1,669 results match your criteria AAPS J[Journal]


Protein Corona-Enabled Systemic Delivery and Targeting of Nanoparticles.

AAPS J 2020 Jun 3;22(4):83. Epub 2020 Jun 3.

Department of Pharmaceutical Sciences, Bouvé College of Health Sciences, Boston, Massachusetts, USA.

Upon systemic administration, nanoparticles encounter serum proteins in the biological system resulting in the formation of "protein corona" on the surface. Increased understanding of the relationship between nanoparticles' "chemical identity" and "biological identity" can contribute to improved clinical translation. Recent studies of protein corona composition on nanoparticles, including from our group, suggest that a strategic choice of materials can influence the types of protein adsorbed from plasma and lead to improved delivery efficiency. Read More

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http://dx.doi.org/10.1208/s12248-020-00464-xDOI Listing

Development of a Highly Specific Anti-drug Antibody Assay in Support of a Nanoparticle-based Therapeutic.

AAPS J 2020 Jun 2;22(4):81. Epub 2020 Jun 2.

BioMedicine Design, Pfizer Inc, One Burtt Road, Andover, Massachusetts, 01810, USA.

PEGylated biotherapeutics can elicit anti-PEG (polyethylene glycol) immune responses in patients treated with this category of drugs. While anti-PEG antibody assays for this class of biotherapeutics have become a common element of the clinical immunogenicity testing strategy, the overall antibody incidence induced by the nanoparticle (NP) delivery system (such as ACCURINS®) has not been fully studied to date. To support the immunogenicity assessment of one of Pfizer's NP-based therapeutics, consisting of gedatolisib (GEDA) encapsulated in ACCURINS® (GEDA-NP), we developed an anti-GEDA-NP antibody (ADA) assay on the MSD platform for the detection of GEDA-NP induced ADA in human serum. Read More

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http://dx.doi.org/10.1208/s12248-020-00462-zDOI Listing

Evaluation of Heat Effects on Transdermal Nicotine Delivery In Vitro and In Silico Using Heat-Enhanced Transport Model Analysis.

AAPS J 2020 Jun 2;22(4):82. Epub 2020 Jun 2.

Division of Pharmaceutical Sciences, James L Winkle College of Pharmacy, University of Cincinnati, Cincinnati, Ohio, 45267, USA.

A combined experimental and computational model approach was developed to assess heat effects on drug delivery from transdermal delivery systems (TDSs) in vitro and nicotine was the model drug. A Franz diffusion cell system was modified to allow close control of skin temperature when heat was applied from an infrared lamp in vitro. The effects of different heat application regimens on nicotine fluxes from two commercial TDSs across human cadaver skin were determined. Read More

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http://dx.doi.org/10.1208/s12248-020-00457-wDOI Listing

High-Dose IV Administration of Rasburicase Suppresses Anti-rasburicase Antibodies, Depletes Rasburicase-Specific Lymphocytes, and Upregulates Treg Cells.

AAPS J 2020 May 27;22(4):80. Epub 2020 May 27.

Laboratory of Immunobiology, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Building 72, Room 2324, 10903 New Hampshire Ave, Silver Spring, Maryland, 20993, USA.

Therapeutic proteins can be potent agents for treating serious diseases, but in many patients these proteins provoke antibody responses that blunt therapeutic efficacy. Intravenous administration of high doses of some proteins induces immune tolerance, but the mechanisms underlying this effect are poorly understood. As a model to study tolerance induction in mice, we used rasburicase, a commercial recombinant uricase used for the treatment of hyperuricemia. Read More

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http://dx.doi.org/10.1208/s12248-020-00461-0DOI Listing

Remdesivir for Treatment of COVID-19: Combination of Pulmonary and IV Administration May Offer Aditional Benefit.

Authors:
Duxin Sun

AAPS J 2020 05 26;22(4):77. Epub 2020 May 26.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, 48109, USA.

Remdesivir is one of the most promising drugs to treat COVID-19 based on the following facts: remdesivir has a broad-spectrum antiviral mechanism of action; it demonstrated in vitro activity against SARS-CoV-2 and in vivo efficacy in animal models against the similar coronavirus MERS-CoV; its safety profile has been tested in Ebola patients and in compassionate use in COVID-19 patients. Currently, remdesivir is being investigated in ten randomized controlled trials against COVID-19. The dose regimen of remdesivir is an IV loading dose of 200 mg on day 1 followed by daily IV maintenance doses of 100 mg for 5-9 days. Read More

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http://dx.doi.org/10.1208/s12248-020-00459-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250281PMC

Physiologically Based Absorption Modelling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Entrectinib.

AAPS J 2020 May 26;22(4):78. Epub 2020 May 26.

Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland.

