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Article ; Online: Evolution of preclinical characterization and insights into clinical pharmacology of checkpoint inhibitors approved for cancer immunotherapy.

Kasichayanula, Sreeneeranj / Mandlekar, Sandhya / Shivva, Vittal / Patel, Maulik / Girish, Sandhya

2022 Volume 15, Issue 8, Page(s) 1818–1837

Abstract: Cancer immunotherapy has significantly advanced the treatment paradigm in oncology, with approvals of immuno-oncology agents for over 16 indications, many of them first line. Checkpoint inhibitors (CPIs) are recognized as an essential backbone for a ... ...

Abstract	Cancer immunotherapy has significantly advanced the treatment paradigm in oncology, with approvals of immuno-oncology agents for over 16 indications, many of them first line. Checkpoint inhibitors (CPIs) are recognized as an essential backbone for a successful anticancer therapy regimen. This review focuses on the US Food and Drug Administration (FDA) regulatory approvals of major CPIs and the evolution of translational advances since their first approval close to a decade ago. In addition, critical preclinical and clinical pharmacology considerations, an overview of the pharmacokinetic and dose/regimen aspects, and a discussion of the future of CPI translational and clinical pharmacology as combination therapy becomes a mainstay of industrial immunotherapy development and in clinical practice are also discussed.
MeSH term(s)	Combined Modality Therapy ; Humans ; Immunotherapy ; Neoplasms/drug therapy ; Pharmacology, Clinical ; United States ; United States Food and Drug Administration
Language	English
Publishing date	2022-06-07
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2433157-0
ISSN	1752-8062 ; 1752-8054
ISSN (online)	1752-8062
ISSN	1752-8054
DOI	10.1111/cts.13312
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Article ; Online: Improving priors for human monoclonal antibody linear pharmacokinetic parameters by using half-lives from non-human primates.

Shivva, Vittal / Fink, Martin / Lowe, Philip J

Journal of pharmacokinetics and pharmacodynamics

2021 Volume 48, Issue 2, Page(s) 295–303

Abstract: Obtaining a good prior for the linear pharmacokinetics of new monoclonal antibodies (mAbs) would be an advantage not only for designing first-in-human (FIH) studies but also for stabilizing fitting of data with non-linear target-mediated disposition ... ...

Abstract	Obtaining a good prior for the linear pharmacokinetics of new monoclonal antibodies (mAbs) would be an advantage not only for designing first-in-human (FIH) studies but also for stabilizing fitting of data with non-linear target-mediated disposition models. We estimated the pharmacokinetics from FIH studies for five mAbs using a two-compartment model, both separately and together, using a simple pool, a third hierarchical level of random effects for between mAb differences and non-human-primate half-lives as a predictor covariate for said differences. There was good agreement between compounds for the rapidly accessible central volume of 2.9 L (70 kg human), but clearances and peripheral volumes differed with terminal half-lives ranging from 15 to 28 days. The simple pool of human studies gave inter-individual variability estimates of 32% coefficient of variation (CV) for clearance and 33% CV for peripheral volume, larger than for separate fits (13-26% CV and 15-35% CV for clearance and volume respectively). Using third level hierarchical random effects gave inter-individual variability estimates close to those of separate fits (24% and 16% CV respectively). The between-mAb differences became predictable if non-human primate body weight scaled terminal half-life estimates were included as covariates on clearance and peripheral volume. In conclusion, ignoring inter-mAb variation leads to inflated estimates of inter-individual variability and unrealistic simulations for FIH studies. However, by using 70 kg body weight scaled terminal half-life estimates from non-human primates one can account for between-mAb differences and provide non-inflated priors for the linear pharmacokinetic parameters of new mAbs.
MeSH term(s)	Animals ; Antibodies, Monoclonal/administration & dosage ; Antibodies, Monoclonal/pharmacokinetics ; Body Weight ; Callithrix ; Clinical Trials, Phase I as Topic ; Datasets as Topic ; Drug Evaluation, Preclinical/methods ; Half-Life ; Humans ; Linear Models ; Macaca fascicularis ; Models, Biological
Chemical Substances	Antibodies, Monoclonal
Language	English
Publishing date	2021-01-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-020-09731-y
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Article: Antibody Format and Serum Disposition Govern Ocular Pharmacokinetics of Intravenously Administered Protein Therapeutics.

