High-Dose IV Administration of Rasburicase Suppresses Anti-rasburicase Antibodies, Depletes Rasburicase-Specific Lymphocytes, and Upregulates Treg Cells
We examined the number of lymphocytes in peripheral blood after rasburicase i.v. injection. Rasburicase caused a transient reduction in B and T cells, but a robust and sustained depletion of rasburicase-specific B cells. Further experiments showed that rasburicase i.v. injection decreased the number of lymphocytes and was associated with apoptosis of both B cells and activated T cells and that the enhanced percentage of Treg cells was likely mediated by a macrophage-dependent pathway. Thus, our data suggest that apoptosis and depletion of antigen-specific B lymphocytes and upregulation of Treg cells may play important role...
Source: The AAPS Journal - May 27, 2020 Category: Drugs & Pharmacology Source Type: research

Remdesivir for Treatment of COVID-19: Combination of Pulmonary and IV Administration May Offer Aditional Benefit
AbstractRemdesivir 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 demonstratedin vitro activity against SARS-CoV-2 andin 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 ...
Source: The AAPS Journal - May 26, 2020 Category: Drugs & Pharmacology Source Type: research

Physiologically Based Absorption Modelling to Explore the Impact of Food and Gastric pH Changes on the Pharmacokinetics of Entrectinib
AbstractEntrectinib 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 physiol ogi...
Source: The AAPS Journal - May 26, 2020 Category: Drugs & Pharmacology Source Type: research

Development and Application of a Physiologically-Based Pharmacokinetic Model to Predict the Pharmacokinetics of Therapeutic Proteins from Full-term Neonates to Adolescents
This study demonstrates the ability of PBPK models accounting for age-dependent changes in relevant parameters to predict the pharmacokinetics of different types of TPs in paediatrics. The information gained from the PBPK models described here can facilitate our understanding of the comple xities of TPs’ disposition during growth and development. (Source: The AAPS Journal)
Source: The AAPS Journal - May 24, 2020 Category: Drugs & Pharmacology Source Type: research

Impact of Magnesium Stearate Presence and Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties
AbstractExcipients 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...
Source: The AAPS Journal - May 21, 2020 Category: Drugs & Pharmacology Source Type: research

In Vitro Dissolution Profiles Similarity Assessment in Support of Drug Product Quality: What, How, When —Workshop Summary Report
This article summarizes key points from the podium presentations and breakout (BO) sessions focusing on (1) contrasting the advantages and disadvantages of several statistical methods; (2) the importance of experimental design for successful similarity evaluation; (3) the value of similarity evaluation in light of clinically relevant specifications; and (4) the need for creating a robust and scientifically appropriate path (e.g., non-prescriptive decision tree) for dissolution profile similarity assessment as a stepping stone for global harmonization. (Source: The AAPS Journal)
Source: The AAPS Journal - May 19, 2020 Category: Drugs & Pharmacology Source Type: research

Population Pharmacokinetics of Sertraline in Healthy Subjects: a Model-Based Meta-analysis
AbstractSertraline 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. Sixty mean plasma concentration-time profiles made of 748 pl...
Source: The AAPS Journal - May 19, 2020 Category: Drugs & Pharmacology Source Type: research

Why Do the Majority of Submissions for Bridging from a Prefilled Syringe to an Autoinjector Include Bioequivalence Studies in Order to Demonstrate Comparability?
AbstractA 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. The author of this Commentary believes that formal BE studies should not be required for such bridging studies. (Source: The AAPS Journal)
Source: The AAPS Journal - May 15, 2020 Category: Drugs & Pharmacology Source Type: research

Drug Absorption Parameters Obtained Using the Isolated Perfused Rat Lung Model Are Predictive of Rat In Vivo Lung Absorption
This study aims to investigate the potential use of IPL data to predict ratin 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 ratin vivo plasma concentration-time profiles and lung amount after inhalation of five different inhalation compounds. The performance of simulations usingex vivo input parameters was compared with simulations usingin vitro input parameters, to determine whether and to what extent predictability could be improved by using inpu...
Source: The AAPS Journal - May 11, 2020 Category: Drugs & Pharmacology Source Type: research

Modeling Temperature-Dependent Dermal Absorption and Clearance for Transdermal and Topical Drug Applications
AbstractA 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 eitherin vitro orin vivo. The approximately 2-fold increase of nicotine absorption with a 10 °C increase in skin surface temperature was consistent with a 50–65 kJ/mol ...
Source: The AAPS Journal - May 10, 2020 Category: Drugs & Pharmacology Source Type: research