Entrectinib is a potent and selective tyrosine kinase inhibitor (TKI) of TRKA/B/C, ROS1, and ALK with both systemic and CNS activities, which has recently received FDA approval for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. This paper describes the application of a physiologically based biophamaceutics modeling (PBBM) during clinical development to understand the impact of food and gastric pH changes on absorption of this lipophilic, basic, molecule with reasonable permeability but strongly pH-dependent solubility. GastroPlus™ was used to develop a physiologically based pharmacokinetics (PBPK) model integrating in vitro and in silico data and dissolution studies and in silico modelling in DDDPlus™ were used to understand the role of self-buffering and acidulant on formulation performance. Read More

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http://dx.doi.org/10.1208/s12248-020-00463-yDOI Listing

Development and Application of a Physiologically-Based Pharmacokinetic Model to Predict the Pharmacokinetics of Therapeutic Proteins from Full-term Neonates to Adolescents.

AAPS J 2020 May 24;22(4):76. Epub 2020 May 24.

Certara UK Limited, Simcyp Division, Level 2-Acero, 1 Concourse Way, Sheffield, S1 2BJ, UK.

Physiologically-based pharmacokinetic (PBPK) modelling provides an integrated framework to predict the disposition of small molecule drugs in children and is increasingly being used for dose recommendation and optimal design of paediatric studies and in regulatory submissions. Existing paediatric PBPK models can be adopted to describe the disposition of therapeutic proteins (TPs) in children by incorporating information on age-related changes of additional physiological and biological parameters (e.g. Read More

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http://dx.doi.org/10.1208/s12248-020-00460-1DOI Listing

Impact of Magnesium Stearate Presence and Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties.

AAPS J 2020 May 21;22(4):75. Epub 2020 May 21.

Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, UK.

Excipients are major components of oral solid dosage forms, and changes in their critical material attributes (excipient variability) and/or amount (excipient variation) in pharmaceutical formulations may present a challenge for product performance. Understanding the biopharmaceutical factors affecting excipient performance is recommended for the successful implementation of excipient variability on Quality by Design (QbD) approaches. The current study investigated the impact of magnesium stearate (MgSt) variability on the apparent solubility of drugs with a wide range of physicochemical properties (drug ionization, drug lipophilicity, drug aqueous solubility). Read More

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http://dx.doi.org/10.1208/s12248-020-00449-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242257PMC

Population Pharmacokinetics of Sertraline in Healthy Subjects: a Model-Based Meta-analysis.

AAPS J 2020 May 19;22(4):73. Epub 2020 May 19.

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.

Sertraline pharmacokinetics is poorly understood and highly variable due to large between-subject variability with inconsistent reports for oral bioavailability. The study objective was to characterize sertraline pharmacokinetics by developing and validating a sertraline population pharmacokinetic (PK) model in healthy subjects using published clinical PK data. We carried a systematic literature search in PubMed in October 2015 and identified 27 pharmacokinetic studies of sertraline conducted in healthy adult subjects and reported in the English language. Read More

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http://dx.doi.org/10.1208/s12248-020-00455-yDOI Listing

In Vitro Dissolution Profiles Similarity Assessment in Support of Drug Product Quality: What, How, When-Workshop Summary Report.

AAPS J 2020 May 19;22(4):74. Epub 2020 May 19.

Global Product Development, Pfizer Inc, Eastern Point Road, Groton, Connecticut, 06340, USA.

The pharmaceutical industry and regulatory agencies rely on dissolution similarity testing to make critical product performance decisions as part of drug product life cycle management. Accordingly, the application of mathematical approaches to evaluate dissolution profile similarity is described in regulatory guidance. However, the requirements (e. Read More

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http://dx.doi.org/10.1208/s12248-020-00458-9DOI Listing

Why Do the Majority of Submissions for Bridging from a Prefilled Syringe to an Autoinjector Include Bioequivalence Studies in Order to Demonstrate Comparability?

AAPS J 2020 May 15;22(3):72. Epub 2020 May 15.

Module 3 Pharmaceutical Consulting, PO Box 3032, Incline Village, Nevada, 89450, USA.

A recent paper reviewed clinical studies intending to bridge a prefilled syringe (PFS) to an autoinjector (AI) based on regulatory submission packages sent to the FDA. An AI generally uses the identical PFS within the AI and the AI typically results in a more consistent injection than can be achieved with a PFS. It is noted that several studies submitted to the FDA did not demonstrate bioequivalence (BE) between the PFS and AI, yet the products were approved anyway. Read More

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http://dx.doi.org/10.1208/s12248-020-00453-0DOI Listing

Drug Absorption Parameters Obtained Using the Isolated Perfused Rat Lung Model Are Predictive of Rat In Vivo Lung Absorption.

AAPS J 2020 May 11;22(3):71. Epub 2020 May 11.

Inhalation PD Unit, Pharmaceutical Technology & Development, Operations, AstraZeneca, Pepparedsleden 1, 43183, Gothenburg, Sweden.

The ex vivo isolated perfused rat lung (IPL) model has been demonstrated to be a useful tool during drug development for studying pulmonary drug absorption. This study aims to investigate the potential use of IPL data to predict rat in vivo lung absorption. Absorption parameters determined from IPL data (ex vivo input parameters) in combination with intravenously determined pharmacokinetic data were used in a biopharmaceutics model to predict experimental rat in vivo plasma concentration-time profiles and lung amount after inhalation of five different inhalation compounds. Read More

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http://dx.doi.org/10.1208/s12248-020-00456-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214485PMC

Modeling Temperature-Dependent Dermal Absorption and Clearance for Transdermal and Topical Drug Applications.