Shivva, Vittal / Boswell, C Andrew / Rafidi, Hanine / Kelley, Robert F / Kamath, Amrita V / Crowell, Susan R

Frontiers in pharmacology

2021 Volume 12, Page(s) 601569

Abstract: Protein therapeutics have witnessed tremendous use and application in recent years in treatment of various diseases. Predicting efficacy and safety during drug discovery and translational development is a key factor for successful clinical development of ...

Abstract	Protein therapeutics have witnessed tremendous use and application in recent years in treatment of various diseases. Predicting efficacy and safety during drug discovery and translational development is a key factor for successful clinical development of these therapies. In general, drug related toxicities are predominantly driven by pharmacokinetic (PK) exposure at off-target sites. This work explores the ocular PK of intravenously administered protein therapeutics to understand impact of antibody format on off-site exposure. Species matched non-binding rabbit antibody proteins (rabFab and rabIgG) were intravenously administered to male New Zealand White rabbits at a single 1 mg bolus dose and exposure was measured up to 3 weeks. As anticipated based on absence of FcRn recycling, rabFab has relatively fast systemic PK (CL-943 mL/day and t
Language	English
Publishing date	2021-05-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2021.601569
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Article ; Online: Preclinical and translational pharmacology of afucosylated anti-CCR8 antibody for depletion of tumour-infiltrating regulatory T cells.

Gampa, Gautham / Spinosa, Phillip / Getz, Jennifer / Zhong, Yu / Halpern, Wendy / Esen, Emel / Davies, John / Chou, Cassie / Kwong, Mandy / Wang, Yingyun / Arenzana, Teresita L / Shivva, Vittal / Huseni, Mahrukh / Hsieh, Robert / Schartner, Jill / Koerber, James T / Rutz, Sascha / Hosseini, Iraj

British journal of pharmacology

2024

Abstract: Background and purpose: RO7502175 is an afucosylated antibody designed to eliminate C-C motif chemokine receptor 8 (CCR8): Experimental approach: We report findings from preclinical studies characterizing pharmacology, pharmacokinetics (PK)/ ... ...

Abstract	Background and purpose: RO7502175 is an afucosylated antibody designed to eliminate C-C motif chemokine receptor 8 (CCR8) Experimental approach: We report findings from preclinical studies characterizing pharmacology, pharmacokinetics (PK)/pharmacodynamics (PD) and safety profile of RO7502175 and discuss the translational PK/PD approach used to inform first-in-human (FiH) dosing strategy and clinical development in solid tumour indications. Key results: RO7502175 demonstrated selective ADCC against human CCR8 Conclusion and implications: This work demonstrates a translational research strategy for collecting and utilizing relevant nonclinical data, developing a mechanistic PK/PD model and using a comprehensive approach to inform clinical study design for RO7502175.
Language	English
Publishing date	2024-03-14
Publishing country	England
Document type	Journal Article
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.16326
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Article ; Online: Complex PK-PD of an engineered IL-15/IL-15Rα-Fc fusion protein in cynomolgus monkeys: QSP modeling of lymphocyte dynamics.

Lu, Dan / Yadav, Rajbharan / Holder, Patrick / Chiang, Eugene / Sanjabi, Shomyseh / Poon, Victor / Bernett, Matthew / Varma, Rajat / Liu, Ke / Leung, Irene / Bogaert, Liz / Desjarlais, John / Shivva, Vittal / Hosseini, Iraj / Ramanujan, Saroja

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

2023 Volume 186, Page(s) 106450

Abstract: XmAb24306 is a lymphoproliferative interleukin (IL)-15/IL-15 receptor α (IL-15Rα) Fc-fusion protein currently under clinical investigation as an immunotherapeutic agent for cancer treatment. XmAb24306 contains mutations in IL-15 that attenuate its ... ...

