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Journal articles on the topic 'Preclinical PK/PD'

Author: Grafiati

Published: 2 June 2025

Last updated: 31 July 2025

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1

Hosseini, Iraj, Brett Fleisher, Jennifer Getz, et al. "A Minimal PBPK/PD Model with Expansion-Enhanced Target-Mediated Drug Disposition to Support a First-in-Human Clinical Study Design for a FLT3L-Fc Molecule." Pharmaceutics 16, no. 5 (2024): 660. http://dx.doi.org/10.3390/pharmaceutics16050660.

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FLT3L-Fc is a half-life extended, effectorless Fc-fusion of the native human FLT3-ligand. In cynomolgus monkeys, treatment with FLT3L-Fc leads to a complex pharmacokinetic/pharmacodynamic (PK/PD) relationship, with observed nonlinear PK and expansion of different immune cell types across different dose levels. A minimal physiologically based PK/PD model with expansion-enhanced target-mediated drug disposition (TMDD) was developed to integrate the molecule’s mechanism of action, as well as the complex preclinical and clinical PK/PD data, to support the preclinical-to-clinical translation of FLT

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2

Zalba, Sara, Ana M. Contreras-Sandoval, Eva Martisova, Reno Debets, Christian Smerdou, and María Jesús Garrido. "Quantification of Pharmacokinetic Profiles of PD-1/PD-L1 Antibodies by Validated ELISAs." Pharmaceutics 12, no. 6 (2020): 595. http://dx.doi.org/10.3390/pharmaceutics12060595.

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Immunotherapy has changed the paradigm of cancer treatments. In this way, several combinatorial strategies based on monoclonal antibodies (mAb) such as anti (a)-PD-1 or anti (a)-PD-L1 are often reported to yield promising clinical benefits. However, the pharmacokinetic (PK) behavior of these mAbs is a critical issue that requires selective analytical techniques. Indeed, few publications report data on a-PD1/a-PD-L1 exposure and its relationship with therapeutic or toxic effects. In this regard, preclinical assays allow the time profiles of antibody plasma concentrations to be characterized rap

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Na, Joo Young, Min Hai, Kyeongmin Kim, et al. "Translational Pharmacokinetic-Pharmacodynamic Modeling of a Novel Oral Dihydroorotate Dehydrogenase (DHODH) Inhibitor, HOSU-53 (JBZ-001)." Pharmaceutics 17, no. 4 (2025): 412. https://doi.org/10.3390/pharmaceutics17040412.

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Background: HOSU-53 (JBZ-001), an orally bioavailable new chemical entity, represents a highly potent dihydroorotate dehydrogenase (DHODH) inhibitor in late preclinical development for application in cancer therapy. Methods: Multiple Good Laboratory Practice (GLP) and non-GLP preclinical studies were conducted in mice, rats, and dogs. Plasma samples of HOSU-53 and dihydroorotate (DHO), the substrate of DHODH, were collected for pharmacokinetic (PK) and pharmacodynamic (PD) assessment and modeling. Two modeling approaches were utilized to understand the PK/PD properties of HOSU-53 and to recomm

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Cheng, Shen, Susheel Kumar Nethi, Mahmoud Al-Kofahi, and Swayam Prabha. "Pharmacokinetic—Pharmacodynamic Modeling of Tumor Targeted Drug Delivery Using Nano-Engineered Mesenchymal Stem Cells." Pharmaceutics 13, no. 1 (2021): 92. http://dx.doi.org/10.3390/pharmaceutics13010092.

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Nano-engineered mesenchymal stem cells (nano-MSCs) are promising targeted drug delivery platforms for treating solid tumors. MSCs engineered with paclitaxel (PTX) loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) are efficacious in treating lung and ovarian tumors in mouse models. The quantitative description of pharmacokinetics (PK) and pharmacodynamics (PD) of nano-MSCs is crucial for optimizing their therapeutic efficacy and clinical translatability. However, successful translation of nano-MSCs is challenging due to their complex composition and physiological mechanisms regulatin

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Howard, Alex, and William Hope. "Assessment of Antifungal Pharmacodynamics." Journal of Fungi 9, no. 2 (2023): 192. http://dx.doi.org/10.3390/jof9020192.

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Pharmacokinetic-pharmacodynamic (PK-PD) analysis is of central importance to the progress of an antifungal agent into clinical use. It is crucial to ensure that preclinical studies give the best possible prediction of the way drugs are likely to behave in a clinical setting. This review details the last 30 years of progress in terms of disease model design, efficacy outcome selection and translational modelling in antifungal PK-PD studies. The principles of how PK-PD parameters inform current clinical practice are also discussed, including a review of how these apply to existing and novel agen

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Pasipanodya, Jotam, and Tawanda Gumbo. "An Oracle: Antituberculosis Pharmacokinetics-Pharmacodynamics, Clinical Correlation, and Clinical Trial Simulations To Predict the Future." Antimicrobial Agents and Chemotherapy 55, no. 1 (2010): 24–34. http://dx.doi.org/10.1128/aac.00749-10.

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ABSTRACTAntimicrobial pharmacokinetic-pharmacodynamic (PK/PD) science and clinical trial simulations have not been adequately applied to the design of doses and dose schedules of antituberculosis regimens because many researchers are skeptical about their clinical applicability. We compared findings of preclinical PK/PD studies of current first-line antituberculosis drugs to findings from several clinical publications that included microbiologic outcome and pharmacokinetic data or had a dose-scheduling design. Without exception, the antimicrobial PK/PD parameters linked to optimal effect were

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Tanaka, Chiaki, Terence O’Reilly, John M. Kovarik, et al. "Identifying Optimal Biologic Doses of Everolimus (RAD001) in Patients With Cancer Based on the Modeling of Preclinical and Clinical Pharmacokinetic and Pharmacodynamic Data." Journal of Clinical Oncology 26, no. 10 (2008): 1596–602. http://dx.doi.org/10.1200/jco.2007.14.1127.

