“Development of Fixed Dose Combination Products” Workshop Report: Considerations of Gastrointestinal Physiology and Overall Development Strategy
This report gives the reader a summary of a 2-day short course that took place on the third and fourth of November at the Annual Association of Pharmaceutical Scientists (AAPS) meeting in 2018 at Washington, D.C. This manuscript will offer a comprehensive view of the most influential aspects of the GI physiology on the absorption of drugs and current techniques to help understand the fate of orally ingested drug products in the complex environment represented by the GI tract. Through case studies on FDC product development and regulatory issues, this manuscript will provide a great opportunity for readers to explore avenue...
Source: The AAPS Journal - June 6, 2019 Category: Drugs & Pharmacology Source Type: research

A Bounded Integer Model for Rating and Composite Scale Data
This study shows that the BI model respects the integer nature of data and is parsimonious in terms of number of estimated parameters. (Source: The AAPS Journal)
Source: The AAPS Journal - June 6, 2019 Category: Drugs & Pharmacology Source Type: research

Correction to: A Translational Quantitative Systems Pharmacology Model for CD3 Bispecific Molecules: Application to Quantify T Cell-Mediated Tumor Cell Killing by P-Cadherin LP DART ®
Typesetting error occurred and Figure 1a and Figure 1b were altered during the uploading process. The original article has been corrected. (Source: The AAPS Journal)
Source: The AAPS Journal - June 4, 2019 Category: Drugs & Pharmacology Source Type: research

Translational Quantitative Systems Pharmacology in Drug Development: from Current Landscape to Good Practices
AbstractSystems pharmacology approaches have the capability of quantitatively linking the key biological molecules relevant to a drug candidate ’s mechanism of action (drug-induced signaling pathways) to the clinical biomarkers associated with the proposed target disease, thereby quantitatively facilitating its development and life cycle management. In this review, the model attributes of published quantitative systems pharmacology (QSP) modeling for lowering cholesterol, treating salt-sensitive hypertension, and treating rare diseases as well as describing bone homeostasis and related pharmacological effects are cri...
Source: The AAPS Journal - June 3, 2019 Category: Drugs & Pharmacology Source Type: research

Anti-drug Antibody Assay Conditions Significantly Impact Assay Screen and Confirmatory Cut-Points
In conclusion, it is suggested that by assessing performance of treatment-naïve samples at various assay conditions, one can identify potential assay protocols that allow to avoid undesirably low screening (e.g.,
Source: The AAPS Journal - June 3, 2019 Category: Drugs & Pharmacology Source Type: research

Skin Delivery and Irritation Potential of Phenmetrazine as a Candidate Transdermal Formulation for Repurposed Indications
In conclusion, it is feasible to deliver therapeutically relevant amounts of phenmetrazine via the transdermal route. (Source: The AAPS Journal)
Source: The AAPS Journal - May 31, 2019 Category: Drugs & Pharmacology Source Type: research

Estimating In Vivo Fractional Contribution of OATP1B1 to Human Hepatic Active Uptake by Mechanistically Modeling Pharmacogenetic Data
AbstractA reasonable estimate on the fractional contribution of transporters to total hepatic active uptake (FT) is a critical factor in understanding and predicting human clearance, drug-drug interaction, and pharmacokinetic variability for hepatic transporter substrates.FT values for organic-anion-transporting polypeptide (OATP) 1B1 have been previously determined usingin vitro assays. However, to date, none of the publishedin vitro FT values has been validated against or compared within vivo FT values due to the lack of clinical data from selective substrates or inhibitors. The possible transporter-dependentin vitro toi...
Source: The AAPS Journal - May 28, 2019 Category: Drugs & Pharmacology Source Type: research

Population Pharmacokinetic Modeling in the Presence of Missing Time-Dependent Covariates: Impact of Body Weight on Pharmacokinetics of Paracetamol in Neonates
The objective of this study is to determine if missing body weights in preterm and term neonates affect estimates of model parameters and which methods can be used to improve performance of a population pharmacokinetic model of paracetamol. Data for our analysis were obtained from previously published studies on the pharmacokinetics of intravenous paracetamol in neonates. We adopted a population model of body weight change in neonates to implement three previously introduced methods of handling missing covariates based on data imputation, likelihood function modification, and full random effects modeling. All models were i...
Source: The AAPS Journal - May 28, 2019 Category: Drugs & Pharmacology Source Type: research

