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AAPS J 2022 May 24;24(4):69. Epub 2022 May 24.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Pharmacy Building, Buffalo, NY, 14214-8033, USA.

AAPS J 2022 May 12;24(3):68. Epub 2022 May 12.

UCB Biopharma SRL, Translational Biomarkers and Bioanalysis, Braine-l'Alleud, Belgium.

The determination of a tailored anti-drug antibody (ADA) testing strategy is based on the immunogenicity risk assessment to allow a correlation of ADAs with changes to pharmacokinetics, efficacy, and safety. The clinical impact of ADA formation refines the immunogenicity risk assessment and defines appropriate risk mitigation strategies. Health agencies request for high-risk biotherapeutics to extend ADA monitoring for patients that developed an ADA response to the drug until ADAs return to baseline levels. Read More

AAPS J 2022 May 10;24(3):67. Epub 2022 May 10.

Department of Pharmacy, School of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, 112, Taiwan.

The objective of this study is to propose a unified, continuous, and bodyweight-only equation to quantify the changes of human basal metabolic rate (BMR), glomerular filtration rate (GFR), and drug clearance (CL) from infancy to adulthood. The BMR datasets were retrieved from a comprehensive historical database of male and female subjects (0.02 to 64 years). Read More

AAPS J 2022 05 9;24(3):66. Epub 2022 May 9.

Pfizer-Retired, 8739 N Homestead Circle, Irons, MI, 49644, USA.

Decades of discussion and publication have gone into the guidance from the scientific community and the regulatory agencies on the use and validation of pharmacokinetic and toxicokinetic assays by chromatographic and ligand binding assays for the measurement of drugs and metabolites. These assay validations are well described in the FDA Guidance on Bioanalytical Methods Validation (BMV, 2018). While the BMV included biomarker assay validation, the focus was on understanding the challenges posed in validating biomarker assays and the importance of having reliable biomarker assays when used for regulatory submissions, rather than definition of the appropriate experiments to be performed. Read More

AAPS J 2022 05 5;24(3):65. Epub 2022 May 5.

Bristol Myers Squibb, Princeton, NJ, USA.

AAPS J 2022 05 2;24(3):60. Epub 2022 May 2.

Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.

Traditionally, excipients have been considered in drug development from the perspective of their influence on drug solubility, manufacturability, and ability to control in vitro and in vivo drug release. These effects have been largely evaluated through studies involving in vitro dissolution methods. However, there is a growing awareness that what had previously been considered biologically inert excipients can exert numerous in vivo effects. Read More

AAPS J 2022 05 2;24(3):61. Epub 2022 May 2.

Molecular Pharmaceutics Lab, College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1, Noji-higashi, Kusatsu, Kyoto, Shiga, 525-8577, Japan.

It is now recognized that a number of excipients previously considered to be "inert" have the capacity to alter drug oral bioavailability through a range of in vivo effects. The various mechanisms through which an excipient can affect in vivo gastrointestinal physiology and drug absorption characteristics were explored in "A Critical Overview of The Biological Effects of Excipients (Part I): Impact on Gastrointestinal Absorption." The next critical issue that needs to be discussed is how these biological effects are evaluated. Read More

AAPS J 2022 05 2;24(3):62. Epub 2022 May 2.

Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, The State University of New York at Buffalo, 455 Pharmacy Building, Buffalo, NY, 14214-8033, USA.

Here, we have investigated the effect of size of protein therapeutics on brain pharmacokinetics (PK) following systemic administration in rats. All tested proteins were derived from trastuzumab that do not bind to any targets in rats. PK data generated with F(ab)(100 kDa), Fab (50 kDa), and scFv (27 kDa) fragments of trastuzumab, along with published PK data for FcRn non-binding and wild-type trastuzumab (150 kDa), were used to establish a relationship between the protein size and brain exposure. Read More

AAPS J 2022 05 2;24(3):63. Epub 2022 May 2.

Office of Research and Standards (ORS), Office of Generic Drugs (OGD), Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration (FDA), Building 75, Room 4702, 10903 New Hampshire Avenue, Silver Spring, Maryland, 20993, USA.