Quality by Design –Based Assessment for Analytical Similarity of Adalimumab Biosimilar HLX03 to Humira®
AbstractQuality 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®. The critical quality attributes (CQAs) were then identified through r isk assessment according to impact of each quality attribute on efficacy ...
Source: The AAPS Journal - May 8, 2020 Category: Drugs & Pharmacology Source Type: research

Development of a FRET-Based Assay for Analysis of mAbs Internalization and Processing by Dendritic Cells in Preclinical Immunogenicity Risk Assessment
AbstractTreatment-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. The assays thus far described in literature to evaluate immunogenicity potential/risk as a function of APC activity mainly focus on internalization of labeled drug candidatesin vitro. Herein, we describe a...
Source: The AAPS Journal - April 16, 2020 Category: Drugs & Pharmacology Source Type: research

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
The objectives of this study were (i) to show how time-scaled deconvolution and convolution-based approaches can be implem ented using population modeling approach using standard nonlinear mixed-effect modeling software such as NONMEM and R, and (ii) to compare the performances of the two methods for assessing IVIVC using complexin vivo drug release process. The impact of different PK scenarios (linear and nonlinear PK disposition models, and increasing levels of inter-individual variability (IIV) onin vivo drug release process) was considered. The performances of the methods were assessed by computing the prediction error...
Source: The AAPS Journal - April 15, 2020 Category: Drugs & Pharmacology Source Type: research

A Translational Physiologically Based Pharmacokinetics/Pharmacodynamics Framework of Target-Mediated Disposition, Target Inhibition and Drug –Drug Interactions of Bortezomib
In conclusion, the mechanistic PBPK/PD model successfully described the complex pharmacokinetics, target inhibition and DDIs of bortezomib in patients. This study illustrates the importance of incorporating target biology, drug –target interactions andin vitro clearance parameters into mechanistic PBPK/PD models and the utility of such models for pharmacokinetic, pharmacodynamic and DDI predictions. (Source: The AAPS Journal)
Source: The AAPS Journal - April 14, 2020 Category: Drugs & Pharmacology Source Type: research

Immunogenicity Risk Assessment for an Engineered Human Cytokine Analogue Expressed in Different Cell Substrates
AbstractThe 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 fact...
Source: The AAPS Journal - April 14, 2020 Category: Drugs & Pharmacology Source Type: research

Clinical Immunogenicity Risk Assessment for a Fusion Protein
AbstractThis 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. However...
Source: The AAPS Journal - April 3, 2020 Category: Drugs & Pharmacology Source Type: research

Subcutaneous Site-of-Absorption Study with the Monoclonal Antibody Tocilizumab in Minipigs: Administration Behind Ear Translates Best to Humans
This study explored different SC administration sites for mAb SC administration, to explore which site translates best to humans. The study assessed the SC absorption of tocilizumab (Actemra ®) following administration at several injection sites: Inguinal area, flank, caudal to the ear, and interscapular area, in comparison with an IV group. After SC administration, tocilizumab absorption was most rapid from the inguinal administration site, and slowest after administration behind the ear, with absorption from the other sites in between. Tocilizumab bioavailability was 98.6, 88.3, 74.1, and 86.3% after administration i...
Source: The AAPS Journal - April 3, 2020 Category: Drugs & Pharmacology Source Type: research

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
AbstractDespite 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., CocH3-Fc) are recognized as potentially promising therapeutic enzyme candidates for cocaine abuse treatment, but all with limited biological half-lives. In order to prolong the biological half-life and, thus, decrease the required frequency of the enzyme administration for cocaine abuse treatment, we have modeled the Fc-fus...
Source: The AAPS Journal - March 18, 2020 Category: Drugs & Pharmacology Source Type: research

Clinical Immunogenicity Risk Assessment Strategy for a Low Risk Monoclonal Antibody
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. A higher incidence of immunogenicity would necessitate a detailed review of the PK, efficacy and safety in anti-drug antibody (ADA) positive and ADA negative subjects, in order to evaluate potential effects. The publication is intended to provide a framew...
Source: The AAPS Journal - March 17, 2020 Category: Drugs & Pharmacology Source Type: research

Applying Beta Distribution in Analyzing Bounded Outcome Score Data
AbstractDisease 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. In addition, a frequent modeling objective is to predict clinical response of treatment using derived disease endpoints, defined as meeting certain criteria of improvement from baseline in disease status. Thi...
Source: The AAPS Journal - March 17, 2020 Category: Drugs & Pharmacology Source Type: research