Mind the Gaps: Ontogeny of Human Brain P-gp and Its Impact on Drug Toxicity
AbstractAvailable data on human brain P-glycoprotein ontogeny during infancy and childhood are limited. This review discusses the current body of data relating to maturation of human brain P-glycoprotein including transporter expression levels in post-mortem human brain samples,in vivo transporter activity using probe substrates, surrogate marker endpoints, and extrapolations from animal models. Overall, the data tend to confirm that human brain P-glycoprotein activity keeps developing after birth, although with a developmental time frame that remains unclear. This knowledge gap is a concern given the critical role of brai...
Source: The AAPS Journal - May 28, 2019 Category: Drugs & Pharmacology Source Type: research

A Translational Quantitative Systems Pharmacology Model for CD3 Bispecific Molecules: Application to Quantify T Cell-Mediated Tumor Cell Killing by P-Cadherin LP DART ®
AbstractCD3 bispecific antibody constructs recruit cytolytic T cells to kill tumor cells, offering a potent approach to treat cancer. T cell activation is driven by the formation of a trimolecular complex (trimer) between drugs, T cells, and tumor cells, mimicking an immune synapse. A translational quantitative systems pharmacology (QSP) model is proposed for CD3 bispecific molecules capable of predicting trimer concentration and linking it to tumor cell killing. The model was used to quantify the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of a CD3 bispecific targeting P-cadherin (PF-06671008). It describes the...
Source: The AAPS Journal - May 22, 2019 Category: Drugs & Pharmacology Source Type: research

Application of Mechanistic Ocular Absorption Modeling and Simulation to Understand the Impact of Formulation Properties on Ophthalmic Bioavailability in Rabbits: a Case Study Using Dexamethasone Suspension
This study reinforces our understanding of the interplay between physiological factors and ophthalmic formulation physicochemical properties and their impact onin vivo ocular drug PK performance in rabbits. (Source: The AAPS Journal)
Source: The AAPS Journal - May 20, 2019 Category: Drugs & Pharmacology Source Type: research

Nanomaterial-Based Modulation of Tumor Microenvironments for Enhancing Chemo/Immunotherapy
AbstractThe tumor microenvironment (TME) has drawn considerable research attention as an alternative target for nanomedicine-based cancer therapy. Various nanomaterials that carry active substances have been designed to alter the features or composition of the TME and thereby improve the delivery and efficacy of anticancer chemotherapeutics. These alterations include disruption of the extracellular matrix and tumor vascular systems to promote perfusion or modulate hypoxia. Nanomaterials have also been used to modulate the immunological microenvironment of tumors. In this context, nanomaterials have been shown to alter popu...
Source: The AAPS Journal - May 17, 2019 Category: Drugs & Pharmacology Source Type: research

In Vitro Metabolism and Hepatic Intrinsic Clearance of the Synthetic Cannabinoid Receptor Agonist JWH-122 and Its Four ω-Halogenated Analogues
This study investigates thein vitro impact of JWH-122 ω-halogenation (fluoro, chloro, bromo and iodo) on the metabolism, apparent intrinsic hepatic clearance and analytical targets for detecting drug consumption. Metabolite profiling was conducted with pooled human liver microsomes, suspended rat hepatocytes and pooled human hepatocytes. Thein vitro half-life was also determined in pooled human hepatocytes. All samples were analysed by liquid chromatography/high-resolution mass spectrometry. All compounds, except for JWH-122, showed high formation rates of phase I metabolites, predominantly ω-COOH and methylnap...
Source: The AAPS Journal - May 15, 2019 Category: Drugs & Pharmacology Source Type: research

Fc-Fusion Drugs Have Fc γR/C1q Binding and Signaling Properties That May Affect Their Immunogenicity
AbstractFusing the human immunoglobulin G1 (IgG1) constant region (Fc-domain) to therapeutic proteins or peptides increases their circulating plasma half-life via neonatal Fc receptor (FcRn) binding and recycling. However, Fc-mediated interactions with other molecules including complement C1q and Fc gamma receptors (Fc γRs) can have immunological consequences and the potential to modulate the immunogenicity of Fc-fusion therapeutics. In a comparative study, we carried out a comprehensive assessment of Fc-mediated interactions for five FDA-approved Fc-fusion therapeutics. C1q binding and complement activation were mea...
Source: The AAPS Journal - May 6, 2019 Category: Drugs & Pharmacology Source Type: research