Abstract	XmAb24306 is a lymphoproliferative interleukin (IL)-15/IL-15 receptor α (IL-15Rα) Fc-fusion protein currently under clinical investigation as an immunotherapeutic agent for cancer treatment. XmAb24306 contains mutations in IL-15 that attenuate its affinity to the heterodimeric IL-15 receptor βγ (IL-15R). We observe substantially prolonged pharmacokinetics (PK) (half-life ∼ 2.5 to 4.5 days) in single- and repeat-dose cynomolgus monkey (cyno) studies compared to wild-type IL-15 (half-life ∼ 1 hour), leading to increased exposure and enhanced and durable expansion of NK cells, CD8+ T cells and CD4-CD8- (double negative [DN]) T cells. Drug clearance varied with dose level and time post-dose, and PK exposure decreased upon repeated dosing, which we attribute to increased target-mediated drug disposition (TMDD) resulting from drug-induced lymphocyte expansion (i.e., pharmacodynamic (PD)-enhanced TMDD). We developed a quantitative systems pharmacology (QSP) model to quantify the complex PKPD behaviors due to the interactions of XmAb24306 with multiple cell types (CD8+, CD4+, DN T cells, and NK cells) in the peripheral blood (PB) and lymphoid tissues. The model, which includes nonspecific drug clearance, binding to and TMDD by IL15R differentially expressed on lymphocyte subsets, and resultant lymphocyte margination/migration out of PB, expansion in lymphoid tissues, and redistribution to the blood, successfully describes the systemic PK and lymphocyte kinetics observed in the cyno studies. Results suggest that after 3 doses of every-two-week (Q2W) doses up to 70 days, the relative contributions of each elimination pathway to XmAb24306 clearance are: DN T cells > NK cells > CD8+ T cells > nonspecific clearance > CD4+ T cells. Modeling suggests that observed cellular expansion in blood results from the influx of cells expanded by the drug in lymphoid tissues. The model is used to predict lymphoid tissue expansion and to simulate PK-PD for different dose regimens. Thus, the model provides insight into the mechanisms underlying the observed PK-PD behavior of an engineered cytokine and can serve as a framework for the rapid integration and analysis of data that emerges from ongoing clinical studies in cancer patients as single-agent or given in combination.
MeSH term(s)	Animals ; Macaca fascicularis/metabolism ; Interleukin-15/metabolism ; Network Pharmacology ; Lymphocytes/metabolism ; Immunologic Factors ; Antineoplastic Agents ; Receptors, Interleukin-15
Chemical Substances	Interleukin-15 ; Immunologic Factors ; Antineoplastic Agents ; Receptors, Interleukin-15
Language	English
Publishing date	2023-04-20
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1154366-8
ISSN	1879-0720 ; 0928-0987
ISSN (online)	1879-0720
ISSN	0928-0987
DOI	10.1016/j.ejps.2023.106450
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Article ; Online: In Vivo Reoxidation Kinetics of Free Thiols in Multiple Domains of IgG1 Antibodies in Rats.

Kim, Michael T / Lechmann, Martin / Rajan, Sharmila / Shivva, Vittal / Lee, Aron / Chen, Yan / Weis, David D

Journal of pharmaceutical sciences

2021 Volume 110, Issue 5, Page(s) 1989–1996

Abstract: While free thiols in monoclonal antibodies (mAbs) have been extensively characterized by in vitro studies to probe its effect on antibody function and stability, their in vivo biotransformation has not been comprehensively studied. In this study, a panel ...