An intrauterine system (IUS) can be implanted in the uterus and deliver drug directly at the site of pharmacological action. Mirena was the first FDA-approved levonorgestrel (LNG) releasing IUS without an approved generic form. Its 5-year application duration presents challenges for bioequivalence (BE) assessment using the conventional in vivo studies with pharmacokinetic and/or comparative clinical endpoints. Read More

AAPS J 2022 05 2;24(3):64. Epub 2022 May 2.

Department of BioAnalytical Sciences, Genentech Inc., 1 DNA Way, South San Francisco, California, 94080-4990, USA.

Autogene cevumeran is an individualized neoantigen-specific therapy (iNeST) under development for the treatment of various solid tumors. It consists of an RNA-Lipoplex (RNA-LPX) in which the encapsulated mRNA molecule encodes up to ten neoepitopes identified from each individual patient. In association with major histocompatibility complex (MHC) class I and MHC class II, these neoantigens can potentially stimulate and expand neoantigen-specific CD4+ and CD8+ T cells, leading to antitumor responses. Read More

AAPS J 2022 04 29;24(3):59. Epub 2022 Apr 29.

Quantitative Clinical Pharmacology, Daiichi Sankyo, Inc., 211 Mt. Airy Road, Basking Ridge, New Jersey, 07920, USA.

The food effects for orally administered drugs have been widely investigated and reviewed. In contrast, our knowledge of food effects for non-orally administered drugs is scarce. In this review paper, we did a literature survey to collect clinical food effect data for non-orally administered drugs. Read More

AAPS J 2022 04 28;24(3):58. Epub 2022 Apr 28.

Clinical Pharmacology, Genentech-Roche, Marseille, France.

Longitudinal changes of tumor size or tumor-associated biomarkers have been receiving growing attention as early markers of treatment benefits. Tumor growth inhibition-overall survival (TGI-OS) models represent mathematical frameworks used to establish a link from tumor size trajectory to survival outcome with the aim of predicting survival benefit with tumor data from a small number of subjects with a short follow-up time. In the present study, we applied the TGI-OS model to assess treatment benefit in the IMpower150 study for patients who exhibited development of anti-drug antibodies (ADA). Read More

AAPS J 2022 04 21;24(3):56. Epub 2022 Apr 21.

European Directorate for the Quality of Medicines & HealthCare, 7 Allée Kastner CS 30026, 67081, Strasbourg, France.

Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their jurisdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage forms (FDFs) and 215 API samples) tested beginning in November of 2019 through July of 2020. Read More

AAPS J 2022 04 21;24(3):57. Epub 2022 Apr 21.

Department of Biomedical Data Science, Stanford University, Stanford, California, USA.

Clinical trials are the gatekeepers and bottlenecks of progress in medicine. In recent years, they have become increasingly complex and expensive, driven by a growing number of stakeholders requiring more endpoints, more diverse patient populations, and a stringent regulatory environment. Trial designers have historically relied on investigator expertise and legacy norms established within sponsor companies to improve operational efficiency while achieving study goals. Read More

AAPS J 2022 Apr 19;24(3):55. Epub 2022 Apr 19.

BioAgilytix Labs, 2300 Englert Drive, Durham, NC, 27713, USA.

AAPS J 2022 04 6;24(3):54. Epub 2022 Apr 6.

Pharmaceutical Sciences, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA, 19486, United States of America.

The pharmaceutical industry and regulatory agencies rely on dissolution similarity testing to make critical product 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 with the emphasis given to the similarity factor f with little discussion of alternative methods. In an effort to highlight current practices to assess dissolution profile similarity and to strive toward global harmonization, a workshop entitled "In Vitro Dissolution Similarity Assessment in Support of Drug Product Quality: What, How, When" was held on May 21-22, 2019 at the University of Maryland, Baltimore. Read More

AAPS J 2022 04 6;24(3):52. Epub 2022 Apr 6.

Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., Kenilworth, New Jersey, USA.