Towards Improved Pharmacokinetic Models for the Analysis of Transporter-Mediated Hepatic Disposition of Drug Molecules with Positron Emission Tomography
In this study, we evaluated the suitability of different compartment models to describe the hepatic disposition of [11C]erlotinib as a small-molecule model drug which undergoes transporter-mediated hepatobiliary excretion. We analyzed two different, previously published data sets in healthy volunteers, in which a baseline [11C]erlotinib PET scan was followed by a second PET scan either after oral intake of unlabeled erlotinib (300  mg) or after intravenous infusion of the prototypical organic anion-transporting polypeptide inhibitor rifampicin (600 mg). We assessed a three-compartment (3C) and a four-compartment ...
Source: The AAPS Journal - April 29, 2019 Category: Drugs & Pharmacology Source Type: research

A Novel Method for Analysing Frequent Observations from Questionnaires in Order to Model Patient-Reported Outcomes: Application to EXACT ® Daily Diary Data from COPD Patients
AbstractChronic obstructive pulmonary disease (COPD) is a progressive lung disease with approximately 174 million cases worldwide. Electronic questionnaires are increasingly used for collecting patient-reported-outcome (PRO) data about disease symptoms. Our aim was to leverage PRO data, collected to record COPD disease symptoms, in a general modelling framework to enable interpretation of PRO observations in relation to disease progression and potential to predict exacerbations. The data were collected daily over a year, in a prospective, observational study. The e-questionnaire, the EXAcerbations of COPD Tool (EXACT ®...
Source: The AAPS Journal - April 26, 2019 Category: Drugs & Pharmacology Source Type: research

Biodegradable Thermosensitive PLGA-PEG-PLGA Polymer for Non-irritating and Sustained Ophthalmic Drug Delivery
In this study, excellent biocompatibility of blank PLGA-PEG-PLGA (1800-1500-1800) thermogel was demonstrated with insignificant difference from saline noted in rat eye enucleation test,in vivo inflammation test upon topical instillation, and subconjunctival injection. After subconjunctival injection, thermogel formulations loaded with hydrophilic (rhodamine B) or hydrophobic (coumarin 6) fluorescent dyes were retained up to 4  weeks in eye tissues and significantly higher level was detected than rhodamine B solution or coumarin 6 suspension in weeks 3 and 4. Moreover,in vivo whole body imaging showed that dye-loaded (...
Source: The AAPS Journal - April 24, 2019 Category: Drugs & Pharmacology Source Type: research

Effect of Grapefruit Juice Intake on Serum Level of the Endogenous CYP3A4 Metabolite 4 β-Hydroxycholesterol—an Interaction Study in Healthy Volunteers
Abstract4 β-Hydroxycholesterol (4βOHC) is an endogenous CYP3A4 metabolite. However, it is unclear whether circulating levels of 4βOHC may reflect hepatic CYP3A4 activity or both hepatic and intestinal enzyme activity. The aim of this study was to investigate the effect of grapefruit juice, regarded to be a selective intestinal CYP3A4 inhibitor, on serum 4βOHC levels in healthy volunteers. The participants (n = 22) consumed grapefruit juice twice daily for 3 weeks followed by a 2-week washout period. Blood samples for measurements of 4βOHC and the non-CYP3A4-derived oxysterols 24-...
Source: The AAPS Journal - April 24, 2019 Category: Drugs & Pharmacology Source Type: research

Targeting Cancer Via Resveratrol-Loaded Nanoparticles Administration: Focusing on In Vivo Evidence
AbstractResveratrol (RSV) is a polyphenol endowed with potential therapeutic effects in chronic diseases, particularly in cancer, the second leading cause of death worldwide in the twenty-first century. The advent of nanotechnology application in the field of drug delivery allows to overcome the constrains associated with the conventional anticancer treatments, in particular chemotherapy, reducing its adverse side effects, off target risks and surpassing cancer multidrug chemoresistance. Moreover, the use of nanotechnology-based carriers in the delivery of plant-derived anticancer agents, such as RSV, has already demonstra...
Source: The AAPS Journal - April 23, 2019 Category: Drugs & Pharmacology Source Type: research

