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Printable Handouts
Navigable Slide Index
- Introduction
- Lecture outline (1)
- Antibody-drug conjugate: modality
- Antibody-drug conjugate: heterogeneity
- Antibody-drug conjugate: the opportunity
- Antibody-drug conjugate: analytes
- Antibody-drug conjugate: typical in vivo PK
- ADC PK: examples
- Lecture outline (2)
- Cellular PK of released drug (1)
- Cellular PK of released drug (2)
- Cellular PK of ADC
- Cellular PK of ADC: the parameters
- Sensitivity analysis: cellular PK model
- Lecture outline (3)
- Mechanism-based PK/PD model for ADCs
- Case study with Brentuximab Vedotin
- Step 1: intracellular payload concentrations
- Step 2: MMAE PK in plasma & tumor tissue
- Step 3: SGN-35 PK in mouse plasma
- Step 4: a multi-scale integrated tumor model
- Step 4: prediciting tumor MMAE using the model
- Step 5: model integration
- Step 5: predicting data with the PK/PD model
- Step 6: SGN-35 & MMAE PK in cancer patients
- Step 7: preclinical to clinical translation of the model
- Step 7: PK/PD model clinical trial simulations
- Step 7: clinical trial simulation results
- Step 7: simulations vs. published results
- Lecture outline (4)
- Platform PBPK model for ADCs: approach (1)
- Platform PBPK model for ADCs: approach (2)
- ADC PBPK Model: Kadcyla® case study
- Step-1: unconjugated/released drug PK
- Step 2: ADC stability (DAR vs. time)
- Step-3: predicting preclinical PK: ADC
- Step-3: predicting preclinical PK: released drug
- Step-4: prediction of human PK (scale-up) (1)
- Step-4: prediction of human PK (scale-up) (2)
- Analysis of determinants for ADC PK
- Lecture summary
- Acknowledgements
Topics Covered
- Antibody drug conjugates (ADCs) and their uses
- Different ways to measure ADCs in the cell
- Typical ADC PK in cells
- Modeling the cellular PK of ADCs
- Modeling the tumor PK of ADCs
- 7 steps
- Modeling whole-body PK of ADCs
- Combining PK and PD models
- Kadcyla® case study
Links
Series:
Categories:
Therapeutic Areas:
Talk Citation
Shah, D.K. (2019, June 30). Modeling of antibody-drug conjugate pharmacokinetics [Video file]. In The Biomedical & Life Sciences Collection, Henry Stewart Talks. Retrieved December 14, 2024, from https://doi.org/10.69645/LXCF1517.Export Citation (RIS)
Publication History
Financial Disclosures
- Dr. Dhaval K. Shah has not informed HSTalks of any commercial/financial relationship that it is appropriate to disclose.
Other Talks in the Series: Periodic Reports: Advances in Clinical Interventions and Research Platforms
Transcript
Please wait while the transcript is being prepared...
0:00
The topic of this presentation is "Modeling of Antibody-Drug Conjugate Pharmacokinetics".
My name is Dhaval K.Shah,
I'm an Associate Professor in
the Department of Pharmaceutical Sciences at the State University of New York at Buffalo.
0:14
Here's the outline for today's talk.
I'll mainly go over the basic tenets of antibody-drug conjugate pharmacokinetics.
How the profiles typically look like, and then we will
go over several examples of mathematical modeling,
the pharmacokinetics of ADCs at the cellular level,
at the tumor level, and at the whole-body level.
0:35
So, as the name suggests,
antibody-drug conjugates are basically conjugates of
antibodies with potent small molecule drugs.
As shown on the left, over here,
an antibody is basically a molecule with 150 Kilodaltons in size;
the ability of an antibody to specifically bind to a target is really
what makes them attractive for targeting certain tissues within the body.
However, small molecules which can be very potent some times don't have the selectivity.
So, what is done, basically these drugs are attached to antibodies and
this conjugate is now able to bring
the drugs to the desired location with the help of the antibody.
What is shown here is a cartoon of antibody-drug conjugates.
It consists of three different components: your own antibody,
you have a chemical linker, and you have a drug.
On average, the amount of drug on an antibody can range from
2 to 12 and this ratio is known as the Drug-Antibody Ratio or DAR.
What is shown in the middle is a typical mechanism of action of ADCs.
When the ADCs are administered in the systemic circulation,
it circulates in the system and goes outside the cell which expresses
the target that the antibody portion of the ADC binds.
Then the target internalizes the ADC and within the cell,
depending on the nature of the linker,
the small molecule drug is released and then
the small molecule drug can supposedly diffuse
it in the cytosol and go to
the desired location, such as if the small molecule is a tubulin binder,
then it will go to tubulins and bind there.
Or, if it is a DNA damaging agent, it will go to the nucleus and that will lead to
the pharmacology and most of the time this pharmacology is the killing of a cell.
While the antibody-drug conjugate platform can be used to treat any disease per se,
cancer as a disease has the most potential and there are four FDA approved ADCs out there-
all approved for cancer.
So, for today's talk, we'll be mainly focusing on
oncology usage of the antibodies-drug conjugate.