Abstract	While free thiols in monoclonal antibodies (mAbs) have been extensively characterized by in vitro studies to probe its effect on antibody function and stability, their in vivo biotransformation has not been comprehensively studied. In this study, a panel of five recombinant IgG1 mAbs with elevated free thiols in the VH, VL, and CH2 domains were intravenously administered into Wistar rats. In vivo biotransformation of thirty-five free thiol sites in total (7 disulfide pairs in VL, CL, VH, CH1, HH, CH2, CH3 domains across the 5 mAbs) were monitored using a denaturing differential isotopic tagging procedure on immunopurified timepoints followed by LC-MS of tryptic digests. The free thiol levels in two VH domain and one CH2 domain disulfide sites decreased in vivo following first order kinetics. Free thiol levels of the remaining 32 sites were remarkably stable in vivo. Further analytical characterization highlighted a positive association between a free thiol's solvent accessibility and a free thiol's reoxidation propensity. The data and discussion presented here shed valuable insights into the in vivo fate of free thiols in several recombinant IgG1s and its implications for free thiols as a product quality attribute in therapeutic mAb products.
MeSH term(s)	Animals ; Immunoglobulin G ; Kinetics ; Mass Spectrometry ; Rats ; Rats, Wistar ; Sulfhydryl Compounds
Chemical Substances	Immunoglobulin G ; Sulfhydryl Compounds
Language	English
Publishing date	2021-02-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	3151-3
ISSN	1520-6017 ; 0022-3549
ISSN (online)	1520-6017
ISSN	0022-3549
DOI	10.1016/j.xphs.2021.02.009
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Article ; Online: An In Silico Knockout Model for Gastrointestinal Absorption Using a Systems Pharmacology Approach - Development and Application for Ketones.

Shivva, Vittal / Tucker, Ian G / Duffull, Stephen B

PloS one

2016 Volume 11, Issue 9, Page(s) e0163795

Abstract: Gastrointestinal absorption and disposition of ketones is complex. Recent work describing the pharmacokinetics (PK) of d-β-hydroxybutyrate (BHB) following oral ingestion of a ketone monoester ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate) found multiple ... ...

Abstract	Gastrointestinal absorption and disposition of ketones is complex. Recent work describing the pharmacokinetics (PK) of d-β-hydroxybutyrate (BHB) following oral ingestion of a ketone monoester ((R)-3-hydroxybutyl (R)-3-hydroxybutyrate) found multiple input sites, nonlinear disposition and feedback on endogenous production. In the current work, a human systems pharmacology model for gastrointestinal absorption and subsequent disposition of small molecules (monocarboxylic acids with molecular weight < 200 Da) was developed with an application to a ketone monoester. The systems model was developed by collating the information from the literature and knowledge gained from empirical population modelling of the clinical data. In silico knockout variants of this systems model were used to explore the mechanism of gastrointestinal absorption of ketones. The knockouts included active absorption across different regions in the gut and also a passive diffusion knockout, giving 10 gut knockouts in total. Exploration of knockout variants has suggested that there are at least three distinct regions in the gut that contribute to absorption of ketones. Passive diffusion predominates in the proximal gut and active processes contribute to the absorption of ketones in the distal gut. Low doses are predominantly absorbed from the proximal gut by passive diffusion whereas high doses are absorbed across all sites in the gut. This work has provided mechanistic insight into the absorption process of ketones, in the form of unique in silico knockouts that have potential for application with other therapeutics. Future studies on absorption process of ketones are suggested to substantiate findings in this study.
Language	English
Publishing date	2016-09-29
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0163795
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Article ; Online: Translatability of

Chu, Phillip Y / Wang, Hui / Ross, Emily / Stephens, Nicole / Zhang, Hui-Min / Andersen, Nisana / Chan, Wayman / Shivva, Vittal / Crowell, Susan R / Spiess, Christoph / Holder, Patrick G / Agard, Nicholas J / Ji, Chengjie / Chen, John / Sreedhara, Alavattam / Wang, Jianyong / Wu, Cong / Liu, Yichin / Tran, John C

Analytical chemistry

2023 Volume 95, Issue 49, Page(s) 17957–17961

Abstract: Biotransformation leading to single residue modifications (e.g., deamidation, oxidation) can contribute to decreased efficacy/potency, poor pharmacokinetics, and/or toxicity/immunogenicity for protein therapeutics. Identifying and characterizing such ... ...