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PurposeTo use preclinical and clinical pharmacokinetic (PK)/pharmacodynamic (PD) modeling to predict optimal clinical regimens of everolimus, a novel oral mammalian target of rapamycin (mTOR) inhibitor, to carry forward to expanded phase I with tumor biopsy studies in cancer patients.Patients and MethodsInhibition of S6 kinase 1 (S6K1), a molecular marker of mTOR signaling, was selected for PD analysis in peripheral blood mononuclear cells (PBMCs) in a phase I clinical trial. PK and PD were measured up to 11 days after the fourth weekly dose. A PK/PD model was used to describe the relationship

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8

Bajaj, Gaurav, Fereshteh Nazari, Marc Presler, et al. "786 Dose selection for DuoBody®-PD-L1×4-1BB (GEN1046) using a semimechanistic pharmacokinetics/pharmacodynamics model that leverages preclinical and clinical data." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (2021): A821. http://dx.doi.org/10.1136/jitc-2021-sitc2021.786.

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BackgroundDuoBody-PD-L1×4-1BB (GEN1046) is a class-defining bispecific antibody, designed to elicit an anti-tumor immune response by simultaneous and complementary blockade of PD-L1 on tumor cells and conditional stimulation of 4-1BB on T-cells and NK cells. Optimizing target engagement for a bispecific antibody is challenging, as it involves binding with two targets, and predicting trimer levels in tumors based on affinity of individual arms and target expression. Here we describe a semimechanistic, physiologically based pharmacokinetic/pharmacodynamic (PK/PD) model that predicts a dosing reg

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9

Lindhardt, Emma, and Peter Gennemark. "Automated analysis of routinely generated preclinical pharmacokinetic and pharmacodynamic data." Journal of Bioinformatics and Computational Biology 12, no. 03 (2014): 1450010. http://dx.doi.org/10.1142/s0219720014500103.

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Model-based analysis of routinely generated pharmacokinetic and pharmacodynamic (PK–PD) data is a key component of preclinical drug discovery. The work process of such analyses can be automated by properly designed computer programs that reduce the number of manual steps, resulting in time saving and significantly fewer errors. Critical decisions can still be made by modelers. Using concrete animal data examples this paper illustrates when, and demonstrates how, automated PK–PD approaches can be used and what benefits they offer to the modeling and simulation community. Specifically, we descri

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Zhang, Shuang, Min Zhang, Weiwei Wu, et al. "Preclinical characterization of Sintilimab, a fully human anti-PD-1 therapeutic monoclonal antibody for cancer." Antibody Therapeutics 1, no. 2 (2018): 65–73. http://dx.doi.org/10.1093/abt/tby005.

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ABSTRACT Background Programmed cell death 1 (PD-1) is an inhibitory immune checkpoint expressed on activatedT cells. Upon the formation of T cell receptor (TCR)-pMHC complexes, concomitant PD-1 ligation to its ligands programmed death-ligand 1 (PD-L1) or programmed death-ligand 2 (PD-L2) downregulates TCR signaling and effector function. Here we describe the preclinical characterization of Sintilimab, a fully human IgG4 antibody that potently blocks PD-1 interactions with PD-L1 and PD-L2. Methods The binding affinity and blockade function were detected by using surface plasmon resonance (SPR),

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11

Patel, Chirag G., Mayank Patel, Arijit Chakravarty, et al. "Clinical pharmacokinetics (PK) and translational PK-pharmacodynamic (PD) modeling and simulation to predict antitumor response of various dosing schedules to guide the selection of a recommended phase II dose (RP2D) and schedule for the investigational agent MLN0128." Journal of Clinical Oncology 31, no. 15_suppl (2013): 2567. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2567.

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2567 Background: MLN0128 (INK128) is an investigational oral, potent, and highly selective inhibitor of mammalian target of rapamycin complex 1 and 2 (mTORC1/2) currently in clinical investigation. In the phase1 study INK128-001, MLN0128 was administered once daily (QD), once weekly (QW), QDx3D/week, and QDx5D/week, with respective MTDs of 6, 40, 16, and 10 mg. To guide selection of dose/schedule for further investigation, PD modulation in skin (pS6, p4EBP1, pNDRG1, pPRAS40) was put into context of clinical PK in INK128-001. A preclinical translational dynamic-PK efficacy model was used to des

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Choi, Suein, Seunghoon Han, Sangil Jeon, and Dong-Seok Yim. "Quantitative Prediction of Human Pharmacokinetics and Pharmacodynamics of CKD519, a Potent Inhibitor of Cholesteryl Ester Transfer Protein (CETP)." Pharmaceutics 11, no. 7 (2019): 336. http://dx.doi.org/10.3390/pharmaceutics11070336.

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CKD519, a selective inhibitor of cholesteryl ester transfer protein(CETP), is undergoing development as an oral agent for the treatment of primary hypercholesterolemia and mixed hyperlipidemia. The aim of this study was to predict the appropriate efficacious dose of CKD519 for humans in terms of the inhibition of CETP activity by developing a CKD519 pharmacokinetic/pharmacodynamic (PK/PD) model based on data from preclinical studies. CKD519 was intravenously and orally administered to hamsters, rats, and monkeys for PK assessment. Animal PK models of all dose levels in each species were develo

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Drusano, G. L., S. L. Preston, C. Hardalo, et al. "Use of Preclinical Data for Selection of a Phase II/III Dose for Evernimicin and Identification of a Preclinical MIC Breakpoint." Antimicrobial Agents and Chemotherapy 45, no. 1 (2001): 13–22. http://dx.doi.org/10.1128/aac.45.1.13-22.2001.

