PKPD MODELING OF IMMUNEMODULATORS CORTICOSTEROIDS AND CYTOKINES

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PK/PD MODELING OF IMMUNEMODULATORS
CORTICOSTEROIDS AND CYTOKINES
William J. Jusko, Ph.D. Department of
Pharmaceutical Sciences
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OUTLINE
? Perspectives in Pharmacodynamics ? Diverse
Effects of Corticosteroids ? Pharmacogenomics of
Steroids ? Other Agents IL-10, FTY720, IFN?1
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Components of PK/PD Models
Drug
kin
H
R
CP
Biosignal
Ce
keo
H
kout
DispositionKinetics
BiophaseDistribution
Biosensor Process
BiosignalFlux
Trans-duction
Response
Pharmacokinetics
Pharmacodynamics
Jusko et.al., JPB 23 5, 1995
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Family of Pharmacodynamic Indirect Response Models
koin
kout
Response (R)
Model
I
III
II
IV
III. STIMULATION - koin
I. INHIBITION - koin
Smax . Cp
koin . (1 ) - kout . R

SC50 Cp
Smax 0
IV. STIMULATION - kout
II. INHIBITION - kout
Smax . Cp
koin - kout (1 ) . R

SC50 Cp
Smax 0
Dayneka et al, JPB 21 457 (1993) Sharma and
Jusko, Br. J. Clin. Pharmacol. 45 229 (1998)
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Corticosteroids

• Important class of drugs used for the treatment
  of
• - Rheumatoid arthritis - Lupus erythematosus
• - Bronchial asthma - Ocular disorders
• - Renal diseases - Organ transplantation

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T-LYMPHOCYTE PROLIFERATION AND MAJOR
IMMUNOSUPPRESSANTS
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CYCLOSPORINE/PREDNISOLONE/SIROLIMUS INTERACTIONS
IN THREE HUMAN LYMPHOCYTE PROLIFERATION ASSAYS
GM Ferron, NA Pyszczynski, and WJ Jusko,
Transplantation 65 1203 (1998).
Prednisolone
Sirolimus
Sir \ IC50
Smax
Pred \ IC50
Drug Concentration, nM
Results of inhibition studies for three types of
cell culture systems (left and center panels)
and isobologram for drug combinations yielding
the URSA interaction parameter, ?.
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Lymphocyte Suppression and Relative Receptor
AffinitiesMager et al, J Pharm Sci (2003)
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Potency RRA Various Steroids
Log (1 / IC50) 0.868 (? 0.068) ? Log RRA 2.77
(? 0.14)
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Pharmacoimmunodynamic Interactions of
Interleukin-10and Prednisone in
HealthyVolunteers
Pharmacokinetics
A Chakraborty, RA Blum, DL Cutler, and WJ Jusko,
CPT 65 304-18 (1999).
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Joint Effects of Prednisolone and IL-10 on
Lymphocyte Trafficking
Rin
kout
Lymphocytes
Pred
IL-10
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Prednisolone Lymphocyte Trafficking and
Proliferation
IC50 7.17 ng/mL
Ex vivo WBLP
In vitro WBLP
IC50 38.7 ng/mL
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PK/PD Model for Trafficking and Suppression of
Proliferation
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Metabolic Effects of Corticosteroids
Tyrosine Aminotransferase (TAT)
Catabolic
Anabolic
Dhahbi et al, American Journal of Physiology,
E352-60, 1999
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Fifth-Generation Modelfor CorticosteroidPharmaco
dynamicsApplication to Steady-State Receptor
Down-Regulation and Enzyme Induction Patterns
during Seven-Day Continuous Infusion of
Methylprednisolone in Rats
R. Ramakrishnan, DC Debois, RR Almon, NA
Pyszczynski, and WJ Jusko
J. Pharmacokin. Pharmacodyn. 21 1-24 (2002).
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Giant Rat Study
A population approach is necessary to
characterize tissue events.
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Methylprednisolone PK/PD in Rats
Hepatic Cytosol
Nuclear Receptors Binding DR (N)
MPL Plasma Conc., (ng/ml)
GR Density (fmole/mg protein)
Time, hour
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Tyrosine Aminotransfererase Induction in Rat
Liver by MPL (Dose 50 mg/kg)
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Corticosteroid Pharmacogenomics
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(No Transcript)
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Results (Scrubbed to 5300 Genes)
20 10 0 -10 -20
Normalized Intensity
0 4 7 12 18 30
48
72
Time, hr
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Cluster 1 (23 genes)
Normalized Intensity
Time, hr
Time, hr
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Cluster 2 (8 genes)
Normalized Intensity
Time, hr
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Cluster 3 (21 genes)
Normalized Intensity
Time, hr
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Cluster 4 (66 genes)
Normalized Intensity
Time, hr
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Cluster 5 (6 genes)
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Cluster 6 (68 genes)
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Diverse Changes in Gene Expression Were Related
to
? Immunosuppression ? Blood Clotting ?
Dyslipidemia ? Carbohydrate Metabolism ?
Amino Acid Metabolism ? Xenobiotic Metabolism
Almon et al, JPP. 29 103 (2002) .Artwork by
Amanda Almon.
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Acute Phase/Immune Response Genes
? Pre-pro-complement C host immune response ?
Parathymosin thymocyte maturation ? MHC class
1 presages immune-mediated damage ? 2, 5, -
OAS INF-induced antiviral response ? target of
antiproliferative antibody regulation of mitotic
activity ? anti-acetylcholine receptor
antibody immunoglobulin expression ?
thiol-specific antioxidant NF?B signaling
pathway ? Biglycan increased in
inflammation ? ?2 - ? globulin
acute phase protein ?
growth hormone regulated protein
anti-protease ? thrombin blood
clotting/pro-inflammatory ? ?1 -
macroglobulin Inhibit inflammatory proteases ?
?2 - macroglobulin Inhibit inflammatory
proteases ? ?1 - acid glycoprotein inhibits
microvascular permeability ? serum amyloid
P scavenges chromatin ? Vitamin D binding
protein Vitamin D carrier/scavenges actin ? ?
-fibrinogen blood clotting ? fibrinogen
?-chain blood clotting ? fibrinogen
?-chain blood clotting ? proline rich
protein blood clotting ? metallothionein-2/-1
metal binding protein ? metallothionein-I metal
binding protein ? delta-aminolaevulinate
synthase heme synthesis
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Corticosteroid Pharmacogenomics

