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Comparison of RT-qPCR With Branched DNA to Quantify a Lipid Nanoparticle-Encapsulated mRNA Therapeutic in Serum and Liver Tissue Samples From Nonclinical PK Studies

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AAPS JOURNAL 2025年第1期27卷 1-10页

作者： Ortiz, Jessica Brunner, Laura Ci, Lei Baek, Rena jani, darshana Marshall, Jean-Claude Pennucci, Jason Moderna Inc Cambridge MA 02142 USA

While the branched DNA (bDNA) assay is an established bioanalytical method for measurement of lipid nanoparticle (LNP)-encapsulated messenger RNA (mRNA) pharmacokinetic parameters, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) has been considered as an alternative platform. RT-qPCR and bDNA platforms were compared for sensitivity, specificity, correlation, and overall assay performance using serum and tissue samples from 2 nonclinical mouse studies of a therapeutic mRNA candidate, LNP-PAH-mRNA, which encodes for human phenylalanine hydroxylase enzyme. Pharmacokinetic parameter noncompartmental analysis was completed using Phoenix WinNonlin. The assays were compared using simple linear regression and Bland-Altman analyses. Sensitivity ranged from 0.05 to 6.40 ng/mL for the bDNA assays, from 0.00000761 to 7.61 ng/mL in serum, and from 0.000179 to 179 ng/g in tissue for the RT-qPCR assay. Inter-assay accuracy was within +/- 10%, inter-assay precision was <= 10%, and the total error for both assays was <= 20%. RT-qPCR serum mRNA concentrations were 2- to fourfold lower compared with the bDNA assay, whereas tissue samples were comparable between assays. A linear relationship with - 0.37 to - 0.02 systematic bias demonstrated acceptable concordance. Bland-Altman plots demonstrated close equivalence, with a negative bias of < 0.5, and >= 95% of the data points were within the 95% limits of agreement. The comparison of the RT-qPCR with bDNA assay platforms for quantification of pharmacokinetic properties of an mRNA-LNP therapeutic has demonstrated acceptable concordance. This comparison reinforces the use of the RT-qPCR, a widely accessible strategy, as an alternative platform for the quantification of subsequent mRNA-LNP therapeutics.

关键词： bDNA bioanalytical mRNA therapeutics pharmacokinetics RT-qPCR

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Population Pharmacokinetic Analysis of Dalteparin in Pediatric Patients With Venous Thromboembolism

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JOURNAL OF CLINICAL PHARMACOLOGY 2021年第2期61卷 172-180页

作者： Damle, Bharat Jen, Frank Sherman, Nancy jani, darshana Sweeney, Kevin Pfizer Inc Clin Pharmacol New York NY 10017 USA Pfizer Inc Global Prod Dev New York NY 10017 USA Pfizer Inc Clin Pharmacol Cambridge MA USA Pfizer Inc Clin Pharmacol Groton CT USA

This article describes the population pharmacokinetics (PK) of dalteparin in pediatric patients with venous thromboembolism (VTE). A prospective multicenter open-label study was conducted in children who required anticoagulation for the treatment of VTE. The study population included children with and without cancer. The goal was to describe the pharmacokinetics of dalteparin using anti-Xa as a surrogate marker and to determine the dose required to achieve therapeutic anti-Xa levels (0.5-1.0 IU/mL). The anti-Xa data were supplemented with 2 published studies and analyzed using population pharmacokinetic approaches. The pharmacokinetics of dalteparin following subcutaneous injection in pediatric patients was described by a 1-compartment model with linear absorption and elimination. Body weight was added as a covariate on both CL/F and Vd/F as a power function with fixed exponents of 0.75 and 1.0, respectively. The estimates of CL/F and Vd/F in the full model were 929 mL/h and 7180 mL, respectively, for a reference female patient aged 12 years with body weight of 43 kg. Body weight-normalized CL/F decreased with age. Cancer status and sex did not have significant effects on CL/F and Vd/F. Simulations were conducted to select starting doses of dalteparin that would rapidly achieve therapeutic anti-Xa levels. These simulations suggested that the recommended starting doses of dalteparin administered subcutaneously in pediatric patients of different age cohort groups for treatment of VTE were 150 IU/kg every 12 hours (1 month to <2 years), 125 IU/kg every 12 hours (>= 2 to <8 years), and 100 IU/kg every 12 hours (>= 8 to <19 years).