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ABSTRACT One of the most challenging issues in the design of phase II/III clinical trials of antimicrobial agents is dose selection. The choice is often based on preclinical data from pharmacokinetic (PK) studies with animals and healthy volunteers but is rarely linked directly to the target organisms except by the MIC, an in vitro measure of antimicrobial activity with many limitations. It is the thesis of this paper that rational dose-selection decisions can be made on the basis of the pharmacodynamics (PDs) of the test agent predicted by a mathematical model which uses four data sets: (i) t

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Garralda, Elena, Rodrigo Dienstmann, and Josep Tabernero. "Pharmacokinetic/Pharmacodynamic Modeling for Drug Development in Oncology." American Society of Clinical Oncology Educational Book, no. 37 (May 2017): 210–15. http://dx.doi.org/10.1200/edbk_180460.

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High drug attrition rates remain a critical issue in oncology drug development. A series of steps during drug development must be addressed to better understand the pharmacokinetic (PK) and pharmacodynamic (PD) properties of novel agents and, thus, increase their probability of success. As available data continues to expand in both volume and complexity, comprehensive integration of PK and PD information into a robust mathematical model represents a very useful tool throughout all stages of drug development. During the discovery phase, PK/PD models can be used to identify and select the best d

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Li, Chao, Lowell Hart, Taofeek K. Owonikoko, et al. "Trilaciclib dose selection: an integrated pharmacokinetic and pharmacodynamic analysis of preclinical data and Phase Ib/IIa studies in patients with extensive-stage small cell lung cancer." Cancer Chemotherapy and Pharmacology 87, no. 5 (2021): 689–700. http://dx.doi.org/10.1007/s00280-021-04239-9.

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Abstract Purpose Trilaciclib is a first-in-class CDK4/6 inhibitor that transiently arrests hematopoietic stem and progenitor cells (HSPCs) in the G1 phase of the cell cycle to preserve them from chemotherapy-induced damage (myelopreservation). We report integrated analyses of preclinical and clinical data that informed selection of the recommended Phase II dose (RP2D) used in trilaciclib trials in extensive-stage small cell lung cancer (ES-SCLC). Methods A semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model developed from preclinical data guided selection of an optimal dose for G1 b

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16

Yao, Yunqi, Xiaoning Yang, Jing Li, et al. "Preclinical Characterization of Efficacy and Pharmacodynamic Properties of Finotonlimab, a Humanized Anti-PD-1 Monoclonal Antibody." Pharmaceuticals 18, no. 3 (2025): 395. https://doi.org/10.3390/ph18030395.

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Background/Objectives: Finotonlimab (SCTI10A) is a humanized anti-PD-1 antibody tested in Phase III trials for several solid tumor types. Methods: This study characterized the in vitro and in vivo efficacy, Fc-mediated effector function, and non-clinical PK/PD properties of finotonlimab. Results: The results demonstrated that finotonlimab is effective in stimulating human T cell function in vitro and exhibits marked antitumor efficacy in vivo using both PD-1-humanized and PBMC-reconstructed mouse models. Additionally, finotonlimab exhibited minimal impact on the activation of effector cells vi

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Yang, Sung-yoon, Lien Thi Ngo, Soyoung Lee, et al. "Model-Based Evaluation of HangAmDan-B1 and Afatinib Combination Therapy in HCC827 Xenograft Mice with Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor." Pharmaceuticals 18, no. 5 (2025): 748. https://doi.org/10.3390/ph18050748.

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Objectives: HangAmDan-B1 (HAD-B1), a blended herbal mixture, has been investigated as an adjuvant therapy with afatinib (AFT) to treat non-small lung cancer (NSCLC). Although preclinical studies demonstrated promising synergistic results, clinical trials have not yet confirmed the expected benefits. This study aims to quantitatively examine the exposure–response relationship and synergistic interactions through pharmacokinetic/pharmacodynamic (PK/PD) modeling. Methods: A PK/PD model was established and validated based on tumor growth profiles from a xenograft mouse study of gefitinib-resistant

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Chen, Dapeng. "Targeted Protein Degraders (TPD): PK/PD translation from preclinical to clinical." Drug Metabolism and Pharmacokinetics 61 (June 2025): 101085. https://doi.org/10.1016/j.dmpk.2025.101085.

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19

Seeger, Johanna, Sebastian Guenther, Katharina Schaufler, Stefan E. Heiden, Robin Michelet, and Charlotte Kloft. "Novel Pharmacokinetic/Pharmacodynamic Parameters Quantify the Exposure–Effect Relationship of Levofloxacin against Fluoroquinolone-Resistant Escherichia coli." Antibiotics 10, no. 6 (2021): 615. http://dx.doi.org/10.3390/antibiotics10060615.

