conjugated Antibody-Drug Conjugates Are Impacted by the IgG Subclass.

AAPS J 2018 Sep 25;20(6):103. Epub 2018 Sep 25.

Department of Biotechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana, USA.

Among the numerous antibody-drug conjugate (ADC) clinical candidates, one of the most prevalent types utilizes the interchain cysteines in antibodies to conjugate auristatin via a maleimide-containing linker. In this class of ADCs, there are a paucity of systematic studies characterizing how IgG subclass influences the biophysical properties and in vivo pharmacokinetics of the ADC molecules. In the current investigation, we studied cysteine-conjugated ADCs using a model system consisting of human IgG1, IgG2, and IgG4 antibodies with the same variable region. Read More

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http://link.springer.com/10.1208/s12248-018-0263-0
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http://dx.doi.org/10.1208/s12248-018-0263-0DOI Listing
September 2018
5 Reads

Michaelis-Menten from an In Vivo Perspective: Open Versus Closed Systems.

AAPS J 2018 Sep 12;20(6):102. Epub 2018 Sep 12.

Mathematical Institute, Leiden University, PB9512, 2300 RA, Leiden, The Netherlands.

After a century of applications of the seminal Michaelis-Menten equation since its advent it is timely to scrutinise its principal parts from an in vivo point of view. Thus, the Michaelis-Menten system was revisited in which enzymatic turnover, i.e. Read More

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http://dx.doi.org/10.1208/s12248-018-0256-zDOI Listing
September 2018
21 Reads

Additive Manufacturing with 3D Printing: Progress from Bench to Bedside.

AAPS J 2018 Sep 12;20(6):101. Epub 2018 Sep 12.

Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Texas A&M University, College Station, Texas, 77843, USA.

Three-dimensional (3D) printing was discovered in the 1980s, and many industries have embraced it, but the pharmaceutical industry is slow or reluctant to adopt it. Spiritam® is the first and only 3D-printed drug product approved by FDA in 2015. Since then, the FDA has not approved any 3D-printed drug product due to technical and regulatory issues. Read More

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http://link.springer.com/10.1208/s12248-018-0225-6
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http://dx.doi.org/10.1208/s12248-018-0225-6DOI Listing
September 2018
13 Reads

Adding the T to ADME: Predictive Toxicity in Renal Drug Development.

AAPS J 2018 Sep 5;20(6):98. Epub 2018 Sep 5.

Division of Pharmacology, Utrecht Institute of Pharmaceutical Sciences, Utrecht, The Netherlands.

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http://dx.doi.org/10.1208/s12248-018-0258-xDOI Listing
September 2018
29 Reads

Imaging Techniques in the Diagnosis and Management of Ocular Tumors: Prospects and Challenges.

AAPS J 2018 Sep 5;20(6):97. Epub 2018 Sep 5.

Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Ajman University, P.O. Box 346, Ajman, United Arab Emirates.

Different types of imaging modalities are used in the diagnosis of ocular cancer. Selection of an imaging modality is based on the features of a tumor as well as the inherent characteristics of the imaging technique. It is vital to select an appropriate imaging modality in diagnosis of ocular tumor with confidence. Read More

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http://dx.doi.org/10.1208/s12248-018-0259-9DOI Listing
September 2018
7 Reads

Individualized Dosing of Therapeutic Monoclonal Antibodies-a Changing Treatment Paradigm?

AAPS J 2018 Sep 5;20(6):99. Epub 2018 Sep 5.

Projections Research Inc., 535 Springview Lane, Phoenixville, Pennsylvania, 19460, USA.

The introduction of monoclonal antibodies (mAbs) to the treatment of inflammatory bowel disease (IBD) was an important medical milestone. MAbs have been demonstrated as safe and efficacious treatments of IBD. However, a large percentage of patients either fail to respond initially or lose response to therapy after a period of treatment. Read More

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http://dx.doi.org/10.1208/s12248-018-0257-yDOI Listing
September 2018
3 Reads

Porcine and Human In Vivo Simulations for Doxorubicin-Containing Formulations Used in Locoregional Hepatocellular Carcinoma Treatment.

AAPS J 2018 Aug 30;20(6):96. Epub 2018 Aug 30.

Department of Pharmacy, Uppsala University, Box 580, 751 23, Uppsala, Sweden.

It is important to be able to simulate and predict formulation effects on the pharmacokinetics of a drug in order to optimize effectivity in clinical practice and drug development. Two formulations containing doxorubicin are used in the treatment of hepatocellular carcinoma (HCC): a Lipiodol-based emulsion (LIPDOX) and a loadable microbead system (DEBDOX). Although equally effective, the formulations are vastly different, and little is known about the parameters affecting doxorubicin release in vivo. Read More

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http://dx.doi.org/10.1208/s12248-018-0251-4DOI Listing
August 2018
3 Reads

Time Scaling for In Vitro-In Vivo Correlation: the Inverse Release Function (IRF) Approach.

AAPS J 2018 Aug 29;20(6):95. Epub 2018 Aug 29.

Dynakin SL, PTB 801, 48160, Derio, Vizcaya, Spain.

In vitro-in vivo correlations (IVIVC) are methods used to create a link between biopharmaceutical properties such as dissolution and physiological response such as plasma concentration. Level A IVIVC defines 1:1 relationship between the percent absorbed in vivo and the percent dissolved in vitro. A successful level A IVIVC provides the capacity to predict in vivo behavior based only on in vitro data with application in formulation development and support of biowaivers recognized by regulatory agencies across the world. Read More

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http://dx.doi.org/10.1208/s12248-018-0250-5DOI Listing
August 2018
21 Reads

Emerging Cancer Therapeutic Targets in Protein Homeostasis.

AAPS J 2018 Aug 27;20(6):94. Epub 2018 Aug 27.

Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico Health Sciences Center, 915 Camino de Salud NE, Albuquerque, NM, 87131, USA.

Genomic aberrations inside malignant cells through copy number alterations, aneuploidy, and mutations can exacerbate misfolded and unfolded protein burden resulting in increased proteotoxic stress. Increased proteotoxic stress can be deleterious to malignant cells; therefore, these cells rely heavily on the protein quality control mechanisms for survival and proliferation. Components of the protein quality control, such as the unfolded protein response, heat shock proteins, autophagy, and the ubiquitin proteasome system, orchestrate a cascade of downstream events that allow the mitigation of the proteotoxic stress. Read More

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http://dx.doi.org/10.1208/s12248-018-0254-1DOI Listing
August 2018
16 Reads

Applications of Clinically Relevant Dissolution Testing: Workshop Summary Report.

AAPS J 2018 Aug 27;20(6):93. Epub 2018 Aug 27.

Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA.

This publication summarizes the proceedings of day 3 of a 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." Specifically, this publication discusses the current approaches in building clinical relevance into drug product development for solid oral dosage forms, along with challenges that both industry and regulatory agencies are facing in setting clinically relevant drug product specifications (CRDPS) as presented at the workshop. The concept of clinical relevance is a multidisciplinary effort which implies an understanding of the relationship between the critical quality attributes (CQAs) and their impact on predetermined clinical outcomes. Read More

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http://dx.doi.org/10.1208/s12248-018-0252-3DOI Listing
August 2018
22 Reads