Optimal Sampling Strategies for Irinotecan (CPT-11) and its Active Metabolite (SN-38) in Cancer Patients
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. Population pharmacokinetic analysis of CPT-11 and SN-38 was performed by non-linear mixed effects modeling. The optimal sampling strategy model was developed using D-optimality with expected distribution approach. The pharmacokinetic profiles of CPT-11 and SN-38 were best described by a 3- and 2-compartment model, respectively, with first-order elimination. Body surface area and co-administration with 5-F...
Source: The AAPS Journal - March 17, 2020 Category: Drugs & Pharmacology Source Type: research

Machine Learning Analysis of Individual Tumor Lesions in Four Metastatic Colorectal Cancer Clinical Studies: Linking Tumor Heterogeneity to Overall Survival
AbstractTotal 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. Data from four mCRC clinical studies were analyzed (1781 patients, 6369 iTLs). CICIL was used to assess differences in lesion TS d...
Source: The AAPS Journal - March 16, 2020 Category: Drugs & Pharmacology Source Type: research

Correction to: Development and Utility of an ELISA Method for Sensitive and Specific Detection of IgE Antidrug Antibodies
During the production process, the author order of Zhandong Don Zhong and Lynn L. Jiang were inadvertently placed. Lynn L. Jiang is the first author of this manuscript; Zhandong Don Zhong is the last author. (Source: The AAPS Journal)
Source: The AAPS Journal - March 16, 2020 Category: Drugs & Pharmacology Source Type: research

Development of a Cell-Based Assay for the Detection of Neutralizing Antibodies to PF-06730512 Using Homogenous Time-Resolved Fluorescence
AbstractThe 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. As such, the inclusion of an assay to detect NAb in clinical samples is critical to the effectiveness of a tiered approach to immunogenicity assessment. P...
Source: The AAPS Journal - March 12, 2020 Category: Drugs & Pharmacology Source Type: research

Investigation on the Effect of Capillary Microsampling on Hematologic and Toxicokinetic Evaluation in Regulatory Safety Studies in Mice
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. The focus was on the impact of microsampling on toxicokinetic assessment and on the subsequent hematology assessment in the same animal. A seventy (70)- μL blood collection via CMS from the tail vein had a minimal effect on the hematology parameters of mice (strain C57BL/6) in samples taken within 24 h of blood collection. TK parameters were similar in plasma samples collected via CMS and cardiac puncture sampling. A bioanalytical as...
Source: The AAPS Journal - March 9, 2020 Category: Drugs & Pharmacology Source Type: research

Co-administration of Paediatric Medicines with Food and Drinks in the Context of Their Physicochemical Properties —a Global Perspective on Practices and Recommendations
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. Logistic regression analysis was performed to further understand the biopharmaceutical basis of the choice of recommended vehicle for medicine co-administration. Differences were identified in the type of vehicles globally recommended for medicine co-administration. Ultimately, a statistical model was developed which provided an understanding on which vehicle is recommended f...
Source: The AAPS Journal - March 4, 2020 Category: Drugs & Pharmacology Source Type: research

A Microfluidic Perfusion Platform for In Vitro Analysis of Drug Pharmacokinetic-Pharmacodynamic (PK-PD) Relationships
AbstractStaticin 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 ofin 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 ena...
Source: The AAPS Journal - March 2, 2020 Category: Drugs & Pharmacology Source Type: research

Systematic Review of Device Parameters and Design of Studies Bridging Biologic-Device Combination Products Using Prefilled Syringes and Autoinjectors
This study represents an initial attempt to identify the potential influencing factors on device bridging, including the characteristics of the device and the clinical pharmacology study. These findings may inform the combination produc t development strategy, specifically design considerations for device and PK comparability studies. (Source: The AAPS Journal)
Source: The AAPS Journal - February 27, 2020 Category: Drugs & Pharmacology Source Type: research

Physiologically Based Pharmacokinetic Modeling and Tissue Distribution Characteristics of SHetA2 in Tumor-Bearing Mice
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. SHetA2 concentrations in plasma and 14 different tissues were measured at various time points after a single intravenous dose of 10  mg/kg and oral dose of 60 mg/kg, and these data were used to develop a whole-body PBPK model. SHetA2 exhibited a multi-exponential plasma concent...
Source: The AAPS Journal - February 21, 2020 Category: Drugs & Pharmacology Source Type: research