AAPS J 2020 May 10;22(3):70. Epub 2020 May 10.

Division of Pharmaceutical Sciences, James L Winkle College of Pharmacy, University of Cincinnati Academic Health Center, 231 Albert Sabin Way, Cincinnati, Ohio, 45267-0514, USA.

A computational model was developed to better understand the impact of elevated skin temperatures on transdermal drug delivery and dermal clearance. A simultaneous heat and mass transport model with emphasis on transdermal delivery system (TDS) applications was developed to address transient and steady-state temperature effects on dermal absorption. The model was tested using representative data from nicotine TDS applied to human skin either in vitro or in vivo. Read More

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http://dx.doi.org/10.1208/s12248-020-00451-2DOI Listing

Quality by Design-Based Assessment for Analytical Similarity of Adalimumab Biosimilar HLX03 to Humira®.

AAPS J 2020 May 8;22(3):69. Epub 2020 May 8.

Shanghai Engineering Research Center of Anti-tumor Biologic Drugs, Shanghai Henlius Biotech Inc., Shanghai, China.

Quality by design (QbD) is an efficient but challenging approach for the development of biosimilar due to the complex relationship among process, quality, and efficacy. Here, the analytical similarity of adalimumab biosimilar HLX03 to Humira® was successfully established following a QbD quality study. Quality target product profile (QTPP) of HLX03 was first generated according to the public available information and initial characterization of 3 batches of Humira®. Read More

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http://dx.doi.org/10.1208/s12248-020-00454-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210234PMC

Development of a FRET-Based Assay for Analysis of mAbs Internalization and Processing by Dendritic Cells in Preclinical Immunogenicity Risk Assessment.

AAPS J 2020 04 16;22(3):68. Epub 2020 Apr 16.

Lilly Biotechnology Center, Lilly Research Laboratories, Eli Lilly and Company, 10290 Campus Point Drive, San Diego, California, 92121, USA.

Treatment-emergent antidrug antibodies (TE-ADA) pose a major challenge to the development of biotherapeutics. The antidrug antibody responses are highly orchestrated and involve many types of immune cells and biological processes. Biological drug internalization and processing by antigen-presenting cells (APCs) are two initial and critical steps in the cascade of events leading to T cell-dependent ADA production. Read More

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http://dx.doi.org/10.1208/s12248-020-00444-1DOI Listing

Comparison of Alternative Population Modeling Approaches for Implementing a Level A IVIVC and for Assessing the Time-Scaling Factor Using Deconvolution and Convolution-Based Methods.

AAPS J 2020 04 15;22(3):67. Epub 2020 Apr 15.

R&D, Pharmacometrica, Lieu-dit Longcol, 12270, La Fouillade, France.

Different approaches based on deconvolution and convolution analyses have been proposed to establish IVIVC. A new implementation of the convolution-based model was used to evaluate the time-scaled IVIVC using the convolution (method 1) and the deconvolution-based (method 2) approaches. With the deconvolution-based approach, time-scaling was detected and estimated using Levy's plots while with the convolution-based approach, time-scaling was directly determined by a time-scaling sub-model of the convolution integral model by nonlinear regression. Read More

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http://dx.doi.org/10.1208/s12248-020-00445-0DOI Listing

A Translational Physiologically Based Pharmacokinetics/Pharmacodynamics Framework of Target-Mediated Disposition, Target Inhibition and Drug-Drug Interactions of Bortezomib.

AAPS J 2020 04 14;22(3):66. Epub 2020 Apr 14.

Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International, Co., 35 Landsdowne Street, Cambridge, Massachusetts, USA.

Bortezomib is a potent 20S proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma. Despite the extensive clinical use of bortezomib, the mechanism of the complex time-dependent pharmacokinetics of bortezomib has not been fully investigated in context of its pharmacodynamics (PD) and drug-drug interaction (DDI) profiles. Here, we aimed to develop a mechanistic physiologically based (PB) PK/PD model to project PK, blood target inhibition and DDI of bortezomib in patients. Read More

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http://dx.doi.org/10.1208/s12248-020-00448-xDOI Listing

Immunogenicity Risk Assessment for an Engineered Human Cytokine Analogue Expressed in Different Cell Substrates.

AAPS J 2020 04 14;22(3):65. Epub 2020 Apr 14.

Bonnie Rup Consulting, LLC, Reading, Massachusetts, USA.

The purpose of this article is to illustrate how performance of an immunogenicity risk assessment at the earliest stage of product development can be instructive for critical early decision-making such as choice of host system for expression of a recombinant therapeutic protein and determining the extent of analytical characterization and control of heterogeneity in co- and post-translational modifications. Application of a risk-based approach for a hypothetical recombinant DNA analogue of a human endogenous cytokine with immunomodulatory functions is described. The manner in which both intrinsic and extrinsic factors could interact to influence the relative scale of risk associated with expression in alternative hosts, namely Chinese hamster ovary (CHO) cells, Pichia pastoris, Escherichia coli, or Nicotinia tabacum is considered in relation to the development of the investigational product to treat an autoimmune condition. Read More

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http://dx.doi.org/10.1208/s12248-020-00443-2DOI Listing

Clinical Immunogenicity Risk Assessment for a Fusion Protein.