In-clinic dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling for improved logistical feasibility and decreased blood volume burden. However, an interim PK analysis revealed verubecestat concentrations in DBS samples declined with time to assay in both trials. An investigation revealed wide variation in implementation practices for DBS sample handling procedures resulting in insufficient desiccation which caused verubecestat instability. Read More

AAPS J 2022 04 6;24(3):53. Epub 2022 Apr 6.

Merck & Co., Inc., Kenilworth, New Jersey, USA.

In-clinic venous dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling. Initially, plasma and DBS PK samples were collected concurrently to better understand the DBS-plasma verubecestat concentration relationship, with the intention of discontinuing DBS or plasma sampling following interim analysis. Following initial analyses and comparison of results with prespecified selection criteria, plasma PK sampling was discontinued; however, a stability issue resulting in generally lower DBS verubecestat concentrations with longer collection-to-assay times was subsequently discovered (associated with non-compliance in DBS sample handling), prompting reintroduction of plasma sampling. Read More

AAPS J 2022 04 5;24(3):51. Epub 2022 Apr 5.

Division of Pharmacoengineering & Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina, 27599, USA.

AAPS J 2022 03 29;24(3):50. Epub 2022 Mar 29.

Regulatory Affairs, Simulations Plus Inc., Lancaster, California, USA.

This report summarizes podium presentations and breakout sessions from the second day of the 2019 M-CERSI workshop on In Vitro Dissolution Similarity Assessment in Support of Drug Product Quality: What, How, and When? Presenters from the U.S. Food and Drug Administration (FDA), Health Canada (HC), European Medicines Agency (EMA), Brazilian Health Surveillance Agency (ANVISA), and the pharmaceutical industry shared experiences/concerns with dissolution profile similarity assessment supporting minor/moderate Chemistry, Manufacturing and Control (CMC) changes. Read More

AAPS J 2022 03 29;24(3):49. Epub 2022 Mar 29.

Johnson & Johnson, New Brunswick, New Jersey, USA.

Assessment of bioperformance to inform formulation selection and development decisions is an important aspect of drug development. There is high demand in the pharmaceutical industry to develop an efficient and streamlined approach for better understanding and predicting drug product performance to support acceleration of clinical timelines. This manuscript presents an effort from the IQ Formulation Bioperformance Prediction Working Group composed of members from 12 pharmaceutical companies under the IQ Consortium to develop a database around the topic of formulation bioperformance prediction and report findings from the database analysis. Read More

AAPS J 2022 03 25;24(3):47. Epub 2022 Mar 25.

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

This work describes use of anti-carcinoembryonic antigen antibodies (10H6, T84.66) for targeted delivery of an endosomal escape peptide (H6CM18) and gelonin, a type I ribosome inactivating protein. The viability of colorectal cancer cells (LS174T, LoVo) was assessed following treatment with gelonin or gelonin immunotoxins, with or without co-treatment with T84. Read More

AAPS J 2022 03 25;24(3):48. Epub 2022 Mar 25.

Unit for Pharmacokinetics and Drug Metabolism, Sahlgrenska Academy, University of Gothenburg, Box 431, S-405 30, Gothenburg, Sweden.

Eflornithine is a recommended treatment against late-stage gambiense human African trypanosomiasis, a neglected tropical disease. Standard dosing of eflornithine consists of repeated intravenous infusions of a racemic mixture of L- and D-eflornithine. Data from three clinical studies, (i) eflornithine intravenous monotherapy, (ii) nifurtimox-eflornithine combination therapy, and (iii) eflornithine oral monotherapy, were pooled and analyzed using a time-to-event pharmacodynamic modeling approach, supported by in vitro activity data of the individual enantiomers. Read More

AAPS J 2022 03 21;24(3):45. Epub 2022 Mar 21.

Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., RY800-D211, 126 East Lincoln Avenue, Rahway, New Jersey, 07065, USA.

Inhibitory effects of asunaprevir, daclatasvir, grazoprevir, paritaprevir, simeprevir, and voxilaprevir, direct-acting antiviral (DAA) drugs for the treatment of chronic hepatitis C virus (HCV) infection, were evaluated in vitro against a range of clinically important drug transporters. In vitro inhibition studies were conducted using transporter transfected cells and membrane vesicles. The risk of clinical drug-drug interactions (DDIs) was assessed using simplified static models recommended by regulatory agencies. Read More

AAPS J 2022 03 21;24(3):46. Epub 2022 Mar 21.