• Six major dynamic response patterns suggest that
  a limited array of control processes account for
  pharmacogenomic effects of steroids.
• Response profiles and PK/PD models offer
  opportunities to formulate hypotheses regarding
  factors and mechanisms of genomic effects.

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Pharmacodynamic Complexities in Pharmacogenomics
? Initiating factors (eg. drugs,
receptors) ? Variable expression of mRNA ? Direct
versus Indirect causes ? Dose - and Time -
Dependence ? Down - regulation of
receptors ? mRNA vs. Protein time
patterns ? Interactions of multiple genes,
proteins, mediators
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FTY720, a Novel Immunosuppressive Agent
2-Amino-2-2-(4-octylphenyl)ethylpropane-1,3-diol
HCL
C19H33O2NHCl MW 341.5 log Kp
5.09
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FTY720 PK/PD in Rats
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Interferons
?
Fundamental Immunology. Ed. W. Paul.
Lippincott-Raven p 755 (1999)
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Receptor-Mediated Kinetics Dynamics of
Interferon-? (Mager et al, Pharm. Res. 19
1537, 2002)
Drug Input
IFN?
IFN?
Nonspecific Binding
R
Secondary Elimination
Drug-Receptor Binding
GTP
DR Complex

Signal Transduction
NTP
N
Internalization Degradation
Neopterin (Biomarker)
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PK and PD of IV and SC IFN-? in Monkeys
IV
IV
IFN? 1a Serum Concentration (IU/mL)
Neopterin Serum Concentration (ng/mL)
SC
SC
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SUMMARY PK/PD - IMMUNOMODULATORS
? Immunomodulators are important
therapeutic agents with various mechanisms of
action which require further study. ? Assessment
of the PK/PD properties of these drugs have
offered numerous insights into new PK/PD models
to describe underlying control processes. ? Pharm
acogenomics provides an opportunity to examine
factors affecting the diverse molecular actions
of drugs. ? PK/PD models of the future will
further integrate pharmacokinetics, molecular
biology, and systems pharmacology.
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Acknowledgments
Collaborators Richard R. Almon, PhD Debra
Dubois, PhD Wojciech Krzyzanski, PhD PhD
Students Yu-Nien (Tom) Sun, PhD Rohini
Ramakrishnan, PhD Jin Yan Jin, PhD Candidate
Technicians Nancy Pyszczynski Suzette
Mis NIH Grants GM-24211 GM-57980