1,535 results match your criteria Aaps Journal[Journal]


Report of the AAPS Guidance Forum on the FDA Draft Guidance for Industry: "Drug Products, Including Biological Products, that Contain Nanomaterials".

AAPS J 2019 Apr 17;21(4):56. Epub 2019 Apr 17.

VPS Consulting LLC, North Potomac, Maryland, USA.

To guide developers of innovative and generic drug products that contain nanomaterials, the U.S. Food and Drug Administration issued the draft guidance for industry titled: "Drug Products, Including Biological Products, that Contain Nanomaterials" in December 2017. Read More

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http://dx.doi.org/10.1208/s12248-019-0329-7DOI Listing

Report on the AAPS Immunogenicity Guidance Forum.

AAPS J 2019 Apr 16;21(4):55. Epub 2019 Apr 16.

Pharmaceutical Consultant, North Potomac, Maryland, 20878, USA.

In September 2018, the American Association of Pharmaceutical Scientists (AAPS) conducted an Annual Guidance Forum on the considerations related to immunogenicity testing for therapeutic protein products. In addition to a broad representation by the pharmaceutical industry, the event included strong representation by leading scientists from the US Food and Drug Administration (FDA). The agency and industry perspectives and updates to the guidance were presented. Read More

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http://link.springer.com/10.1208/s12248-019-0328-8
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http://dx.doi.org/10.1208/s12248-019-0328-8DOI Listing
April 2019
1 Read

Fetal Concentrations of Budesonide and Fluticasone Propionate: a Study in Mice.

AAPS J 2019 Apr 16;21(4):53. Epub 2019 Apr 16.

Departments of Pharmaceutics, JHMHC, P3-33, University of Florida, 100494, Gainesville, Florida, 32610, USA.

The study goal was to evaluate the transplacental transfer of two corticosteroids, budesonide (BUD) and fluticasone propionate (FP), in pregnant mice and investigate whether P-glycoprotein (P-gp) might be involved in reducing BUD transplacental transfer. Pregnant mice (N = 18) received intravenously either low (104.9 μg/kg) or high (1049 μg/kg) dose of [H]-BUD or a high dose of [H]-FP (1590 μg/kg). Read More

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http://link.springer.com/10.1208/s12248-019-0313-2
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http://dx.doi.org/10.1208/s12248-019-0313-2DOI Listing
April 2019
1 Read

In Vitro and In Vivo Co-delivery of siRNA and Doxorubicin by Folate-PEG-Appended Dendrimer/Glucuronylglucosyl-β-Cyclodextrin Conjugate.

AAPS J 2019 Apr 16;21(4):54. Epub 2019 Apr 16.

Graduate School of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto, 862-0973, Japan.

We have previously reported the utility of folate-polyethylene glycol-appended dendrimer conjugate with glucuronylglucosyl-β-cyclodextrin (Fol-PEG-GUG-β-CDE) (generation 3) as a tumor-selective carrier for siRNA against polo-like kinase 1 (siPLK1) in vitro. In the present study, we evaluated the potential of Fol-PEG-GUG-β-CDE as a carrier for the low-molecular antitumor drug doxorubicin (DOX). Further, to fabricate advanced antitumor agents, we have prepared a ternary complex of Fol-PEG-GUG-β-CDE/DOX/siPLK1 and evaluated its antitumor activity both in vitro and in vivo. Read More

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http://dx.doi.org/10.1208/s12248-019-0327-9DOI Listing

Induction and Impact of Anti-Drug Responses Elicited by a Human Recombinant Coagulation Factor FXa in Preclinical Species.

AAPS J 2019 Apr 11;21(3):52. Epub 2019 Apr 11.

Pfizer Biomedicine Design, Pharmacokinetics Pharmacodynamics Metabolism, 610 Main St., Cambridge, Massachusetts, 02139, USA.

This paper presents a systemic investigation of ADA development and ADA impact of a human coagulation factor in nonclinical species during drug development and provides insights into potential implications in human if a similar ADA occurs. FXa-induced ADA response was characterized in monkey, mouse, rat, and dog in different studies, and ADA effects on pharmacokinetic and/or pharmacodynamics of FXa were further examined in ADA-negative and ADA-positive animals. After repeated administrations, FXa elicited a dose and exposure day-dependent ADA response which ranged from no response to a transient or persistent response. Read More

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http://dx.doi.org/10.1208/s12248-019-0324-zDOI Listing

Dissolution Chamber for Small Drug Delivery System in the Periodontal Pocket.

AAPS J 2019 Apr 10;21(3):51. Epub 2019 Apr 10.