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Minimal inhibitory concentration-based pharmacokinetic/pharmacodynamic (PK/PD) indices are commonly applied to antibiotic dosing optimisation, but their informative value is limited, as they do not account for bacterial growth dynamics over time. We aimed to comprehensively characterise the exposure–effect relationship of levofloxacin against Escherichia coli and quantify strain-specific characteristics applying novel PK/PD parameters. In vitro infection model experiments were leveraged to explore the exposure–effect relationship of three clinical Escherichia coli isolates, harbouring differen

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Świerczek, Artur, Krzysztof Pociecha, Hanna Plutecka, Marietta Ślusarczyk, Grażyna Chłoń-Rzepa, and Elżbieta Wyska. "Pharmacokinetic/Pharmacodynamic Evaluation of a New Purine-2,6-Dione Derivative in Rodents with Experimental Autoimmune Diseases." Pharmaceutics 14, no. 5 (2022): 1090. http://dx.doi.org/10.3390/pharmaceutics14051090.

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Current treatment strategies of autoimmune diseases (ADs) display a limited efficacy and cause numerous adverse effects. Phosphodiesterase (PDE)4 and PDE7 inhibitors have been studied recently as a potential treatment of a variety of ADs. In this study, a PK/PD disease progression modeling approach was employed to evaluate effects of a new theophylline derivative, compound 34, being a strong PDE4 and PDE7 inhibitor. Activity of the studied compound against PDE1 and PDE3 in vitro was investigated. Animal models of multiple sclerosis (MS), rheumatoid arthritis (RA), and autoimmune hepatitis were

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Reniguntla, Mahesh Kumar, Randhir Yedle, Ramesh Puttaswamy, et al. "Pharmacokinetics/Pharmacodynamics (PK/PD) of Ciprofloxacin in the Complicated Urinary Tract Infection (cUTI) Model in Diabetic Mice." Current Drug Metabolism 21, no. 2 (2020): 132–39. http://dx.doi.org/10.2174/1389200221666200310105227.

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Background: The translation of Pharmacokinetics (PK)/Pharmacodynamics (PD) from preclinical models to the clinic has not been studied in detail for drugs used to treat complicated urinary tract infections (cUTI). Objective: The PK/PD of Ciprofloxacin (CIP), a drug used to treat cUTI, was evaluated in a mouse model of cUTI infected with Escherichia coli, and compared with clinical PK/PD in cUTI patients. Methods: Streptozotocin induced diabetic female BALB/c mice were infected transurethrally with Escherichia coli. Four hours post infection, CIP oral doses of 3, 10, 30,100, and 300 mg/kg, were

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Li, Tommy, Ida H. Hiemstra, Christopher Chiu, et al. "Novel Semi-Mechanistic Model Leveraging Preclinical and Clinical Data to Inform the Recommended Phase 2 Dose (RP2D) Selection for Epcoritamab (DuoBody CD3xCD20)." Blood 136, Supplement 1 (2020): 35–36. http://dx.doi.org/10.1182/blood-2020-139457.

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Introduction: Epcoritamab (DuoBody-CD3×CD20) is a subcutaneously administered bispecific antibody (bsAb) that simultaneously binds to CD3 on T cells and CD20 on malignant B cells, resulting in T-cell activation and expansion and selective T-cell-mediated killing of CD20+ cells. Target engagement (TE) and crosslinking of CD3 and CD20 (trimer formation) lead to activation and expansion of T cells, which in turn leads to tumor cell killing and is the first step driving the pharmacology of epcoritamab. Hence, the optimal clinical dose of epcoritamab can be informed by TE and trimer formation. Unli

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Wang, Yan, Lanyu Liu, Qiping Wu, Qiufen Yin, and Feifan Xie. "Defining Exposure Predictors of Meropenem That Are Associated with Improved Survival for Severe Bacterial Infection: A Preclinical PK/PD Study in Sepsis Rat Model." Antibiotics 11, no. 11 (2022): 1660. http://dx.doi.org/10.3390/antibiotics11111660.

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Background: The pharmacokinetic/pharmacodynamic (PK/PD) index of carbapenems that best correlates with in vivo antimicrobial activity is percent time of dosing interval in which free drug concentration remains above MIC (%fT > MIC), while the magnitudes of the PK/PD index of carbapenems remains undefined in critically ill sepsis patients. Methods: A sepsis rat model was first developed by comparing the survival outcomes after intraperitoneal injection of different inoculum size (1–10 × 107 CFU) of Pseudomonas aeruginosa ATCC9027 (MIC = 0.125 mg/L) in neutropenic rats. The PK characteristics

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Bauer, Sebastian, George D. Demetri, Ensar Halilovic, et al. "Pharmacokinetic–pharmacodynamic guided optimisation of dose and schedule of CGM097, an HDM2 inhibitor, in preclinical and clinical studies." British Journal of Cancer 125, no. 5 (2021): 687–98. http://dx.doi.org/10.1038/s41416-021-01444-4.

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Abstract Background CGM097 inhibits the p53-HDM2 interaction leading to downstream p53 activation. Preclinical in vivo studies support clinical exploration while providing preliminary evidence for dosing regimens. This first-in-human phase I study aimed at assessing the safety, MTD, PK/PD and preliminary antitumor activity of CGM097 in advanced solid tumour patients (NCT01760525). Methods Fifty-one patients received oral treatment with CGM097 10–400 mg 3qw (n = 31) or 300–700 mg 3qw 2 weeks on/1 week off (n = 20). Choice of dose regimen was guided by PD biomarkers, and quantitative models desc

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Housand, Conrad, Nil Roy, Tine Wyseure, et al. "Abstract C126: Translational pharmacokinetic/pharmacodynamic (PK/PD) modeling of novel covalent Kelch-like ECH-associated protein 1 (KEAP1) activators." Molecular Cancer Therapeutics 22, no. 12_Supplement (2023): C126. http://dx.doi.org/10.1158/1535-7163.targ-23-c126.