AAPS J 2020 04 3;22(3):64. Epub 2020 Apr 3.

Clinical Immunology-Translational Medicine, Amgen Inc., Thousand Oaks, CA, USA.

This document highlights some relevant factors in the assessment of immunogenicity risk of fusion protein therapeutics. Our aim is to highlight specific risks associated with this type of molecule, while also aligning with general risk assessment factors, through a hypothetical case study, where the therapeutic molecule of interest is a Receptor-Fc Fusion protein (RFF) expressed within a typical manufacturing process in Chinese Hamster Ovary Cells (CHO). Given that the components are comprised of endogenous sequences, the risk of developing an ADA response to this molecule is generally considered to be low. Read More

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http://dx.doi.org/10.1208/s12248-020-00447-yDOI Listing

Subcutaneous Site-of-Absorption Study with the Monoclonal Antibody Tocilizumab in Minipigs: Administration Behind Ear Translates Best to Humans.

AAPS J 2020 04 3;22(3):63. Epub 2020 Apr 3.

Device Development, Pharmaceutical Technical Development Europe, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070, Basel, Switzerland.

Minipigs have been proposed as animal model to study the subcutaneous (SC) absorption of monoclonal antibodies (mAb), because they are more translatable to humans than other species. However, the minipig SC tissue structure differs markedly depending on its location. This study explored different SC administration sites for mAb SC administration, to explore which site translates best to humans. Read More

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http://dx.doi.org/10.1208/s12248-020-00446-zDOI Listing

Structure-Based Design and Discovery of a Long-Acting Cocaine Hydrolase Mutant with Improved Binding Affinity to Neonatal Fc Receptor for Treatment of Cocaine Abuse.

AAPS J 2020 03 18;22(3):62. Epub 2020 Mar 18.

Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, Kentucky, 40536, USA.

Despite decades of efforts to develop a pharmacotherapy for cocaine abuse treatment, there is still no FDA-approved treatment of diseases associated with this commonly abused drug. Our previously designed highly efficient cocaine hydrolases (CocHs) and the corresponding Fc-fusion proteins (e.g. Read More

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http://dx.doi.org/10.1208/s12248-020-00442-3DOI Listing

Machine Learning Analysis of Individual Tumor Lesions in Four Metastatic Colorectal Cancer Clinical Studies: Linking Tumor Heterogeneity to Overall Survival.

AAPS J 2020 03 16;22(3):58. Epub 2020 Mar 16.

Merck Institute for Pharmacometrics, Merck Serono S.A., Switzerland, a Subsidiary of Merck KGaA, Darmstadt, Germany.

Total tumor size (TS) metrics used in TS models in oncology do not consider tumor heterogeneity, which could help to better predict drug efficacy. We analyzed individual target lesions (iTLs) of patients with metastatic colorectal carcinoma (mCRC) to determine differences in TS dynamics by using the ClassIfication Clustering of Individual Lesions (CICIL) methodology. Results from subgroup analyses comparing genetic mutations and TS metrics were assessed and applied to survival analyses. Read More

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http://dx.doi.org/10.1208/s12248-020-0434-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078147PMC

Optimal Sampling Strategies for Irinotecan (CPT-11) and its Active Metabolite (SN-38) in Cancer Patients.

AAPS J 2020 03 17;22(3):59. Epub 2020 Mar 17.

Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.

Irinotecan (CPT-11) is an anticancer agent widely used in the treatment of a variety of adult solid tumors. The objective of this study was to develop an optimal sampling strategy model that accurately estimates pharmacokinetic parameters of CPT-11 and its active metabolite, SN-38. This study included 221 patients with advanced solid tumors or lymphoma receiving CPT-11 single or combination therapy with 5-fluorouracil (5-FU)/leucovorin (LV) (FOLFIRI) plus bevacizumab from 4 separate clinical trials. Read More

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http://dx.doi.org/10.1208/s12248-020-0429-4DOI Listing

Clinical Immunogenicity Risk Assessment Strategy for a Low Risk Monoclonal Antibody.

AAPS J 2020 03 17;22(3):60. Epub 2020 Mar 17.

Predictive and Clinical Immunogenicity, Merck & Co., Inc., West Point, PA, USA.

This article provides a theoretical case-study risk assessment report for a low-risk monoclonal antibody (mAb) therapeutic. In terms of risk, there are considerations around risks to safety, but also risks regarding effects on pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Much of the discussion in this document is around the risk of immunogenicity incidence. Read More

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http://dx.doi.org/10.1208/s12248-020-00440-5DOI Listing

Correction to: Development and Utility of an ELISA Method for Sensitive and Specific Detection of IgE Antidrug Antibodies.

AAPS J 2020 03 16;22(3):57. Epub 2020 Mar 16.

Specialty Bioanalytics, Teva Pharmaceuticals Inc., West Chester, Pennsylvania, 19380, USA.

During the production process, the author order of Zhandong Don Zhong and Lynn L. Jiang were inadvertently placed. Lynn L. Read More

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http://dx.doi.org/10.1208/s12248-020-00439-yDOI Listing

Applying Beta Distribution in Analyzing Bounded Outcome Score Data.