Division of Pharmaceutical Sciences, James L Winkle College of Pharmacy, University of Cincinnati, 231 Albert Sabin Way, MSB # 3005, Cincinnati, Ohio, 45267-0514, USA.

Existing dissolution chambers have relatively large volume compared to the size of the periodontal pocket. A small volume dissolution method that simulates the physiological release environment for periodontal drug delivery is needed. The objectives were to construct a small, more physiologically relevant, dissolution chamber and investigate the properties of the new dissolution chamber for the assessment of sustained drug release systems in periodontal delivery. Read More

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http://link.springer.com/10.1208/s12248-019-0317-y
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http://dx.doi.org/10.1208/s12248-019-0317-yDOI Listing
April 2019
3 Reads

CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies.

AAPS J 2019 Apr 8;21(3):50. Epub 2019 Apr 8.

Department of Medicine, Mayo Clinic Division of Hematology, Rochester, Minnesota, 55905, USA.

The advent of the genome editing era brings forth the promise of adoptive cell transfer using engineered chimeric antigen receptor (CAR) T cells for targeted cancer therapy. CAR T cell immunotherapy is probably one of the most encouraging developments for the treatment of hematological malignancies. In 2017, two CAR T cell therapies were approved by the US Food and Drug Administration: one for the treatment of pediatric acute lymphoblastic leukemia (ALL) and the other for adult patients with advanced lymphomas. Read More

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http://dx.doi.org/10.1208/s12248-019-0322-1DOI Listing
April 2019
2 Reads

HER3-Targeted Affibodies with Optimized Formats Reduce Ovarian Cancer Progression in a Mouse Xenograft Model.

AAPS J 2019 Apr 4;21(3):48. Epub 2019 Apr 4.

Fischell Department of Bioengineering, University of Maryland, 3116 A. James Clark Hall, College Park, Maryland, 20742, USA.

Expression of the receptor tyrosine kinase HER3 is negatively correlated with survival in ovarian cancer, and HER3 overexpression is associated with cancer progression and therapeutic resistance. Thus, improvements in HER3-targeted therapy could lead to significant clinical impact for ovarian cancer patients. Previous work from our group established multivalency as a potential strategy to improve the therapeutic efficacy of HER3-targeted ligands, including affibodies. Read More

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http://dx.doi.org/10.1208/s12248-019-0318-xDOI Listing
April 2019
1 Read

Bacteriophage PEV20 and Ciprofloxacin Combination Treatment Enhances Removal of Pseudomonas aeruginosa Biofilm Isolated from Cystic Fibrosis and Wound Patients.

AAPS J 2019 Apr 4;21(3):49. Epub 2019 Apr 4.

Advanced Drug Delivery Group, School of Pharmacy, The University of Sydney, Sydney, NSW, 2006, Australia.

Antibiotic resistance in Pseudomonas aeruginosa biofilms necessitates the need for novel antimicrobial therapy with anti-biofilm properties. Bacteriophages (phages) are recognized as an ideal biopharmaceutical for combating antibiotic-resistant bacteria especially when used in combination with antibiotics. However, previous studies primarily focused on using phages against of P. Read More

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http://dx.doi.org/10.1208/s12248-019-0315-0DOI Listing
April 2019
3 Reads

Trial Design and Statistical Considerations on the Assessment of Pharmacodynamic Similarity.

AAPS J 2019 Apr 3;21(3):47. Epub 2019 Apr 3.

Janssen Research & Development Inc, Spring House, PA, USA.

Pharmacodynamics (PD) similarity is an important component to support the claim of similarity between two drugs or devices. This article investigates the trial design and statistical considerations in the equivalence test of PD endpoints. Using bone resorption marker CTX as a case study, the relationship between the PD readouts and drug potency was explored to evaluate the sensitivity of the PD endpoint and guide equivalence margin selection. Read More

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http://dx.doi.org/10.1208/s12248-019-0321-2DOI Listing

Neutralizing Antibody Assay Development with High Drug and Target Tolerance to Support Clinical Development of an Anti-TFPI Therapeutic Monoclonal Antibody.

AAPS J 2019 Mar 29;21(3):46. Epub 2019 Mar 29.

Pfizer Inc, Andover, Massachusetts, USA.