Abstract	Biotransformation leading to single residue modifications (e.g., deamidation, oxidation) can contribute to decreased efficacy/potency, poor pharmacokinetics, and/or toxicity/immunogenicity for protein therapeutics. Identifying and characterizing such liabilities
MeSH term(s)	Animals ; Rabbits ; Oxidation-Reduction ; Biotransformation
Chemical Substances	2,2'-azobis(2-amidinopropane) (7381JDR72F)
Language	English
Publishing date	2023-11-30
Publishing country	United States
Document type	Journal Article
ZDB-ID	1508-8
ISSN	1520-6882 ; 0003-2700
ISSN (online)	1520-6882
ISSN	0003-2700
DOI	10.1021/acs.analchem.3c02133
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Article ; Online: The Population Pharmacokinetics of D-β-hydroxybutyrate Following Administration of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate.

Shivva, Vittal / Cox, Pete J / Clarke, Kieran / Veech, Richard L / Tucker, Ian G / Duffull, Stephen B

The AAPS journal

2016 Volume 18, Issue 3, Page(s) 678–688

Abstract: The administration of ketones to induce a mild ketosis is of interest for the alleviation of symptoms associated with various neurological disorders. This study aimed to understand the pharmacokinetics (PK) of D-β-hydroxybutyrate (BHB) and quantify the ... ...

Abstract	The administration of ketones to induce a mild ketosis is of interest for the alleviation of symptoms associated with various neurological disorders. This study aimed to understand the pharmacokinetics (PK) of D-β-hydroxybutyrate (BHB) and quantify the sources of variability following a dose of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (ketone monoester). Healthy volunteers (n = 37) were given a single drink of the ketone monoester, following which, 833 blood BHB concentrations were measured. Two formulations and five dose levels of ketone monoester were used. A nonlinear mixed effect modelling approach was used to develop a population PK model. A one compartment disposition model with negative feedback effect on endogenous BHB production provided the best description of the data. Absorption was best described by two consecutive first-order inputs and elimination by dual processes involving first-order (CL = 10.9 L/h) and capacity limited elimination (V max = 4520 mg/h). Covariates identified were formulation (on relative oral bioavailable fraction and absorption rate constant) and dose (on relative oral bioavailable fraction). Lean body weight (on first-order clearance) and sex (on apparent volume of distribution) were also significant covariates. The PK of BHB is complicated by complex absorption process, endogenous production and nonlinear elimination. Formulation and dose appear to strongly influence the kinetic profile following ketone monoester administration. Further work is needed to quantify mechanisms of absorption and elimination of ketones for therapeutic use in the form of ketone monoester.
MeSH term(s)	Female ; Humans ; Hydroxybutyrates/administration & dosage ; Hydroxybutyrates/pharmacokinetics ; Male ; Models, Theoretical
Chemical Substances	Hydroxybutyrates
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article
ISSN	1550-7416
ISSN (online)	1550-7416
DOI	10.1208/s12248-016-9879-0
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Article ; Online: Parameterisation affects identifiability of population models.

Shivva, Vittal / Korell, Julia / Tucker, Ian G / Duffull, Stephen B

Journal of pharmacokinetics and pharmacodynamics

2013 Volume 41, Issue 1, Page(s) 81–86

Abstract: Identifiability is an important aspect of model development. In this work, using a simple one compartment population pharmacokinetic model, we show that identifiability of the variances of the random effects parameters are affected by the ... ...

Abstract	Identifiability is an important aspect of model development. In this work, using a simple one compartment population pharmacokinetic model, we show that identifiability of the variances of the random effects parameters are affected by the parameterisation of the fixed effects parameters.
MeSH term(s)	Models, Biological ; Nonlinear Dynamics ; Population
Language	English
Publishing date	2013-12-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2041601-5
ISSN	1573-8744 ; 1567-567X
ISSN (online)	1573-8744
ISSN	1567-567X
DOI	10.1007/s10928-013-9347-8
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