NDLI: Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for THIOMAB™ Drug Conjugates

Content Provider	Springer Nature Link
Author	Sukumaran, Siddharth Gadkar, Kapil Zhang, Crystal Bhakta, Sunil Liu, Luna Xu, Keyang Raab, Helga Yu, Shang Fan Mai, Elaine Fourie O’Dohue, Aimee Kozak, Katherine R. Ramanujan, Saroja Junutula, Jagath R. Lin, Kedan
Copyright Year	2014
Abstract	THIOMAB™ drug conjugates (TDCs) with engineered cysteine residues allow site-specific drug conjugation and defined Drug-to-Antibody Ratios (DAR). In order to help elucidate the impact of drug-loading, conjugation site, and subsequent deconjugation on pharmacokinetics and efficacy, we have developed an integrated mathematical model to mechanistically characterize pharmacokinetic behavior and preclinical efficacy of MMAE conjugated TDCs with different DARs. General applicability of the model structure was evaluated with two different TDCs.Pharmacokinetics studies were conducted for unconjugated antibody and purified TDCs with DAR-1, 2 and 4 for trastuzumab TDC and Anti-STEAP1 TDC in mice. Total antibody concentrations and individual DAR fractions were measured. Efficacy studies were performed in tumor-bearing mice.An integrated model consisting of distinct DAR species (DAR0-4), each described by a two-compartment model was able to capture the experimental data well. Time series measurements of each Individual DAR species allowed for the incorporation of site-specific drug loss through deconjugation and the results suggest a higher deconjugation rate from heavy chain site HC-A114C than the light chain site LC-V205C. Total antibody concentrations showed multi-exponential decline, with a higher clearance associated with higher DAR species. The experimentally observed effects of TDC on tumor growth kinetics were successfully described by linking pharmacokinetic profiles to DAR-dependent killing of tumor cells.Results from the integrated model evaluated with two different TDCs highlight the impact of DAR and site of conjugation on pharmacokinetics and efficacy. The model can be used to guide future drug optimization and in-vivo studies.
Starting Page	1884
Ending Page	1893
Page Count	10
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	32
Issue Number	6
e-ISSN	1573904X
Language	English
Publisher	Springer US
Publisher Date	2014-12-02
Publisher Place	New York
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

Pharmacokinetic Considerations for Antibody Drug Conjugates

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of Bidirectional Effect of Danshensu on Plasma Homocysteine in Rats

Preclinical Pharmacokinetic Considerations for the Development of Antibody Drug Conjugates

Antibody-Drug Conjugates

Gene Therapy: A Pharmacokinetic/Pharmacodynamic Modelling Overview

Gompertz Pharmacokinetic Model for Drug Disposition

Receptor-Mediated Pharmacokinetic/Pharmacodynamic Model of Interferon-β 1a in Humans

Pharmacokinetic and Pharmacodynamic Modeling of Romiplostim in Animals

Inotropic Effect of Digoxin in Humans: Mechanistic Pharmacokinetic/Pharmacodynamic Model Based on Slow Receptor Binding

Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for THIOMAB™ Drug Conjugates

Similar Documents

Pharmacokinetic Considerations for Antibody Drug Conjugates

Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling of Bidirectional Effect of Danshensu on Plasma Homocysteine in Rats

Preclinical Pharmacokinetic Considerations for the Development of Antibody Drug Conjugates

Antibody-Drug Conjugates

Gene Therapy: A Pharmacokinetic/Pharmacodynamic Modelling Overview

Gompertz Pharmacokinetic Model for Drug Disposition

Receptor-Mediated Pharmacokinetic/Pharmacodynamic Model of Interferon-β 1a in Humans

Pharmacokinetic and Pharmacodynamic Modeling of Romiplostim in Animals

Inotropic Effect of Digoxin in Humans: Mechanistic Pharmacokinetic/Pharmacodynamic Model Based on Slow Receptor Binding

Mechanism-Based Pharmacokinetic/Pharmacodynamic Model for THIOMAB™ Drug Conjugates