关键词： anti-Xa dalteparin pediatrics population pharmacokinetics venous thromboembolism

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Evolution of Antidrug Antibody Assays During the Development of Anti-Tissue Factor Pathway Inhibitor Monoclonal Antibody Marstacimab

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AAPS JOURNAL 2023年第5期25卷 1-9页

作者： Donley, Jean jani, darshana Zhu, Tong Xiang, Yuhong Gorovits, Boris Arkin, Steven Pfizer Biomed Design Andover MA USA Pfizer Inc Cambridge MA USA Pfizer Worldwide Res & Dev Rare Dis Res Unit 610 Main St 2nd Floor Cambridge MA 02139 USA

Tissue factor pathway inhibitor (TFPI) is an endogenous inhibitor of the extrinsic coagulation pathway. In patients with hemophilia A or B, inhibition of TFPI is an alternative therapeutic approach that augments the extrinsic coagulation pathway. Marstacimab is an investigational fully human monoclonal antibody that binds and neutralizes TFPI and is being evaluated as a prophylactic treatment to prevent or reduce the frequency of bleeding episodes in patients with severe hemophilia A or B, with or without inhibitors (antibodies against coagulation factors). However, the efficacy, safety, and pharmacokinetics of marstacimab may be affected by the induction of antidrug antibody (ADA) responses. Here, we describe the evolution and validation of three quasi-quantitative electrochemiluminescence-based methods to detect marstacimab ADAs, starting from their use in a first-in-human phase 1 study to their use in phase 2 and 3 clinical studies of patients with severe hemophilia. For all three methods, validation criteria evaluated the performance of the assays in screening and confirmatory cut points, precision, selectivity, drug tolerance, target interference, and stability. Additional criteria for validation were dilution linearity (Methods 1 and 2) and low positive control concentration, prozone effect, plate homogeneity, and robustness (Method 3). The three methods met validation criteria and are a potentially valuable tool in detecting the induction of marstacimab ADAs during treatment in patients with hemophilia.

关键词： antibodies hemophilia A hemophilia B neutralizing pharmacokinetics

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Recommendations for the development and validation of confirmatory anti-drug antibody assays

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BIOANALYSIS 2015年第13期7卷 1619-1631页

作者： jani, darshana Marsden, Robin Mikulskis, Alvydas Gleason, Carol Klem, Thomas Fiorotti, Corinna Krinos Myler, Heather Yang, Lin Fiscella, Michele Pfizer Inc Andover MA 01810 USA La Jolla Pharmaceut Co San Diego CA 92121 USA Biogen Idec Inc Boston MA 02142 USA Bristol Myers Squibb Co Princeton NJ 08540 USA Shire Lexington MA 02421 USA Covance Inc Chantilly VA 20151 USA

Identification and characterization of anti-drug antibodies is a critical component of biopharmaceutical drug development. The tiered approach for immunogenicity testing consists of screening, confirmatory, and characterization assays. Herein, we provide recommendations for confirmatory assays by expanding upon published guidance and present common practices across the industry. The authors recommend scientific approaches for development and validation of confirmatory assays using competition methods in ligand-binding assays, along with statistical formulae for routine use and validation. The paper will assist in understanding the confirmatory assay, and carefully implementing validation criteria a priori, as well as during sample analysis. These approaches represent the authors' current knowledge and practices, with the aim that more uniform practices will be applied across the industry.

关键词： Antibodies, Monoclonal/immunology* Antibody Formation Biological Assay/methods* Drug Design Humans

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Feasibility of immuno-PCR technology platforms as an ultrasensitive tool for the detection of anti-drug antibodies

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BIOANALYSIS 2015年第3期7卷 285-294页

作者： jani, darshana Savino, Edward Goyal, Jaya Biogen Idec Inc Translat Sci & Technol Cambridge MA 02142 USA

Aim: During the early clinical development of a receptor-IgG1 fusion protein (Drug X), a risk based strategy was utilized to evaluate immunogenicity from Phase I through Proof of Concept clinical studies. Materials & Methods: Three different technology platforms, enzyme-linked immunosorbant assay, electrochemiluminescent assay and newly emerging immuno-PCR were utilized for evaluation of immunogenic response. Results: An ELISA with adequate sensitivity but significant drug interference was replaced by electrochemiluminescent method with improved drug tolerance;however, an inverse correlation was observed between the administered dose and the incidence of anti-drug antibodies. Further evaluation of an immuno-PCR showed reduced drug interference enabling the detection of anti-drug antibodies in the presence of excess amount of Drug X. Conclusion: Immuno PCR assay proved to be a feasible platform for anti-drug antibody characterization.