AAPS J 2020 03 17;22(3):61. Epub 2020 Mar 17.

Clinical Pharmacology and Pharmacometrics, Janssen Research & Development, LLC, 1400 McKean Road, PO Box 776, Spring House, Pennsylvania, 19477, USA.

Disease status is often measured with bounded outcome scores (BOS) which report a discrete set of values on a finite range. The distribution of such data is often non-standard, such as J- or U-shaped, for which standard analysis methods assuming normal distribution become inappropriate. Most BOS analysis methods aim to either predict the data within its natural range or accommodate data skewness, but not both. Read More

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http://dx.doi.org/10.1208/s12248-020-00441-4DOI Listing

Development of a Cell-Based Assay for the Detection of Neutralizing Antibodies to PF-06730512 Using Homogenous Time-Resolved Fluorescence.

AAPS J 2020 03 12;22(2):56. Epub 2020 Mar 12.

BioMedicine Design, Pfizer, Inc., 1 Burtt Road, Andover, Massachusetts, 01810, USA.

The administration of biotherapeutics has the potential to induce potent immune responses. Among these responses, the production of anti-drug antibodies (ADA), including a subset of ADA referred to as neutralizing antibodies (NAb), is of heightened concern. Aside from their capacity to alter the pharmacological profile of a given biotherapeutic, NAb can also pose significant safety risks, especially in instances where an endogenous counterpart to the drug exists. Read More

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http://dx.doi.org/10.1208/s12248-020-0431-xDOI Listing

Investigation on the Effect of Capillary Microsampling on Hematologic and Toxicokinetic Evaluation in Regulatory Safety Studies in Mice.

AAPS J 2020 03 9;22(2):55. Epub 2020 Mar 9.

Bioanalytical Science, Bristol-Myers Squibb, Princeton, New Jersey, 08543, USA.

Microsampling techniques enable the minimization of blood collection volume from animals and subsequent handling of the blood samples or their derived plasma or serum samples. This offers advantages over conventional large-volume sampling, such as eliminating the need for satellite animals and improving animal welfare aspects, and providing the opportunity for additional assessments in small animals where blood volume constraints limit endpoints. This study evaluated the feasibility of implementation of capillary microsampling (CMS) in a single-dose study in mice with the ultimate goal of enabling its use in toxicology studies. Read More

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http://dx.doi.org/10.1208/s12248-020-00438-zDOI Listing
March 2020
3.799 Impact Factor

Co-administration of Paediatric Medicines with Food and Drinks in the Context of Their Physicochemical Properties-a Global Perspective on Practices and Recommendations.

AAPS J 2020 03 4;22(2):54. Epub 2020 Mar 4.

Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.

Medicine co-administration with food or drink vehicles is a common administration practice in paediatrics. The aims of this review were (i) to describe the current recommended strategies for co-administration of paediatric medicines with food and drinks (vehicles); (ii) to compare current administration recommendations from different countries; and (iii) to obtain a global perspective on the rationale behind the choice of recommended vehicle, in the context of the physicochemical properties of the drug and formulation. This study used a defined search strategy on the practices of paediatric medicine co-administration with vehicles, recommended in a commonly used paediatric and neonatal handbook, in addition to the information previously gathered from UK formularies. Read More

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http://dx.doi.org/10.1208/s12248-020-0432-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056676PMC

A Microfluidic Perfusion Platform for In Vitro Analysis of Drug Pharmacokinetic-Pharmacodynamic (PK-PD) Relationships.

AAPS J 2020 03 2;22(2):53. Epub 2020 Mar 2.

Pharmacokinetics, Dynamics, & Metabolism, Pfizer Worldwide Research and Development, Pfizer Inc., 10646 Science Center Drive, San Diego, California, 92121, USA.

Static in vitro cell culture studies cannot capture the dynamic concentration profiles of drugs, nutrients, and other factors that cells experience in physiological systems. This limits the confidence in the translational relevance of in vitro experiments and increases the reliance on empirical testing of exposure-response relationships and dose optimization in animal models during preclinical drug development, introducing additional challenges owing to species-specific differences in drug pharmacokinetics (PK) and pharmacodynamics (PD). Here, we describe the development of a microfluidic cell culture device that enables perfusion of cells under 2D or 3D culture conditions with temporally programmable concentration profiles. Read More

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http://dx.doi.org/10.1208/s12248-020-0430-yDOI Listing

Systematic Review of Device Parameters and Design of Studies Bridging Biologic-Device Combination Products Using Prefilled Syringes and Autoinjectors.

AAPS J 2020 02 27;22(2):52. Epub 2020 Feb 27.

Office of Clinical Pharmacology, Center for Drug Evaluation and Research, U.S. Food and Drug Administration (OCP/CDER/FDA), 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA.