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
AbstractGiven 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 7.4. Simulations of biomarker and survival were performed using a nonlinear joint model of prostate-specific antigen (PSA) kinetics and survival in metastatic prostate cancer. Several scenarios were evaluated, according to the strength of the association between PSA and survival. For various landmar...
Source: The AAPS Journal - February 19, 2020 Category: Drugs & Pharmacology Source Type: research

Biopharmaceutical Understanding of Excipient Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties: Case Study —Hypromellose (HPMC)
AbstractIdentification 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 pharmacopoei...
Source: The AAPS Journal - February 18, 2020 Category: Drugs & Pharmacology Source Type: research

Model Averaging in Viral Dynamic Models
In conclusion, parameter estimates obtained with MS should be taken with caution, especially when several models well describe the data. In this situation, MA has better performances and could be performed to account for model uncertainty. (Source: The AAPS Journal)
Source: The AAPS Journal - February 13, 2020 Category: Drugs & Pharmacology Source Type: research

Development of an Aerosol Dose Collection Apparatus for In Vitro Dissolution Measurements of Orally Inhaled Drug Products
AbstractThe aim of the study was to develop a robust and standardizedin 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 0.2%w/w sodium dodecyl sulphate. An adapted USP Apparatus V, Paddle over Disk (POD), was used throughout the study. The dissolution characteristics of the ISM dose of a commercial metered-dose inhaler (MDI) an...
Source: The AAPS Journal - February 13, 2020 Category: Drugs & Pharmacology Source Type: research

Biopharmaceutical Understanding of Excipient Variability on Drug Apparent Solubility Based on Drug Physicochemical Properties. Case Study: Superdisintegrants
AbstractThe 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 ...
Source: The AAPS Journal - February 11, 2020 Category: Drugs & Pharmacology Source Type: research

Mechanistic Pharmacokinetic/Pharmacodynamic Model of Sunitinib and Dopamine in MCF-7/Adr Xenografts: Linking Cellular Heterogeneity to Tumour Burden
AbstractThe 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. Female MCF-7/Adr xenografted Balb/c nude mice were treated with sunitinib (p.o., ...
Source: The AAPS Journal - February 10, 2020 Category: Drugs & Pharmacology Source Type: research

Reference Datasets for Studies in a Replicate Design Intended for Average Bioequivalence with Expanding Limits
AbstractIn 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. The datasets were evaluated by seven different software packages according to methods proposed by the European Medicines Agency. For the estimation ofCVwR and Method A, all software packages produced results t...
Source: The AAPS Journal - February 7, 2020 Category: Drugs & Pharmacology Source Type: research

Quantification of T Cell Binding Polyclonal Rabbit Anti-thymocyte Globulin in Human Plasma with Liquid Chromatography Tandem-Mass Spectrometry
In conclusion, we developed a LC-MS/MS-based method to quantify active polyclonal rabbit ATG in human plasma. We suggest that this novel assay can be used to monitor and optimize dosing of ATG in clinical practice. (Source: The AAPS Journal)
Source: The AAPS Journal - February 6, 2020 Category: Drugs & Pharmacology Source Type: research

Correction to: Recommendations for the Development of Cell-Based Anti-Viral Vector Neutralizing Antibody Assays
The first author ’s name was published incorrectly as “Gorovits Boris”. The correct name is “Boris Gorovits”. (Source: The AAPS Journal)
Source: The AAPS Journal - February 4, 2020 Category: Drugs & Pharmacology Source Type: research

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
In conclusion, this work demonstrates that for parameter estimation involving PBPK models and dimensionality reduction purposes, less influential parameters might be assigned fixed values depending on the parameter space, while influential parameters could be subject to parameters estimation. (Source: The AAPS Journal)
Source: The AAPS Journal - February 3, 2020 Category: Drugs & Pharmacology Source Type: research

Application of Reticulocyte-Based Estimation of Red Blood Cell Lifespan in Anemia Management of End-Stage Renal Disease Patients
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. The reticulocyte-based estimation of RBC lifespan (REBEL) and the population modeling of RBC count data were used. A total of 120 blood samples collected biweekly over 10 weeks in 24 patients receiving maintenance doses of recombinant human erythropoietin (rHuEPO) subcutaneously were included in this analysis. Typical RBC lifespan was estimated to be 63.3 days. RBC li...
Source: The AAPS Journal - February 3, 2020 Category: Drugs & Pharmacology Source Type: research