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Abstract Introduction: The KEAP1-nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis is a key homeostatic mechanism for cells to maintain redox balance. In oxidative stress, reactive oxygen species (ROS) modify residues on KEAP1, impairing its binding and ubiquitination of NRF2. This leads to an accumulation and translocation of NRF2 to the nucleus where it increases transcription of genes for antioxidant response [Pillai 2022]. The KEAP1-NRF2 pathway is hijacked in cancers through NRF2 gain of function or KEAP1 loss of function mutations leading to aberrant activation of NRF2. W

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Thi, Emily P., Andrew G. Cole, Gavin Heffernan, et al. "Preclinical anti-tumor activity of small-molecule oral PD-L1 checkpoint inhibitors." Journal of Clinical Oncology 40, no. 16_suppl (2022): e14558-e14558. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.e14558.

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e14558 Background: The PD-1/PD-L1 checkpoint axis is a validated target in oncology, and immunotherapy with antibody approaches have proven efficacy across various tumor types. Oral small-molecule inhibitors of PD-L1 may offer advantages over antibody approaches by enabling tunable on-target engagement and the potential for better tissue penetration and improved efficacy. Here we report the preclinical in vitro activity of small-molecule inhibitors of PD-L1 possessing a novel mechanism of action, favorable pharmacokinetics, and demonstrated in vivo efficacy in a mouse colon adenocarcinoma mode

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Sullivan, Kathleen M., Shichang Miao, Huibin Yue, et al. "Abstract 4147: CCX559, an orally administered small molecule PD-L1 inhibitor for the treatment of solid tumors." Cancer Research 82, no. 12_Supplement (2022): 4147. http://dx.doi.org/10.1158/1538-7445.am2022-4147.

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Abstract Background: The small molecule CCX559 is a novel, highly potent inhibitor of human PD-L1 being developed as an oral treatment for cancer patients. We have previously demonstrated that CCX559 has nanomolar potency and high selectivity for PD-L1; that it enhances primary T cell activation and has anti-tumor efficacy, including the ability to induce complete responses, using in vivo models1. Results: Safety pharmacology studies in preclinical animal species demonstrated pharmacokinetics and an acceptable safety profile for CCX559, which supported the initiation of human trials in patient

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Adamowicz, Karina, David Cebrian, Fabio dell' Aquila, et al. "Abstract 1222: Integrating in vitro and in vivo data with algorithm-driven PK/PD modeling: a fast and efficient tool for evaluating cancer therapies in preclinical models." Cancer Research 85, no. 8_Supplement_1 (2025): 1222. https://doi.org/10.1158/1538-7445.am2025-1222.

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Preclinical in vivo PK/PD studies of cancer therapies are invaluable for cancer drug discovery and the translation of therapies from bench to bedside. However, conventional in vivo experimentation are often time-intensive, resource-demanding, and may require redesign due to inefficient and/or toxic range of concentrations, or suboptimal study parameters. To address these challenges, we developed an integrated approach combining in vitro and in vivo data to generate in silico PK/PD models of anti-cancer compounds. Our algorithm was verified using standard chemotherapies, including Cisplatin and

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Jackson, Robert C. "Pharmacodynamic Modelling of Biomarker Data in Oncology." ISRN Pharmacology 2012 (February 16, 2012): 1–12. http://dx.doi.org/10.5402/2012/590626.

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The development of pharmacodynamic (PD) biomarkers in oncology has implications for design of clinical protocols from preclinical data and for predicting clinical outcomes from early clinical data. Two classes of biomarkers have received particular attention. Phosphoproteins in biopsy samples are markers of inhibition of signalling pathways, target sites for many novel agents. Biomarkers of apoptosis in plasma can measure tumour cell killing by drugs in phase I clinical trials. The predictive power of PD biomarkers is enhanced by data modelling. With pharmacokinetic models, PD models form PK/P

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Ogden, Adam, Michael Kuhn, Michael Dority, et al. "Evaluation of Pharmacokinetic/Pharmacodynamic Relationships of PD-0162819, a Biotin Carboxylase Inhibitor Representing a New Class of Antibacterial Compounds, UsingIn VitroInfection Models." Antimicrobial Agents and Chemotherapy 56, no. 1 (2011): 124–29. http://dx.doi.org/10.1128/aac.00090-11.

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ABSTRACTThe present study investigated the pharmacokinetic/pharmacodynamic (PK/PD) relationships of a prototype biotin carboxylase (BC) inhibitor, PD-0162819, againstHaemophilus influenzae3113 in static concentration time-kill (SCTK) and one-compartment chemostatin vitroinfection models.H. influenzae3113 was exposed to PD-0162819 concentrations of 0.5 to 16× the MIC (MIC = 0.125 μg/ml) and area-under-the-curve (AUC)/MIC ratios of 1 to 1,100 in SCTK and chemostat experiments, respectively. Serial samples were collected over 24 h. For efficacy driver analysis, a sigmoid maximum-effect (Emax) mod

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Mazzei, T. "KS1-2 PK–PD of antifungal drugs: from preclinical data to clinical applications." International Journal of Antimicrobial Agents 42 (June 2013): S7. http://dx.doi.org/10.1016/s0924-8579(13)70138-9.

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Yeo, Pauline, P. Venkatesh, Evelyn Goh, et al. "Pharmacokinetic and Pharmacodynamic Properties of SB1317, a Potent and Orally Active Multi-Kinase Inhibitor." Blood 110, no. 11 (2007): 4201. http://dx.doi.org/10.1182/blood.v110.11.4201.4201.