DigiM Solution LLC, 67 South Bedford Street, Suite 400 West, Burlington, Massachusetts, 01803, USA.

This work reports the use of X-ray microscopy (XRM) imaging to characterize the microstructure of semisolid formulations containing multiple immiscible phases. For emulsion-based semisolid formulations, the disperse phase globule size and its distribution can be critical quality attributes of the product. Optical microscopy and light diffraction techniques are traditionally used to characterize globule size distribution. Read More

AAPS J 2022 03 16;24(3):44. Epub 2022 Mar 16.

Pharmaceutical Sciences Small Molecule, Pfizer Worldwide Research, Development and Medical, 441 Eastern Point Road, Groton, Connecticut, 06340, USA.

The objective was to develop a model to a priori identify the most suitable depot technology for a candidate based upon its therapeutic index (TI), pharmacokinetics (PK), and physical chemical properties. A depot map of release rates needed to achieve target PK in TI against release rates predicted based on intrinsic dissolution rate (IDR) and particle size (PS) clearly identified three zones: (a) products and candidates around the line of identity for which suspension is the appropriate depot technology, (b) area to the right of line of identity in which depot candidates would require a controlled release technology such as PLGA microspheres since in vivo release rate needed for PK in TI is significantly lower than predicted based on IDR and PS, and (c) area to the left of the line of identity where IDR is not sufficient to achieve target in vivo release rate for PK in TI and hence enhanced dissolution is needed such as with nanoparticles. Dose-solubility technology map of approved depot products and candidates showed clusters of products around a depot technology such as suspensions and microspheres, for drugs with high dose/low solubility and low dose/high solubility compounds, respectively. Read More

AAPS J 2022 03 15;24(2):43. Epub 2022 Mar 15.

Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio, 43210, USA.

The administration of cells as therapeutic agents has emerged as a novel approach to complement the use of small molecule drugs and other biologics for the treatment of numerous conditions. Although the use of cells for structural and/or functional tissue repair and regeneration provides new avenues to address increasingly complex disease processes, it also faces numerous challenges related to efficacy, safety, and translational potential. Recent advances in nanotechnology-driven cell therapies have the potential to overcome many of these issues through precise modulation of cellular behavior. Read More

AAPS J 2022 03 14;24(2):42. Epub 2022 Mar 14.

Charles River Laboratories, 1407 George Rd, Ashland, Ohio, 44805, USA.

The COVID-19 pandemic has strained the biological matrix supply chain. An upsurge in demand driven by numerous COVID-19 therapeutic and vaccine development programs to combat the pandemic, along with logistical challenges sourcing and transporting matrix, has led to increased lead times for multiple matrices. Biological matrix shortages can potentially cause significant delays in drug development programs across the pharmaceutical and biotechnology industry. Read More

AAPS J 2022 03 11;24(2):40. Epub 2022 Mar 11.

Division of Complex Drug Analysis, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, St. Louis, Missouri, 63110, USA.

In vitro dissolution testing is widely used to mimic and predict in vivo performance of oral drug products in the gastrointestinal (GI) tract. This literature review assesses the current in vitro dissolution methodologies being employed to simulate and predict in vivo drug dissolution under fasted and fed conditions, with emphasis on immediate release (IR) solid oral dosage forms. Notable human GI physiological conditions under fasted and fed states have been reviewed and summarized. Read More

AAPS J 2022 03 11;24(2):41. Epub 2022 Mar 11.

Department of Drug Metabolism and Pharmacokinetics (DMPK), The Healthcare Business of Merck KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany.

Accurate prediction of human pharmacokinetics using in vitro tools is an important task during drug development. Albeit, currently used in vitro systems for clearance extrapolation such as microsomes and primary human hepatocytes in suspension culture show reproducible turnover, the utility of these systems is limited by a rapid decline of activity of drug metabolizing enzymes. In this study, a multi-well array culture of primary human hepatocyte spheroids was compared to suspension and single spheroid cultures from the same donor. Read More