Biologic-device combination products using prefilled syringes (PFSs) and autoinjectors (AIs) are popular for biological products administered subcutaneously. Pharmacokinetic (PK) comparability studies commonly provide the scientific data to support introduction of AI presentations via bridging with PFS. A survey of biological products approved by FDA's Center for Drug Evaluation and Research identified 17 biologics license applications (BLAs) with both PFS and AI presentations for subcutaneous (SC) administration, including 16 approved on February 1, 2018, and one with AI presentation under review. Read More

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http://dx.doi.org/10.1208/s12248-020-0433-8DOI Listing
February 2020

Physiologically Based Pharmacokinetic Modeling and Tissue Distribution Characteristics of SHetA2 in Tumor-Bearing Mice.

AAPS J 2020 02 21;22(2):51. Epub 2020 Feb 21.

Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

The orally available novel small molecule SHetA2 is the lead sulfur-containing heteroarotinoid that selectively inhibits cancer cells over normal cells, and is currently under clinical development for anticancer treatment and cancer prevention. The objective of this study was to assess and characterize the tissue distribution of SHetA2 in tumor-bearing mice by developing a physiologically based pharmacokinetic (PBPK) model. An orthotopic SKOV3 ovarian cancer xenograft mouse model was used to most accurately mimic the ovarian cancer tumor microenvironment in the peritoneal cavity. Read More

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http://dx.doi.org/10.1208/s12248-020-0421-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194160PMC
February 2020

Bayesian Individual Dynamic Predictions with Uncertainty of Longitudinal Biomarkers and Risks of Survival Events in a Joint Modelling Framework: a Comparison Between Stan, Monolix, and NONMEM.

AAPS J 2020 02 19;22(2):50. Epub 2020 Feb 19.

Université de Paris, IAME, INSERM , F-75018, Paris, France.

Given a joint model and its parameters, Bayesian individual dynamic prediction (IDP) of biomarkers and risk of event can be performed for new patients at different landmark times using observed biomarker values. The aim of the present study was to compare IDP, with uncertainty, using Stan 2.18, Monolix 2018R2 and NONMEM 7. Read More

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http://dx.doi.org/10.1208/s12248-019-0388-9DOI Listing
February 2020

Biopharmaceutical Understanding of Excipient Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties: Case Study-Hypromellose (HPMC).

AAPS J 2020 02 18;22(2):49. Epub 2020 Feb 18.

Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, UK.

Identification of the biopharmaceutical risks of excipients and excipient variability on oral drug performance can be beneficial for the development of robust oral drug formulations. The current study investigated the impact of Hypromellose (HPMC) presence and varying viscosity type, when used as a binder in immediate release formulations, on the apparent solubility of drugs with wide range of physicochemical properties (drug ionization, drug lipophilicity, drug aqueous solubility). The role of physiological conditions on the impact of excipients on drug apparent solubility was assessed with the use of pharmacopoeia (compendial) and biorelevant media. Read More

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http://dx.doi.org/10.1208/s12248-019-0411-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028811PMC
February 2020

Development of an Aerosol Dose Collection Apparatus for In Vitro Dissolution Measurements of Orally Inhaled Drug Products.

AAPS J 2020 02 13;22(2):47. Epub 2020 Feb 13.

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

The aim of the study was to develop a robust and standardized in vitro dissolution methodology for orally inhaled drug products (OIDPs). An aerosol dose collection (ADC) system was designed to uniformly deposit the whole impactor stage mass (ISM) over a large filter area for dissolution testing. All dissolution tests were performed under sink conditions in a sodium phosphate buffered saline solution containing 0. Read More

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http://dx.doi.org/10.1208/s12248-020-0422-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021740PMC
February 2020

Model Averaging in Viral Dynamic Models.

AAPS J 2020 02 13;22(2):48. Epub 2020 Feb 13.

Université de Paris, IAME, INSERM, Henri Huchard, F-75018, Paris, France.

The paucity of experimental data makes both inference and prediction particularly challenging in viral dynamic models. In the presence of several candidate models, a common strategy is model selection (MS), in which models are fitted to the data but only results obtained with the "best model" are presented. However, this approach ignores model uncertainty, which may lead to inaccurate predictions. Read More

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http://dx.doi.org/10.1208/s12248-020-0426-7DOI Listing
February 2020

Biopharmaceutical Understanding of Excipient Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties. Case Study: Superdisintegrants.

AAPS J 2020 02 11;22(2):46. Epub 2020 Feb 11.

Department of Pharmacy and Pharmacology, University of Bath, Bath, BA2 7AY, UK.

The presence of different excipient types/brands in solid oral dosage forms may affect product performance and drug bioavailability. Understanding the biopharmaceutical implications of superdisintegrant variability (changes in material properties), variation (changes in excipient amount) and interchangeability (use of different excipient types with the same intended functionality) in oral drug performance would be beneficial for the development of robust final dosage forms. The current study investigated the impact of superdisintegrants (sodium starch glycolate, croscarmellose sodium, crospovidone) on the apparent solubility of drugs with different physicochemical properties (drug ionisation, drug lipophilicity, drug aqueous solubility). Read More

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http://dx.doi.org/10.1208/s12248-019-0406-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012964PMC
February 2020

Mechanistic Pharmacokinetic/Pharmacodynamic Model of Sunitinib and Dopamine in MCF-7/Adr Xenografts: Linking Cellular Heterogeneity to Tumour Burden.