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Recommendations for Use and Fit-for-Purpose Validation of Biomarker Multiplex Ligand Binding Assays in Drug Development

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AAPS JOURNAL 2016年第1期18卷 1-14页

作者： jani, darshana Allinson, John Berisha, Flora Cowan, Kyra J. Devanarayan, Viswanath Gleason, Carol Jeromin, Andreas Keller, Steve Khan, Masood U. Nowatzke, Bill Rhyne, Paul Stephen, Laurie Pfizer Inc Andover MA 01810 USA LGC Ltd Fordham CB7 5WW Cambs England Kyowa Kirin Pharmaceut Princeton NJ 08540 USA Genentech Inc San Francisco CA 94080 USA AbbVie Inc Chicago IL 60064 USA Bristol Myers Squibb Co Princeton NJ 08540 USA Quanterix Corp Lexington MA 02421 USA Abbvie Inc Redwood City CA 94063 USA KCAS Bioanalyt & Biomarker Serv Shawnee KS 66216 USA Radix Biosolut Georgetown TX 78626 USA Quintiles Corp Marietta GA 30067 USA Ampersand Biosci LLC Saranac Lake NY 12983 USA

Multiplex ligand binding assays (LBAs) are increasingly being used to support many stages of drug development. The complexity of multiplex assays creates many unique challenges in comparison to single-plexed assays leading to various adjustments for validation and potentially during sample analysis to accommodate all of the analytes being measured. This often requires a compromise in decision making with respect to choosing final assay conditions and acceptance criteria of some key assay parameters, depending on the intended use of the assay. The critical parameters that are impacted due to the added challenges associated with multiplexing include the minimum required dilution (MRD), quality control samples that span the range of all analytes being measured, quantitative ranges which can be compromised for certain targets, achieving parallelism for all analytes of interest, cross-talk across assays, freeze-thaw stability across analytes, among many others. Thus, these challenges also increase the complexity of validating the performance of the assay for its intended use. This paper describes the challenges encountered with multiplex LBAs, discusses the underlying causes, and provides solutions to help overcome these challenges. Finally, we provide recommendations on how to perform a fit-for-purpose-based validation, emphasizing issues that are unique to multiplex kit assays.

关键词： biomarker diagnostics ligand binding assay multiplex validation

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Assessment of clinical immunogenicity of inotuzumab ozogamicin in patients with non-Hodgkin lymphoma and acute lymphoblastic leukemia

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AAPS Open 2018年第1期4卷 1-14页

作者： jani, darshana Nowak, John Chen, Ying Boni, Joseph Gorovits, Boris Pfizer Inc Cambridge USA Pfizer Inc Andover USA Pfizer La Jolla USA Pfizer Inc Collegeville USA

Inotuzumab ozogamicin (InO) is an antibody-drug conjugate composed of a recombinant, humanized immunoglobulin type G, subtype 4 (IgG4) antibody covalently bound to a semisynthetic derivative of calicheamicin via an acid-labile linker. It was developed for the treatment of relapsed or refractory non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL). Based on the perceived relatively low immunogenicity risk for this product, a standard approach to immunogenicity testing was utilized during the clinical studies. This manuscript describes the analytical aspects of antibody measurement and highlights the immunogenicity data from clinical studies in patients with hematologic malignancies. Anti-drug antibodies (ADAs) were determined using an enzyme-linked immunosorbent assay for patients with NHL and a bridging electrochemiluminescence assay for patients with ALL. ALL patients who tested positive for ADA were also tested for neutralizing antibodies (pivotal studies only) using a cell-based assay. Immunogenicity assays were validated per current industry practice and regulatory guidelines. Positive ADAs were observed in 7 of 164 (4%) patients with ALL during the pivotal trial. Neutralizing antibodies were not detected in any patients with positive ADAs. No ADAs were detected during the phase I/II ALL study. In NHL studies, antibodies to InO were observed in 27 of 630 (4%) patients. InO clearance was similar between ADA-positive and ADA-negative ALL patients. Standard immunogenicity strategy provided data to evaluate impact on InO efficacy, pharmacokinetics, or other clinical parameters in patients. The incidence of ADA to InO is low and is not clinically meaningful.