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Abstract Key physicochemical properties such as solubility, lipophilicity (logD7.4, logP) and pKa (the negative log of the acid dissociation constant) can be used to predict protein binding, tissue distribution, and gastrointestinal (GI) absorption. More recent application of computational methods allows even better prediction of compound oral bioavailability from in vitro and/or in silico properties. During the lead optimization process in our multi-kinase inhibitor program a good correlation between physicochemical properties like logD and solubility (determined experimentally at pH 7) versu

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Buchner, Anton, Udo W. Mueller, Peter Bias, and Andreas Engert. "Preclinical and clinical data for tbo-filgrastim: A short-acting filgrastim." Journal of Clinical Oncology 31, no. 15_suppl (2013): e13555-e13555. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.e13555.

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e13555 Background: Tbo-filgrastim is a G-CSF approved in the US as a biologic under the BLA 351(a) pathway, for reducing duration of severe neutropenia (DSN) in patients with non-myeloid malignancies receiving chemotherapy (CTx) associated with a clinically significant incidence of febrile neutropenia (FN). Here, we summarize data from the development program (16 preclinical studies; 2 Phase I and 3 Phase III clinical studies). Methods: Preclinical: The PK, safety pharmacology, PD, and toxicology of tbo-filgrastim vs reference filgrastim were investigated in 3 in vitro studies and 13 animal mo

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Lee, James J., John D. Powderly, Manish R. Patel, et al. "Phase 1 trial of CA-170, a novel oral small molecule dual inhibitor of immune checkpoints PD-1 and VISTA, in patients (pts) with advanced solid tumor or lymphomas." Journal of Clinical Oncology 35, no. 15_suppl (2017): TPS3099. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.tps3099.

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TPS3099 Background: Programmed-death 1 (PD-1) and V-domain Ig suppressor of T-cell activation (VISTA) are independent immune checkpoints that negatively regulate T-cell function and are implicated in various malignancies. Preclinical studies have demonstrated that dual blockade of these pathways is synergistic. CA-170 is a first-in-class oral small molecule that directly targets both PD-1/PD-L1 and VISTA pathways and has shown anti-tumor activity in multiple preclinical models. Methods: The dose escalation phase has a target enrollment of 50 pts with advanced solid tumors or lymphomas onto esc

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Jiang, Li-Juan, Lisha Xu, Meng Huang, et al. "667. Preclinical Pharmacokinetic and Pharmacodynamic Characterization of EDP-938, a Novel and Potent NonFusion Replication Inhibitor of Respiratory Syncytial Virus." Open Forum Infectious Diseases 6, Supplement_2 (2019): S305—S306. http://dx.doi.org/10.1093/ofid/ofz360.735.

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Abstract Background Respiratory syncytial virus (RSV) infection presents a significant health challenge in young children, elderly and immunocompromised patients. To date, there are no effective treatments available. EDP-938 was designed to meet this unmet medical need and is currently in Phase 2 clinical trials. Herein we report its preclinical pharmacokinetic (PK) and pharmacodynamic (PD) properties. Methods The pharmacokinetics of EDP-938 following single intravenous and oral doses were determined in mice, rats, dogs, and monkeys. In vitro cellular permeability and metabolic stability were

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Li, Ying, Xiao Luan, Shaonan Zhou, et al. "Abstract 3426: Preclinical development of CD-001, a novel fusion protein combining PD-1 blockade with IL-21 for solid tumors." Cancer Research 85, no. 8_Supplement_1 (2025): 3426. https://doi.org/10.1158/1538-7445.am2025-3426.

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Background: Immune checkpoint blockade (ICB) has revolutionized cancer immunotherapy, offering significant clinical benefits. However, these successes are unfortunately limited to a minority of patients. Meanwhile, cytokine-based therapies have shown promise in cancer treatment, but are accompanied by potential severe systemic toxicity. CD-001 is a novel fusion protein integrating anti-PD-1 antibody with mutated IL-21. This dual-targeting approach enables simultaneous blockade of the PD-1/PD-L1 axis and targeted delivery of IL-21 to PD-1+ T cells, aiming to enhance tumor-specific immune respon

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Carr, Michael I., Li-Ya Chiu, Yige Guo та ін. "DNA-PK Inhibitor Peposertib Amplifies Radiation-Induced Inflammatory Micronucleation and Enhances TGFβ/PD-L1 Targeted Cancer Immunotherapy". Molecular Cancer Research 20, № 4 (2022): 568–82. http://dx.doi.org/10.1158/1541-7786.mcr-21-0612.

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Abstract Radiotherapy is the most widely used cancer treatment and improvements in its efficacy and safety are highly sought-after. Peposertib (also known as M3814), a potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor, effectively suppresses the repair of radiation-induced DNA double-strand breaks (DSB) and regresses human xenograft tumors in preclinical models. Irradiated cancer cells devoid of p53 activity are especially sensitive to the DNA-PK inhibitor, as they lose a key cell-cycle checkpoint circuit and enter mitosis with unrepaired DSBs, leading to catastrophic conseq

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Tu, Xiaolong, Xinhe Feng, Weifang Wang, et al. "Abstract 7174: Pharmacokinetics and immunogenicity of anti-PD-1 antibody in humanized FcRn mouse models compared to immunocompetent mouse models." Cancer Research 84, no. 6_Supplement (2024): 7174. http://dx.doi.org/10.1158/1538-7445.am2024-7174.