AAPS J 2020 02 10;22(2):45. Epub 2020 Feb 10.

Department of Pharmaceutics, School of Pharmaceutical sciences, Peking University, Beijing, 100191, China.

The self-renewal and differentiation of cancer stem-like cells (CSCs) leads to cellular heterogeneity, causing one of the greatest challenges in cancer therapy. Growing evidence suggests that CSC-targeting therapy enhances the effect of concomitant antitumour therapy. To gain an in-depth understanding of this enhanced effect, the kinetic profile of estimated CSC frequency (the fraction of CSCs in tumour) was evaluated for in vivo characterization of cellular heterogeneity using sunitinib and dopamine as a paradigm combination therapy. Read More

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http://dx.doi.org/10.1208/s12248-020-0428-5DOI Listing
February 2020

Reference Datasets for Studies in a Replicate Design Intended for Average Bioequivalence with Expanding Limits.

AAPS J 2020 02 7;22(2):44. Epub 2020 Feb 7.

Fuglsang Pharma, Hiort Lorenzens Vej 6c st.tv., 6100, Haderslev, Denmark.

In order to help companies qualify and validate the software used to evaluate bioequivalence trials in a replicate design intended for average bioequivalence with expanding limits, this work aims to define datasets with known results. This paper releases 30 reference datasets into the public domain along with proposed consensus results. A proposal is made for results that should be used as validation targets. Read More

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http://dx.doi.org/10.1208/s12248-020-0427-6DOI Listing
February 2020

Quantification of T Cell Binding Polyclonal Rabbit Anti-thymocyte Globulin in Human Plasma with Liquid Chromatography Tandem-Mass Spectrometry.

AAPS J 2020 02 6;22(2):43. Epub 2020 Feb 6.

Department of Clinical Pharmacy, Division of Laboratory Medicine and Pharmacy, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, Room no. D.00.318A, Internal post no. D.00.204, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands.

The addition of rabbit anti-human thymocyte globulin (ATG) to the conditioning regimen prior to allogeneic hematopoietic cell transplantation has significantly reduced the risk of graft-versus-host disease (GvHD) and graft failure. However, ATG has a small therapeutic window. Overexposure of ATG post-HCT hampers T cell immune reconstitution and has been associated with increased relapse rates and viral reactivations, whereas underexposure has been associated with an increased incidence of GvHD, both of which lead to increased mortality. Read More

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http://dx.doi.org/10.1208/s12248-020-0419-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005072PMC
February 2020

Correction to: Recommendations for the Development of Cell-Based Anti-Viral Vector Neutralizing Antibody Assays.

AAPS J 2020 Feb 4;22(2):42. Epub 2020 Feb 4.

Alzheimer's Drug Discovery Foundation, New York, NY, USA.

The first author's name was published incorrectly as "Gorovits Boris". The correct name is "Boris Gorovits". Read More

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http://dx.doi.org/10.1208/s12248-020-0425-8DOI Listing
February 2020

Global Sensitivity Analysis of the Rodgers and Rowland Model for Prediction of Tissue: Plasma Partitioning Coefficients: Assessment of the Key Physiological and Physicochemical Factors That Determine Small-Molecule Tissue Distribution.

AAPS J 2020 02 3;22(2):41. Epub 2020 Feb 3.

Roche Pharma and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland.

In physiologically based pharmacokinetic (PBPK) modelling, the large number of input parameters, limited amount of available data and the structural model complexity generally hinder simultaneous estimation of uncertain and/or unknown parameters. These parameters are generally subject to estimation. However, the approaches taken for parameter estimation vary widely. Read More

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http://dx.doi.org/10.1208/s12248-020-0418-7DOI Listing
February 2020

Application of Reticulocyte-Based Estimation of Red Blood Cell Lifespan in Anemia Management of End-Stage Renal Disease Patients.

AAPS J 2020 02 3;22(2):40. Epub 2020 Feb 3.

Department of Pharmaceutical Sciences, The State University of New York at Buffalo, 370 Pharmacy Building, Buffalo, New York, 14214, USA.

Shortened red blood cell (RBC) lifespan is one of the major factors contributing to anemia in end-stage renal disease (ESRD) patients and should be taken into account in anemia management protocols. In this study, we aimed to estimate RBC lifespan and the source of between-subject variability in ESRD patients. The resulting individual parameters (empirical Bayes estimates) were used to predict hemoglobin concentrations 2 weeks in advance. Read More

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http://dx.doi.org/10.1208/s12248-020-0424-9DOI Listing
February 2020

Quantitative Assessment of Pulmonary Targeting of Inhaled Corticosteroids Using Ex Vivo Receptor Binding Studies.

AAPS J 2020 01 30;22(2):39. Epub 2020 Jan 30.

Department of Pharmaceutics, JHMHC, P3-33, College of Pharmacy, University of Florida, P.O. Box 100494, Gainesville, FL, 32610, USA.