Report of the AAPS Guidance Forum on the FDA Draft Guidance for Industry: “Drug Products, Including Biological Products, that Contain Nanomaterials”
AbstractTo 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. During the AAPS Guidance Forum on September 11, 2018, participants from industry, academia, and regulatory bodies discussed this draft guidance in an open setting. Two questions raised by the AAPS member ship were discussed in more detail:what is the appropriate regulatory pathway for approval of drug products containing nanomaterials, andhow...
Source: The AAPS Journal - April 17, 2019 Category: Drugs & Pharmacology Source Type: research

Fetal Concentrations of Budesonide and Fluticasone Propionate: a Study in Mice
AbstractThe 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 [3H]-BUD or a high dose of [3H]-FP (1590  μg/kg). In a separate experiment, pregnant mice (N = 12) received subcutaneously either the P-gp inhibitor zosuquidar (20 mg/kg) or vehicle, followed by an intravenous ...
Source: The AAPS Journal - April 16, 2019 Category: Drugs & Pharmacology Source Type: research

Report on the AAPS Immunogenicity Guidance Forum
AbstractIn 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. Specific topics that were discussed included the strategies of anti-drug antibody (ADA) assay cut-point assessments, the selection of ADA-positive controls...
Source: The AAPS Journal - April 16, 2019 Category: Drugs & Pharmacology Source Type: research

In Vitro and In Vivo Co-delivery of siRNA and Doxorubicin by Folate-PEG-Appended Dendrimer/Glucuronylglucosyl- β-Cyclodextrin Conjugate
AbstractWe 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 bothin vitro andin vivo. Fol-PEG-GUG- β-CDE re...
Source: The AAPS Journal - April 16, 2019 Category: Drugs & Pharmacology Source Type: research

Induction and Impact of Anti-Drug Responses Elicited by a Human Recombinant Coagulation Factor FXa I16L in Preclinical Species
AbstractThis 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. FXaI16L-induced ADA response was characterized in monkey, mouse, rat, and dog in different studies, and ADA effects on pharmacokinetic and/or pharmacodynamics of FXaI16L were further examined in ADA-negative and ADA-positive animals. After repeated administrations, FXaI16L elicited a dose and exposure day-dependent ADA response which ranged from no response to a transient or pers...
Source: The AAPS Journal - April 11, 2019 Category: Drugs & Pharmacology Source Type: research

Dissolution Chamber for Small Drug Delivery System in the Periodontal Pocket
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. Flow-through dissolution chambers were constructed using three-dimensional (3D) printing. Drug release experiments were performed using the dissolution chamber and a commercially available long-acting periodontal insert product, PerioChip ®. Similar experiments were performed under more traditional larger volume bulk solution conditions for comparison. Computer simulations and experimental ...
Source: The AAPS Journal - April 10, 2019 Category: Drugs & Pharmacology Source Type: research

CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies
AbstractThe 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. However, despite significant progress in the area, CAR T cell therapy is still in its early days and face...
Source: The AAPS Journal - April 8, 2019 Category: Drugs & Pharmacology Source Type: research

HER3-Targeted Affibodies with Optimized Formats Reduce Ovarian Cancer Progression in a Mouse Xenograft Model
AbstractExpression 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. Others have established HER3 affibodies as viable and potentially superior alternatives to monoclonal antibodies for cancer therapy. Here, bivalent H...
Source: The AAPS Journal - April 4, 2019 Category: Drugs & Pharmacology Source Type: research

Bacteriophage PEV20 and Ciprofloxacin Combination Treatment Enhances Removal of Pseudomonas aeruginosa Biofilm Isolated from Cystic Fibrosis and Wound Patients
AbstractAntibiotic resistance inPseudomonas 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 ofP. aeruginosa biofilms of laboratory strains. In the present study, biofilms of sixP. aeruginosa isolated from cystic fibrosis and wound patients, and one laboratory strain was treated singly and with combinations of anti-Pseudomonas phage PEV20...
Source: The AAPS Journal - April 4, 2019 Category: Drugs & Pharmacology Source Type: research

Trial Design and Statistical Considerations on the Assessment of Pharmacodynamic Similarity
This study showcased the drawbacks of the conventional method for PD data that were close to inhibition saturation, as the baseline-normalization significantly skewed the distribution of the PD data toward non-log-normal. In such cases, the standard BE test can produce an inflated type I error. Alternatively, ANCOVA, when applied to the un-normalized PD data with the baseline as a covariate, produced a satisfactory type I error with sufficient power. Therefore, ANCOVA was recommended for equivalence test of PD markers that has a saturated inhibition profile and high variability at baseline. Moreover, the relationship betwe...
Source: The AAPS Journal - April 3, 2019 Category: Drugs & Pharmacology Source Type: research