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Abstract Introduction: The development and use of therapeutic antibodies in cancer therapy has increased significantly in recent years, led by the success of approved immune checkpoint blockade antibodies targeting PD-1 and PD-L1 axis. However, obtaining more clinically relevant pharmacokinetics (PK), safety and efficacy data for antibodies is still challenging in preclinical phase. Humanized FcRn (hFcRn) transgenic mouse model has a more faithful catabolism compared to WT mice, providing more accurate and predictable PK data of innovative antibody-based therapeutics at discovery stage[1]. In

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Souza, Anacleto Silva de, Vitor Martins de Freitas Amorim, Eduardo Pereira Soares, Robson Francisco de Souza, and Cristiane Rodrigues Guzzo. "Antagonistic Trends Between Binding Affinity and Drug-Likeness in SARS-CoV-2 Mpro Inhibitors Revealed by Machine Learning." Viruses 17, no. 7 (2025): 935. https://doi.org/10.3390/v17070935.

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The SARS-CoV-2 main protease (Mpro) is a validated therapeutic target for inhibiting viral replication. Few compounds have advanced clinically, underscoring the difficulty in optimizing both target affinity and drug-like properties. To address this challenge, we integrated machine learning (ML), molecular docking, and molecular dynamics (MD) simulations to investigate the balance between pharmacodynamic (PD) and pharmacokinetic (PK) properties in Mpro inhibitor design. We developed ML models to classify Mpro inhibitors based on experimental IC50 data, combining molecular descriptors with struc

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Roth, Karsten, Barbara Gastl, Dirk Lehnick, Karin Jacob, and Ruediger Jankowsky. "Demonstration of Pharmacokinetic and Pharmacodynamic Equivalence in Healthy Volunteers for B12019, a New Proposed Pegfilgrastim Biosimilar." Blood 128, no. 22 (2016): 5079. http://dx.doi.org/10.1182/blood.v128.22.5079.5079.

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Abstract B12019 is being developed as a biosimilar to Neulasta® (INN pegfilgrastim), a long-acting, pegylated form of recombinant human granulocyte-colony stimulating factor (r-metHuG-CSF, INN filgrastim) for the prevention of chemotherapy-induced neutropenia. A comprehensive analytical, functional and preclinical comparability program has already demonstrated a high degree of similarity of B12019 as compared to Neulasta®. In order to confirm the similarity on the clinical level, a pharmacokinetics/pharmacodynamics (PK/PD) study was conducted with B12019 in comparison to EU-authorised Neulasta

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Le, K., A. Chakravarty, R. Walker, et al. "600 Preclinical pharmacokinetics–pharmacodynamics (PK-PD) modeling of TAK-733, an investigational MEK inhibitor." European Journal of Cancer Supplements 8, no. 7 (2010): 188–89. http://dx.doi.org/10.1016/s1359-6349(10)72307-7.

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Yap, Timothy A., Aurelius Omlin, and Johann S. de Bono. "Development of Therapeutic Combinations Targeting Major Cancer Signaling Pathways." Journal of Clinical Oncology 31, no. 12 (2013): 1592–605. http://dx.doi.org/10.1200/jco.2011.37.6418.

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Signaling networks play key homeostatic processes in living organisms but are commonly hijacked in oncogenesis. Prominent examples include genetically altered receptor tyrosine kinases and dysregulated intracellular signaling molecules. The discovery and development of targeted therapies against such oncogenic proteins has imparted clinical benefit. Nevertheless, concerns remain about the limited single-agent efficacy and narrow therapeutic indices of many of these antitumor agents. Moreover, it is apparent that oncogenic proteins comprise complex signaling networks that interact through cross

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Diab, S., S. Eckhardt, A. Tan, et al. "A phase I study of R547, a novel, selective inhibitor of cell cycle and transcriptional cyclin dependent kinases (CDKs)." Journal of Clinical Oncology 25, no. 18_suppl (2007): 3528. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.3528.

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3528 Background: R547, a potent inhibitor of CDKs 1, 2, 4, 7, and 9, has shown broad antitumor activity in preclinical models. This phase Ia study assessed safety, pharmacokinetic (PK), and pharmacodynamic (PD) endpoints. Methods: R547 given as a 90 or 180 min infusion D1, D8 (21 day cycle). Key inclusion criteria: ECOG 0–2, adequate hematologic, hepatic, and renal function. Exclusion: brain metastases, NYHA III/IV CHF, CVA, current antihypertensive therapy. Blood samples on cycle 1, D1, D8 for PK and PD. PD endpoint is inhibition of retinoblastoma phosphorylation (pRB) in PBMCs. Results: 41 p

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Mistry, Hitesh, David Hodson, David Orrell, et al. "Abstract A141: Preclinical pharmacokinetic (PK) and tumor growth inhibition (TGI) modeling for mANK-101, an anchored murine interleukin-12 (IL-12) complex for intratumoral administration for solid cancer." Molecular Cancer Therapeutics 22, no. 12_Supplement (2023): A141. http://dx.doi.org/10.1158/1535-7163.targ-23-a141.

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Abstract Introduction – Murine ANK-101 (mANK-101) is a stable complex composed of a modified murine IL-12 cytokine with aluminum hydroxide at a 1:10 ratio designed for intratumoral delivery to established solid cancers. The objective of this work was to build a preclinical PK/PD/TGI model to gain a better mechanistic understanding of the pharmacology of mANK-101 and potential impact on therapeutic efficacy. Methods - Data were collected from in vivo studies measuring PK, intratumoral immune cells and tumor growth inhibition (TGI) in a CT26 syngeneic mouse model treated with mANK-101. A PK mode

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Lignet, Florian, Christina Esdar, Manja Friese-Hamim, et al. "Quantitative PK/PD Prediction of the Efficacious and Safe Dose Ranges of the LMP7 Inhibitor M3258 for Phase I Application in Relapsed/Refractory Multiple Myeloma Patients." Blood 134, Supplement_1 (2019): 5582. http://dx.doi.org/10.1182/blood-2019-126972.