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Recommendations for Selection and Characterization of Protein Biomarker Assay Calibrator Material

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AAPS JOURNAL 2017年第6期19卷 1550-1563页

作者： Cowan, Kyra J. Amaravadi, Lakshmi Cameron, Mark J. Fink, Damien jani, darshana Kamat, Medha King, Lindsay Neely, Robert J. Ni, Yan Rhyne, Paul Riffon, Renee Zhu, Yuda Merck KGaA Frankfurter Str 250F130-005 D-64293 Darmstadt Germany Sanofi Genzyme 1 Mt Rd Framingham MA 01701 USA Beckmann Coulter 3551 Lawrenceville Rd Princeton NJ 08540 USA Janssen Res & Dev Inc 1400 McKean Rd Spring House PA 19477 USA Pfizer 610 Main St Cambridge MA 02142 USA GlaxoSmithKline 709 Swedeland Rd King Of Prussia PA 19038 USA Bristol Myers Squibb 3551 Lawrenceville Rd Princeton NJ 08540 USA Regeneron Tarrytown NY USA Q2 Solut 5827 South Miami Blvd Morrisville NC 27560 USA CiToxLAB North Amer 445 Blvd Armand Frappier Laval PQ H7V 4B3 Canada Genentech Roche 11 Genentech Roche1 DNA Way San Francisco CA 94080 USA

As biomarkers continue to become an integral part of drug development and decision-making, there are increased expectations for reliable and quantitative assays. Protein biomarker assay results are directly influenced by the calibrator material. The selection of calibrator material presents many challenges that impact the relative accuracy and performance of the assay. There is an industry-wide challenge finding reliable and well-characterized calibrator material with good documentation. Several case studies are presented that demonstrate some of the challenges involved in selecting appropriate calibrators along with the resolutions that were ultimately applied. From these experiences, we present here a set of recommendations for selecting and characterizing calibrator material based on the intended purpose of the assay. Finally, we introduce a commutability approach, based on common clinical chemistry practices, which can be used to demonstrate inter-changeability with calibrator materials across multiple lots and technology platforms for all types of protein biomarker assays.

关键词： biomarker assays calibrator reference material

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Ligand Binding Assays in the 21st Century Laboratory: Platforms

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AAPS JOURNAL 2012年第1期14卷 113-118页

作者： Spriggs, Franklin P. Zhong, Zhandong Don Safavi, Afshin jani, darshana Dontha, Narasaiah Kant, Anita Ly, Jenny Brilando, Lia Osterlund, Karolina Rouleau, Nathalie Fischer, Saloumeh Kadkhodayan Boissonneault, Martin Ray, Chad Pfizer Inc Dept Pharmacokinet Dynam & Metab Andover MA 01810 USA Amgen Inc Dept Med Sci Clin Immunol Thousand Oaks CA 91320 USA BioAgilytix Labs Dept Bioanalyt Operat Res Triangle Pk NC 27713 USA Biogen Idec Inc Dept Translat Sci Cambridge MA 01748 USA Celgene Corp Dept Analyt Res & Dev Summit NJ 07901 USA Mol Devices LLC Dept BioRes Mkt Sunnyvale CA 94089 USA Meso Scale Discovery Dept Sci Support Gaithersburg MD 20877 USA WIL Res Co LLC Dept Project Serv Skokie IL 60077 USA Gyros AB Dept Field Applicat SE-75183 Uppsala Sweden Perkin Elmer Biosignal Inc Dept Biodiscovery Montreal PQ H3J 1R4 Canada Genentech Inc Dept Bioanalyt Res & Dev San Francisco CA 94080 USA Pfizer Inc Dept Pharmacokinet Dynam & Metab San Diego CA 92122 USA

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Assessment of Pharmacological Activity of Baminercept (LTBR-Ig) in Patients with Rheumatoid Arthritis

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CLINICAL IMMUNOLOGY 2010年 135卷 S106-S106页

作者： Plavina, Tatiana Gawlak, Susan Sobolewski, Joyce Wojcik, Melissa Messinese, Nicholas jani, darshana Goyal, Jaya Biogen Idec Inc Cambridge MA USA

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