Quantitative Assessment of Pulmonary Targeting of Inhaled Corticosteroids Using Ex Vivo Receptor Binding Studies
AbstractThe goal of locally acting inhaled corticosteroids is to achieve distinct pulmonary effects with reduced systemic side effects. The present work using anex 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 ...
Source: The AAPS Journal - January 30, 2020 Category: Drugs & Pharmacology Source Type: research

Considerations for Soluble Protein Biomarker Blood Sample Matrix Selection
AbstractBlood-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. The sample matrix for a specific analyte is often chosen based on prior experience or literature searches, without good understanding of the possible effects on analyte quantification. Using a data set of 32 different soluble protein...
Source: The AAPS Journal - January 29, 2020 Category: Drugs & Pharmacology Source Type: research

Development and Utility of an ELISA Method for Sensitive and Specific Detection of IgE Antidrug Antibodies
AbstractBiologics 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. Nevertheless, IgE ADA remains challenging to d...
Source: The AAPS Journal - January 29, 2020 Category: Drugs & Pharmacology Source Type: research

Correction to: Fit-for-Purpose Quality Control System in Continuous Bioanalysis during Long-Term Pediatric Studies
The LENA collaborator list below was not included in the original article.s (Source: The AAPS Journal)
Source: The AAPS Journal - January 29, 2020 Category: Drugs & Pharmacology Source Type: research

Immunogenicity Risk Assessment for PEGylated Therapeutics
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. For the former, the risk assessment covers how to deal with a narrow therape...
Source: The AAPS Journal - January 28, 2020 Category: Drugs & Pharmacology Source Type: research

Investigations of Piperazine Derivatives as Intestinal Permeation Enhancers in Isolated Rat Intestinal Tissue Mucosae
AbstractA 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. Using high-content analysis, PPZ and 1-4-MPPZ decreased mitochondrial membrane potential and increased plasma membrane potential in Caco-2 cells to ...
Source: The AAPS Journal - January 27, 2020 Category: Drugs & Pharmacology Source Type: research

Demonstrating Contribution of Components of Fixed-Dose Drug Combinations Through Longitudinal Exposure-Response Analysis
AbstractExposure-response (ER) modeling for fixed-dose combinations (FDC) has previously been found to have an inflated false positive rate (FP), i.e., observing a significant effect of FDC components when no true effect exists. Longitudinal exposure-response (LER) analysis utilizes the time course of the data and is valid for several clinical endpoints for FDCs. The aim of the study was to investigate if LER is applicable for the validation of FDCs by demonstrating the contribution of each component to the overall effect without inflation of FP rates. FP and FN rates associated with ER and LER analysis were investigated u...
Source: The AAPS Journal - January 27, 2020 Category: Drugs & Pharmacology Source Type: research

Selection of In Vivo Predictive Dissolution Media Using Drug Substance and Physiological Properties
ABSTRACTThe 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 facilitatein vitro prediction ofin 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. In this tutorial, we describe a simple and quantitative methodology for selecting practical, yet physiologically relevant BDM representative of fasted humans for evalua...
Source: The AAPS Journal - January 27, 2020 Category: Drugs & Pharmacology Source Type: research

Physiologically Based Pharmacokinetic Modeling and Simulation of Sunitinib in Pediatrics
AbstractUsing physiologically based pharmacokinetic (PBPK) modeling and simulations, this study estimated the exposure of sunitinib and its active metabolite SU012662 in pediatric patients. A PBPK simulator, SimCYP, was used to develop and validate the pharmacokinetic models. Model development employed a combined “bottom–up” and “top–down” approach to fully utilize the availablein vitro orin silico experimental data andin vivo observed clinical data. First, the PBPK model for sunitinib was established, then the cytochrome P450 3A4 –mediated metabolism of sunitinib was used as the i...
Source: The AAPS Journal - January 23, 2020 Category: Drugs & Pharmacology Source Type: research

Dose Correction for a Michaelis –Menten Approximation of a Target-Mediated Drug Disposition Model with a Multiple Intravenous Dosing Regimens
This study aimed to develop a method for implementing dose correction in a Michaelis –Menten (M-M) approximation of a target-mediated drug disposition (TMDD) model with multiple intravenous (IV) bolus administrations. We derived the formula of a correction factor (Fcorr) for each dose in a multiple IV bolus dosing regimens for M-M model. Fcorr depends on the residual free drug amo unt prior IV bolus dosing event and dose amount. We conducted a stochastic simulation and estimation (SSE) exercise based on therapeutic antibody PK parameters to evaluate the effect of Fcorr on parameter estimation. Previously published cl...
Source: The AAPS Journal - January 16, 2020 Category: Drugs & Pharmacology Source Type: research