Immunogenicity is a major challenge for protein therapeutics which can potentially reduce drug efficacy and safety and is often being monitored by anti-drug antibody (ADA) and neutralizing antibody (NAb) assays. Circulating targets and residual drugs in matrices can have significant impacts on accuracy of results from ADA and NAb assays, and sufficient drug and target tolerance for these assays are necessary. Here, we report the development of a competitive ligand binding (CLB) NAb assay for an anti-TFPI (tissue factor pathway inhibitor) monoclonal antibody (PF-06741086) with high drug and target tolerance to support ongoing clinical studies. Read More

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http://link.springer.com/10.1208/s12248-019-0320-3
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http://dx.doi.org/10.1208/s12248-019-0320-3DOI Listing
March 2019
2 Reads

Mechanisms of CYP3A Induction During Pregnancy: Studies in HepaRG Cells.

AAPS J 2019 Mar 27;21(3):45. Epub 2019 Mar 27.

Department of Pharmaceutics, University of Washington, P.O. Box 357610, Seattle, WA, 98195, USA.

Activity of CYP3A, an enzyme responsible for metabolism of many marketed drugs, is induced by ~ 2-fold in pregnant women. Through studies in sandwich-cultured human hepatocytes (SCHH) and HepaRG cells, our laboratory has shown that this induction is likely mediated by the increase in cortisol plasma concentrations during pregnancy. Cortisol, at plasma concentrations observed during the third trimester (~ 800 nM), either alone or in combination with other pregnancy-related hormones, induces CYP3A activity in SCHH and HepaRG cells when cultured in dexamethasone-free media. Read More

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http://dx.doi.org/10.1208/s12248-019-0316-zDOI Listing

Interfacial Stress in the Development of Biologics: Fundamental Understanding, Current Practice, and Future Perspective.

AAPS J 2019 Mar 26;21(3):44. Epub 2019 Mar 26.

Technical Operations, CRISPR Therapeutics, Cambridge, Massachusetts, 02139, USA.

Biologic products encounter various types of interfacial stress during development, manufacturing, and clinical administration. When proteins come in contact with vapor-liquid, solid-liquid, and liquid-liquid surfaces, these interfaces can significantly impact the protein drug product quality attributes, including formation of visible particles, subvisible particles, or soluble aggregates, or changes in target protein concentration due to adsorption of the molecule to various interfaces. Protein aggregation at interfaces is often accompanied by changes in conformation, as proteins modify their higher order structure in response to interfacial stresses such as hydrophobicity, charge, and mechanical stress. Read More

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http://dx.doi.org/10.1208/s12248-019-0312-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435788PMC

Simulating the Impact of Elevated Levels of Interleukin-6 on the Pharmacokinetics of Various CYP450 Substrates in Patients with Neuromyelitis Optica or Neuromyelitis Optica Spectrum Disorders in Different Ethnic Populations.

AAPS J 2019 Mar 18;21(3):42. Epub 2019 Mar 18.

Roche Pharma Research and Early Development, Roche Innovation Center, Basel, Switzerland.

A physiologically based pharmacokinetic (PBPK) model was used to simulate the impact of elevated levels of interleukin (IL)-6 on the exposure of several orally administered cytochrome P450 (CYP) probe substrates (caffeine, S-warfarin, omeprazole, dextromethorphan, midazolam, and simvastatin). The changes in exposure of these substrates in subjects with rheumatoid arthritis (and hence elevated IL-6 levels) compared with healthy subjects were predicted with a reasonable degree of accuracy. The PBPK model was then used to simulate the change in oral exposure of the probe substrates in North European Caucasian, Chinese, and Japanese population of patients with neuromyelitis optica (NMO) or NMO spectrum disorder with elevated plasma IL-6 levels (up to 100 pg/mL). Read More

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http://link.springer.com/10.1208/s12248-019-0309-y
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http://dx.doi.org/10.1208/s12248-019-0309-yDOI Listing
March 2019
4 Reads

Theoretical Considerations for Direct Translation of Unbound Liver-to-Plasma Partition Coefficient from In Vitro to In Vivo.

AAPS J 2019 Mar 18;21(3):43. Epub 2019 Mar 18.

Medicine Design Modeling and Simulation, Pfizer Inc., 1 Portland St. Pfizer, Cambridge, Massachusetts, 02139, USA.

There is considerable interest in developing methods to predict the asymmetric distribution of unbound drug into tissues. The liver is of particular interest due to the multitude of expressed transporters with potential implications for pharmacokinetics, pharmacodynamics, and toxicology. Empirical correlations of in vitro unbound hepatocyte-to-media partition coefficient (in vitro K) and in vivo unbound liver-to-plasma partition coefficient (in vivo K) have been reported without considering the theoretical aspects which might confound the interpretation of such observations. Read More

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http://dx.doi.org/10.1208/s12248-019-0314-1DOI Listing

Effect of Dibasic Calcium Phosphate Incorporation on Cellulose Nanocrystal/Chitosan Hydrogel Properties for the Treatment of Vertebral Compression Fractures.