The goal of locally acting inhaled corticosteroids is to achieve distinct pulmonary effects with reduced systemic side effects. The present work using an ex vivo receptor binding model in rats was interested in assessing pulmonary targeting for several commercially available corticosteroids by monitoring receptor occupancies in the lung and systemic organs (liver, kidney, spleen, and brain) after intravenous (IV) injection or intratracheal (IT) instillation of a dry powder administration at a dose of 100 μg/kg. Pulmonary targeting, defined as the difference in cumulative receptor occupancies (AUC) between the lung and kidney after pulmonary delivery, differed across the investigated corticosteroids (ΔAUC range, 33 ± 46 to 143 ± 52% *h) with the highest degree found for corticosteroids with high systemic clearance and pronounced lipophilicity (presumably allowing a long pulmonary residence time). Read More

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http://dx.doi.org/10.1208/s12248-019-0404-0DOI Listing
January 2020

Correction to: Fit-for-Purpose Quality Control System in Continuous Bioanalysis during Long-Term Pediatric Studies.

AAPS J 2020 Jan 29;22(2):37. Epub 2020 Jan 29.

Institute of Clinical Pharmacy and Pharmacotherapy, Heinrich Heine University, Universitaetsstr.1, 40225, Dusseldorf, Germany.

The LENA collaborator list below was not included in the original article.s. Read More

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http://dx.doi.org/10.1208/s12248-020-0415-xDOI Listing
January 2020

Considerations for Soluble Protein Biomarker Blood Sample Matrix Selection.

AAPS J 2020 01 29;22(2):38. Epub 2020 Jan 29.

R&D Systems, Minneapolis, Minnesota, USA.

Blood-based soluble protein biomarkers provide invaluable clinical information about patients and are used as diagnostic, prognostic, and pharmacodynamic markers. The most commonly used blood sample matrices are serum and different types of plasma. In drug development research, the impact of sample matrix selection on successful protein biomarker quantification is sometimes overlooked. Read More

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http://dx.doi.org/10.1208/s12248-020-0412-0DOI Listing
January 2020

Development and Utility of an ELISA Method for Sensitive and Specific Detection of IgE Antidrug Antibodies.

AAPS J 2020 01 29;22(2):36. Epub 2020 Jan 29.

Biologics Assays & Technology, Teva Pharmaceuticals Inc., West Chester, Pennsylvania, 19380, USA.

Biologics can potentially induce unwanted immune responses, leading to formation of antidrug antibodies (ADA) of various affinity, isotypes, and subclasses. Among them, antigen and drug-specific immunoglobulin E (IgE) antibodies have been reported to have potential correlation with hypersensitivity and anaphylaxis in particular. Recent regulatory guidance on immunogenicity testing has recommended the measurement of antigen-specific IgE antibodies for biologics with a reported high risk of anaphylaxis using assays with sensitivities in the high pg/mL to low ng/mL range. Read More

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http://dx.doi.org/10.1208/s12248-020-0413-zDOI Listing
January 2020

Immunogenicity Risk Assessment for PEGylated Therapeutics.

AAPS J 2020 01 28;22(2):35. Epub 2020 Jan 28.

Immunogenicity, GlaxoSmithKline, Collegeville, Pennsylvania, USA.

The objective of this manuscript is to provide the reader with two examples on how to present an immunogenicity risk assessment for a PEGylated therapeutic as part of Investigational New Drug (IND) application or during other stages of the drug development process. In order to provide context to the bioanalytical strategies used to support the PEGylated therapeutics presented here, a brief summary of information available for marketed PEGylated biologics is provided. Two case studies are presented, a PEGylated enzyme and a PEGylated growth factor. Read More

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http://dx.doi.org/10.1208/s12248-020-0420-0DOI Listing
January 2020

Investigations of Piperazine Derivatives as Intestinal Permeation Enhancers in Isolated Rat Intestinal Tissue Mucosae.

AAPS J 2020 01 27;22(2):33. Epub 2020 Jan 27.

School of Veterinary Medicine and Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

A limiting factor for oral delivery of macromolecules is low intestinal epithelial permeability. 1-Phenylpiperazine (PPZ), 1-(4-methylphenyl) piperazine (1-4-MPPZ) and 1-methyl-4-phenylpiperazine (1-M-4-PPZ) have emerged as potential permeation enhancers (PEs) from a screen carried out by others in Caco-2 monolayers. Here, their efficacy, mechanism of action and potential for epithelial toxicity were further examined in Caco-2 cells and isolated rat intestinal mucosae. Read More

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http://dx.doi.org/10.1208/s12248-020-0416-9DOI Listing
January 2020

Selection of In Vivo Predictive Dissolution Media Using Drug Substance and Physiological Properties.

AAPS J 2020 01 27;22(2):34. Epub 2020 Jan 27.

Department of Pharmacy, Uppsala Biomedical Centre, Uppsala University, P.O. Box 580, SE-751 23, Uppsala, Sweden.

The rate and extent of drug dissolution in the gastrointestinal (GI) tract are highly dependent upon drug physicochemical properties and GI fluid properties. Biorelevant dissolution media (BDM), which aim to facilitate in vitro prediction of in vivo dissolution performance, have evolved with our understanding of GI physiology. However, BDM with a variety of properties and compositions are available, making the choice of dissolution medium challenging. Read More

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http://dx.doi.org/10.1208/s12248-020-0417-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6985051PMC
January 2020