Neutralizing Antibody Assay Development with High Drug and Target Tolerance to Support Clinical Development of an Anti-TFPI Therapeutic Monoclonal Antibody
AbstractImmunogenicity 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 suppo...
Source: The AAPS Journal - March 29, 2019 Category: Drugs & Pharmacology Source Type: research

Mechanisms of CYP3A Induction During Pregnancy: Studies in HepaRG Cells
AbstractActivity 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 thir d 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. To determine the mechan...
Source: The AAPS Journal - March 27, 2019 Category: Drugs & Pharmacology Source Type: research

Interfacial Stress in the Development of Biologics: Fundamental Understanding, Current Practice, and Future Perspective
AbstractBiologic 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 m olecule to various interfaces. Protein aggregation at interfaces is often accompanied by changes in conformation, as proteins modify their h...
Source: The AAPS Journal - March 26, 2019 Category: Drugs & Pharmacology Source Type: research

Theoretical Considerations for Direct Translation of Unbound Liver-to-Plasma Partition Coefficient from In Vitro to In Vivo
AbstractThere 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 ofin vitro unbound hepatocyte-to-media partition coefficient (in vitro Kpuu) andin vivo unbound liver-to-plasma partition coefficient (in vivo Kpuu) have been reported without considering the theoretical aspects which might confound the interpretation of such observations. To understand the theoretical basis ...
Source: The AAPS Journal - March 18, 2019 Category: Drugs & Pharmacology Source Type: research

Effect of Dibasic Calcium Phosphate Incorporation on Cellulose Nanocrystal/Chitosan Hydrogel Properties for the Treatment of Vertebral Compression Fractures
AbstractVertebral 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. In this research we studied the osteoinductive effect of calcium phosphate incorporation into cellulose nanocrystal/chitosan hydrogels with varying ratios of carbonate as an ionic crosslinker and genipin as a covalent crosslinker. As calcium and phosphate ions have been shown to be osteoinductive in ...
Source: The AAPS Journal - March 18, 2019 Category: Drugs & Pharmacology Source Type: research

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
AbstractA 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...
Source: The AAPS Journal - March 18, 2019 Category: Drugs & Pharmacology Source Type: research

A Receiver Operating Characteristic Framework for Non-adherence Detection Using Drug Concentration Thresholds —Application to Simulated Risperidone Data in Schizophrenic Patients
AbstractNon-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 me...
Source: The AAPS Journal - March 14, 2019 Category: Drugs & Pharmacology Source Type: research

Pharmacokinetic Properties of Humanized IgG1 and IgG4 Antibodies in Preclinical Species: Translational Evaluation
In this study, we have attempted to examine the PK properties of human IgG antibodies in dog and monkey. These studies establish a translational framework for evaluation of IgG antibody PK properties across species. (Source: The AAPS Journal)
Source: The AAPS Journal - March 13, 2019 Category: Drugs & Pharmacology Source Type: research

Scaling Drug Clearance from Adults to the Young Children for Drugs Undergoing Hepatic Metabolism: A Simulation Study to Search for the Simplest Scaling Method
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 (AS0.75) combined with isoenzyme maturation functions (MFPBPK) similar to those implemented in physiologically based pharmacokinetic (PBPK) models (AS0.75  + MFPBPK). A PBPK-based simulation workflow was used, including hypothetical drugs ...
Source: The AAPS Journal - March 8, 2019 Category: Drugs & Pharmacology Source Type: research

Variability Attribution for Automated Model Building
AbstractWe 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. Each example was first linearized; then, we assessed the agreement in improvement of fit between the base model and its extended models for lineari...
Source: The AAPS Journal - March 8, 2019 Category: Drugs & Pharmacology Source Type: research

Dissolution Edge Charts for Immediate Release Products and Their Applications: a Simulation Study to Aid the Setting of Specifications
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) acceptance tables should be targeted. The simulations of dissolution data were performed on a batch of IR products with 1,000,000  units. The desired acceptance criterion wasQ = 80% of the label claim at 30 min. A total of 110 scenarios for IR data were generated, which included various combinations of two determinants...
Source: The AAPS Journal - March 5, 2019 Category: Drugs & Pharmacology Source Type: research