AAPS J 2019 Mar 18;21(3):41. Epub 2019 Mar 18.

Department of Biomedical, Biological, and Chemical Engineering, University of Missouri, Columbia, Missouri, 65211, USA.

Vertebral compression fractures account for approximately 700,000 out of the 1.5 million total osteoporotic fractures that occur annually in the USA. There is growing interest in substituting currently utilized clinical treatments for vertebral compression fractures with an injectable, degradable, and bioactive system. Read More

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http://dx.doi.org/10.1208/s12248-019-0311-4DOI Listing

A Receiver Operating Characteristic Framework for Non-adherence Detection Using Drug Concentration Thresholds-Application to Simulated Risperidone Data in Schizophrenic Patients.

AAPS J 2019 Mar 14;21(3):40. Epub 2019 Mar 14.

Janssen Research & Development, Quantitative Sciences Consulting, Beerse, Belgium.

Non-adherence to antipsychotic medication is a primary factor in disease relapse in schizophrenic patients. We sought to evaluate if plasma concentrations of the antipsychotic risperidone can be used as a predictor of treatment adherence and to identify the optimal plasma concentration threshold to reliably distinguish between adherent and non-adherent patients. A population pharmacokinetic model was used to simulate plasma risperidone steady-state trough concentrations in 1000 virtual patients, where 60% of the patients were 100% adherent to their medication, while 40% of the patients were non-adherent to their medication. Read More

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http://dx.doi.org/10.1208/s12248-019-0299-9DOI Listing

Pharmacokinetic Properties of Humanized IgG1 and IgG4 Antibodies in Preclinical Species: Translational Evaluation.

AAPS J 2019 Mar 13;21(3):39. Epub 2019 Mar 13.

Merck & Co., Inc, Palo Alto, California, USA.

Assessment of the factors that regulate antibody exposure-response relationships in the relevant animal models is critical for the design of successful translational strategies from discovery to the clinic. Depending on the specific clinical indication, preclinical development paradigms may require that the efficacy or dosing-related attributes for the existing antibody be assessed in various species when cross-reactivity of the lead antibody to the intended species is justified. Additionally, with the success of monoclonal antibodies for management of various human conditions, a parallel interest in therapeutic use of these novel modalities in various veterinary species has followed. Read More

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http://dx.doi.org/10.1208/s12248-019-0304-3DOI Listing

Scaling Drug Clearance from Adults to the Young Children for Drugs Undergoing Hepatic Metabolism: A Simulation Study to Search for the Simplest Scaling Method.

AAPS J 2019 Mar 8;21(3):38. Epub 2019 Mar 8.

Division Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands.

Previous research showed that scaling drug clearance from adults to children based on body weight alone is not accurate for all hepatically cleared drugs in very young children. This study systematically assesses the accuracy of scaling methods that, in addition to body weight, also take age-based variables into account for drugs undergoing hepatic metabolism in children younger than five years, namely scaling with (1) a body weight-based function using an age-dependent exponent (ADE) and (2) a body weight-based function with fixed exponent of 0.75 (AS0. Read More

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http://dx.doi.org/10.1208/s12248-019-0295-0DOI Listing
March 2019
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Variability Attribution for Automated Model Building.

AAPS J 2019 Mar 8;21(3):37. Epub 2019 Mar 8.

Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.

We investigated the possible advantages of using linearization to evaluate models of residual unexplained variability (RUV) for automated model building in a similar fashion to the recently developed method "residual modeling." Residual modeling, although fast and easy to automate, cannot identify the impact of implementing the needed RUV model on the imprecision of the rest of model parameters. We used six RUV models to be tested with 12 real data examples. Read More

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http://link.springer.com/10.1208/s12248-019-0310-5
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http://dx.doi.org/10.1208/s12248-019-0310-5DOI Listing
March 2019
4 Reads

Dissolution Edge Charts for Immediate Release Products and Their Applications: a Simulation Study to Aid the Setting of Specifications.

Authors:
John Z Duan

AAPS J 2019 Mar 5;21(3):36. Epub 2019 Mar 5.

, Rockville, USA.

One of the most commonly used methods to establish the clinical relevance of dissolution is to align the dissolution specifications with pivotal clinical batches. The objective of the study was to create edge charts for the dissolution of immediate release (IR) drug products to quantitatively establish the bases for setting clinically relevant and discriminating dissolution specifications and to clarify which stage in the US Pharmacopoeia (USP) <711> acceptance tables should be targeted. The simulations of dissolution data were performed on a batch of IR products with 1,000,000 units. Read More

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http://dx.doi.org/10.1208/s12248-019-0308-zDOI Listing

Model-Based Conditional Weighted Residuals Analysis for Structural Model Assessment.