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M3258 is an orally bioavailable, potent, selective, reversible inhibitor of the large multifunctional peptidase 7 (LMP7, β5i, PSMB8) proteolytic subunit of the immunoproteasome; a crucial component of the cellular protein degradation machinery, which is highly expressed in malignant hematopoietic cells including multiple myeloma. M3258 was previously shown to deliver strong in vivo preclinical efficacy in multiple myeloma xenograft models, as well as a more benign non-clinical safety profile compared to approved pan-proteasome inhibitors, exemplified by a lack of effects on the central and per

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Lee, Byeong ill, Min-Ho Park, Seok-Ho Shin, et al. "Quantitative Analysis of Tozadenant Using Liquid Chromatography-Mass Spectrometric Method in Rat Plasma and Its Human Pharmacokinetics Prediction Using Physiologically Based Pharmacokinetic Modeling." Molecules 24, no. 7 (2019): 1295. http://dx.doi.org/10.3390/molecules24071295.

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Tozadenant is one of the selective adenosine A2a receptor antagonists with a potential to be a new Parkinson’s disease (PD) therapeutic drug. In this study, a liquid chromatography-mass spectrometry based bioanalytical method was qualified and applied for the quantitative analysis of tozadenant in rat plasma. A good calibration curve was observed in the range from 1.01 to 2200 ng/mL for tozadenant using a quadratic regression. In vitro and preclinical in vivo pharmacokinetic (PK) properties of tozadenant were studied through the developed bioanalytical methods, and human PK profiles were predi

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Gutierrez, Pablo Morentin, Ana Quiroga Campano, Antonio Ramos Montoya, et al. "Abstract 4755: Preclinical mechanistic PK/PD-efficacy modeling for AZD9750, a novel oral androgen receptor degrader (PROTAC), to support dose selection during early clinical development." Cancer Research 85, no. 8_Supplement_1 (2025): 4755. https://doi.org/10.1158/1538-7445.am2025-4755.

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Abstract Objectives: The androgen receptor (AR) is highly expressed in prostate cancers and is a clinically validated target in oncology. AZD9750 is a novel potent oral selective AR Proteolysis-targeting chimera (PROTAC) due to start clinical testing in 2025. We present here the preclinical PK/PD modeling work used to understand the required target modulation and concentration required to see anti-tumor efficacy and therefore help support the dose selection during the early clinical development of AZD9750. Methods: We developed a novel mechanistic mathematical model applied to in vivo preclini

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Ghasemi, Mohammad, Reza Khosravan, Ji Yun Kim, Lisa Seitz, Paul Foster та Balaji Agoram. "56 Clinical Pharmacokinetic/Pharmacodynamic (PK/PD) Relationship Confirms Best-in-class Potential of Casdatifan (AB521), a Small Molecule Inhibitor of HIF-2α Being Developed in Renal Cancer". Oncologist 29, Supplement_1 (2024): S30—S31. http://dx.doi.org/10.1093/oncolo/oyae181.049.

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Abstract Background Casdatifan, an orally bioavailable small molecule inhibitor of HIF-2α, potently inhibits transcription of HIF-2α-dependent genes in cell lines and preclinical species. The objective of this analysis was to develop an understanding of the relationship between clinical dose, casdatifan PK, erythropoietin (EPO), a PD biomarker for peripheral (non-tumor) HIF-2α inhibition, and hemoglobin and to use this information to guide dose selection in future clinical trials. Methods Casdatifan plasma concentrations, serum EPO concentration, and hemoglobin data were obtained from 79 healt

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Betts, Alison, Tracey Clark, Paul Jasper, et al. "Use of translational modeling and simulation for quantitative comparison of PF-06804103, a new generation HER2 ADC, with Trastuzumab-DM1." Journal of Pharmacokinetics and Pharmacodynamics 47, no. 5 (2020): 513–26. http://dx.doi.org/10.1007/s10928-020-09702-3.

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Abstract A modeling and simulation approach was used for quantitative comparison of a new generation HER2 antibody drug conjugate (ADC, PF-06804103) with trastuzumab-DM1 (T-DM1). To compare preclinical efficacy, the pharmacokinetic (PK)/pharmacodynamic (PD) relationship of PF-06804103 and T-DM1 was determined across a range of mouse tumor xenograft models, using a tumor growth inhibition model. The tumor static concentration was assigned as the minimal efficacious concentration. PF-06804103 was concluded to be more potent than T-DM1 across cell lines studied. TSCs ranged from 1.0 to 9.8 µg/mL

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Jamois, Candice, Koorosh Korfi, Sylvia Herter, et al. "Integrated Quantitative Clinical Pharmacology Analysis Identifies Optimal Englumafusp Alfa Dose Range for Proof-of-Concept Study with Glofitamab in Second-Line Large B-Cell Lymphoma Patients." Blood 144, Supplement 1 (2024): 4180. https://doi.org/10.1182/blood-2024-201466.

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Background: Englumafusp alfa, an antibody-like fusion protein targeting CD19 on B-cells and 4-1BB on immune effector cells, was investigated in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) in combination with glofitamab [Columvi] in a phase I dose escalation study (NCT04077723; Hutchings et al, submitted to ASH 2024). In the presence of a T-cell receptor signal and dependent on CD19 crosslinking, englumafusp alfa forms a “trimeric complex” with tumor cells and T cells (Betts et al. AAPS J 2019), co-stimulating T cells via 4-1BB agonism that boosts T-cell mediated tumor c

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