A Reappraisal of Sedimentation Nonideality Coefficients for the Analysis of Weak Interactions of Therapeutic Proteins
AbstractThe 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 coefficientB2 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 betweenB2 and the nonideality of sedimentation, commonly measured in sedimentation velocity analytical ultracentrifugation through the nonideality coefficient of sedimentation,k...
Source: The AAPS Journal - February 27, 2019 Category: Drugs & Pharmacology Source Type: research

Model-Based Conditional Weighted Residuals Analysis for Structural Model Assessment
AbstractNonlinear 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). We illustrate this method by assessing prediction bias in two integrated models for glucose homeostasis, the integrated glucos...
Source: The AAPS Journal - February 27, 2019 Category: Drugs & Pharmacology Source Type: research

A Density-Changing Centrifugation Method for Efficient Separation of Free Drugs from Drug-Loaded Particulate Delivery Systems
AbstractCommonly 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. After optimizing TC concentration and centrifugal conditions, DCC showed superior separation efficiency and accuracy over common ultracentrifugati...
Source: The AAPS Journal - February 25, 2019 Category: Drugs & Pharmacology Source Type: research

First-Principles and Empirical Approaches to Predicting In Vitro Dissolution for Pharmaceutical Formulation and Process Development and for Product Release Testing
AbstractThis 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) andIn Vitro Release and Dissolution Testing (IVRDT). The intent of this manuscript is to show recent progress in the field ofin vitro predictive dissolution modeling and to provide recommended general approaches to developingin vitro predictive dissolution models for both early- and late-stage formulation/process development ...
Source: The AAPS Journal - February 21, 2019 Category: Drugs & Pharmacology Source Type: research

Moringa Isothiocyanate Activates Nrf2: Potential Role in Diabetic Nephropathy
AbstractMoringa isothiocyanate (MIC-1) is the main active isothiocyanate found inMoringa 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. MIC-1 showed little toxicity from 1.25 –5 μM. MIC-1 activated Nrf2-ARE at similar levels to SFN. MIC-1 also increased gene expression of downstream Nrf2 genes NQO1, HO-1, and GCLC. Protein expression of HO-1...
Source: The AAPS Journal - February 19, 2019 Category: Drugs & Pharmacology Source Type: research

Activation of Protein Kinase A Stimulates SUMOylation, Expression, and Transport Activity of Organic Anion Transporter 3
In conclusion, this is the first demonstration that PKA stimulated OAT3 expression and transport activity by altering the trafficking kinetics of OAT3 possibly through the crosstalk between SUMOylation and ubiquitination. Our studies are consistent with a remote sensing and signaling model for transporters (Wuet al. in Mol Pharmacol. 79(5):795 –805,2011). (Source: The AAPS Journal)
Source: The AAPS Journal - February 13, 2019 Category: Drugs & Pharmacology Source Type: research

Dissolution and Translational Modeling Strategies Toward Establishing an In Vitro - In Vivo Link —a Workshop Summary Report
ABSTRACTThis 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 anin 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. In this manuscript, case studies of p...
Source: The AAPS Journal - February 11, 2019 Category: Drugs & Pharmacology Source Type: research

Incurred Sample Reanalysis: Time to Change the Sample Size Calculation?
AbstractReliable 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. The methodology of this test is well established, but the estimation of the sample size is still commented on and contested. We have applied the hypergeometric distribution to evaluate ISR te st passing rates in different clinical study sizes. We have t...
Source: The AAPS Journal - February 11, 2019 Category: Drugs & Pharmacology Source Type: research

Estimation of Solid Tumor Doubling Times from Progression-Free Survival Plots Using a Novel Statistical Approach
ABSTRACTTumor 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. The PFS plot showing fastest tumor growth was deemed to best represent the inherent growth kinetics of the solid tumor, and selected for further analysis. The exponential tumor growth rates were extracted from each PFS plot, a...
Source: The AAPS Journal - February 8, 2019 Category: Drugs & Pharmacology Source Type: research

Multiplexed Gene Expression as a Characterization of Bioactivity for Interferon Beta (IFN- β) Biosimilar Candidates: Impact of Innate Immune Response Modulating Impurities (IIRMIs)
AbstractRecombinant 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, asses sment of potency for IFN-β products is based on their antiviral effect, which is not linked to its therapeutic effect. Here, we explore the use of a multiplexed gene expression system to more broadly characterize IFN-β bioactivity. We find that MM6 cells stimulated wit...
Source: The AAPS Journal - February 8, 2019 Category: Drugs & Pharmacology Source Type: research