AAPS J 2019 Feb 27;21(3):34. Epub 2019 Feb 27.

Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.

Nonlinear mixed effects models are widely used to describe longitudinal data to improve the efficiency of drug development process or increase the understanding of the studied disease. In such settings, the appropriateness of the modeling assumptions is critical in order to draw correct conclusions and must be carefully assessed for any substantial violations. Here, we propose a new method for structure model assessment, based on assessment of bias in conditional weighted residuals (CWRES). Read More

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http://dx.doi.org/10.1208/s12248-019-0305-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394649PMC
February 2019

A Reappraisal of Sedimentation Nonideality Coefficients for the Analysis of Weak Interactions of Therapeutic Proteins.

AAPS J 2019 Feb 27;21(3):35. Epub 2019 Feb 27.

Dynamics of Macromolecular Assembly Section, Laboratory of Cellular Imaging and Macromolecular Biophysics, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, 13 South Drive, Bldg. 13, Rm 3N17, Bethesda, Maryland, 20892, USA.

The study of weak or colloidal interactions of therapeutic proteins in different formulations allows prediction and optimization of protein stability. Various biophysical techniques have been applied to determine the second osmotic virial coefficient B as it reflects on the macromolecular distance distribution that governs solution behavior at high concentration. In the present work, we exploit a direct link predicted by hydrodynamic theory between B and the nonideality of sedimentation, commonly measured in sedimentation velocity analytical ultracentrifugation through the nonideality coefficient of sedimentation, k. Read More

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http://dx.doi.org/10.1208/s12248-019-0307-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394620PMC
February 2019

A Density-Changing Centrifugation Method for Efficient Separation of Free Drugs from Drug-Loaded Particulate Delivery Systems.

AAPS J 2019 Feb 25;21(3):33. Epub 2019 Feb 25.

Key Laboratory of Drug Targeting and Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, No 17, Section 3, Southern Remin Rd, Chengdu, 610041, China.

Commonly used separation techniques, such as ultracentrifugation, chromatography, and membrane separation, have inherent drawbacks that limit their usage. Herein, we introduced a new separation method, density-changing centrifugation (DCC), which is based on trisodium citrate (TC) and ultracentrifugation. Paclitaxel-loaded cationic solid lipid nanoparticles (SLNs/PTX) and doxorubicin-loaded PEGylated liposomes (Lipo/Dox) were prepared as model drug delivery particulates. Read More

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http://dx.doi.org/10.1208/s12248-019-0306-1DOI Listing
February 2019
2 Reads

First-Principles and Empirical Approaches to Predicting In Vitro Dissolution for Pharmaceutical Formulation and Process Development and for Product Release Testing.

AAPS J 2019 Feb 21;21(3):32. Epub 2019 Feb 21.

Drug Product Science and Technology, Bristol-Myers Squibb, New Brunswick, New Jersey, 08903, USA.

This manuscript represents the perspective of the Dissolution Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) and of two focus groups of the American Association of Pharmaceutical Scientists (AAPS): Process Analytical Technology (PAT) and In Vitro Release and Dissolution Testing (IVRDT). The intent of this manuscript is to show recent progress in the field of in vitro predictive dissolution modeling and to provide recommended general approaches to developing in vitro predictive dissolution models for both early- and late-stage formulation/process development and batch release. Different modeling approaches should be used at different stages of drug development based on product and process understanding available at those stages. Read More

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http://dx.doi.org/10.1208/s12248-019-0297-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394641PMC
February 2019
1 Read

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
3 Reads

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
2 Reads

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
2 Reads

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373415PMC
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
3 Reads

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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http://link.springer.com/10.1208/s12248-018-0281-y
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http://dx.doi.org/10.1208/s12248-018-0281-yDOI Listing
February 2019
6 Reads

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
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6432930PMC
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
3 Reads

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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http://link.springer.com/10.1208/s12248-018-0288-4
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http://dx.doi.org/10.1208/s12248-018-0288-4DOI Listing
January 2019
21 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
2 Reads

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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http://dx.doi.org/10.1208/s12248-018-0289-3DOI Listing
January 2019
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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
12 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
2 Reads

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
5 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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http://dx.doi.org/10.1208/s12248-018-0279-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466617PMC
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
5 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
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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
2 Reads

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
3 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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http://link.springer.com/10.1208/s12248-018-0275-9
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http://dx.doi.org/10.1208/s12248-018-0275-9DOI Listing
November 2018
9 Reads