Transcript Indirect Pharmacodynamic Models for Tolerance

APPLICATION OF PK/PD MODELING IN
DRUG DEVELOPMENT
Amarnath Sharma, Ph.D.
Pfizer Global R & D
Groton, CT
Objectives of Early Drug Development
 Identification
of critical risk factors prior to
investment in full clinical development
 selection of better compounds
 Provide
critical data to identify safe and
effective dose and dose regimens
 more efficient development
New Paradigm in Drug Development
PK/PD in patients &/or in experimental models
in healthy subjects (POM)
PK/PD in dose-ranging proof of
efficacy study in patients (POC)
Confirm PD in the pivotal studies
New Drug Application
Post-marketing comparative
PK/PD in patients
Why Study PK/PD ?
 Characterize
time course of pharmacologic response
(therapeutic &/or toxic effects)
 Understand complex relationships
– tolerance, sensitization, mechanistic delay
 Explain
variability in response
 Identify biomarkers and validate surrogate endpoints
 Aid dose/dose regimen selection through simulation
 Bridge clinical efficacy and safety results across ethnic
populations
 Bridge clinical results between adult and pediatric
patients
Requirements to Characterize
PK/PD Relationship
 Validated
biomarkers for therapeutic effects & toxicity
– Should be meaningful (relates to MOA), reproducible,
quantitative and allows frequent sampling to characterize the
time course of effect
– Validated Assay (reproducible, high precision….)
– Exposure-response relationship
 Understanding
of pharmacologic behavior of the drug
and pathophysiology of the disease
– Pharmacology and pharmacokinetic modeling
Modeling Direct Responses
Pharmacodynamics
1.0
Static Functions Related
to Hill Equation
0.8
E = Eo ± S. CP
Eq 1
E = Eo ± S. ln CP
Eq 2
0.6
0.4
n
max .Cp
E
E = Eo ±
EC50 n + Cp n
0.2
E max .(Cp - CT )
=
±
o
E E
( EC50 - CT ) + (Cp - CT )
0.0
0.001
0.01
0.1
1
10
100
Eq 3
Eq 4
1000
Concentration/EC50
Examples of direct PD effect with equilibration delay: CNS effects of benzodiazepines &
anesthetics; Muscle Relaxants of d-tubocurarine
Complexities in PK/PD Modeling
 Equilibration
 Mechanistic
delay
delay
 Tolerance
 Sensitization
 Active
 Drug
metabolites
interaction
Modeling Indirect Responses
Drug
Examples: Anticoagulants effects of warfarin;
Gene-mediated effects of corticosteroids
kin
Cp
Vc
ke
Ce
Biosignal
R
o
kout
CL
Pharmacokinetics (equilibration delay)
Cp =
n
Ai.e-li.t
i =1
dCe =
keo .(Cp - Ce )
dt
Pharmacodynamics (mechanistic delay)
dR =
kin .H (t ) - kout .R
dt
dR = kin kout .H (t ).R
dt
Ro = kin / kout
n
E max .Ce
H (t ) = 1±(
)
n
n
EC50 + Ce
Dayneka et al., JPB, 1993
Jusko et al., JPB, 1995
Sharma & Jusko, JPB, 1996
Sharma & Jusko, BJCP, 1998
Examples
 IL12:
Tolerance in efficacy & safety biomarker response
(IFNg).
 CD4
mAbs: Validate a safety biomarker in the preclinical
transgenic mice model.
 IL5
mAb: Biomarker (eosinophil) is not a validated
surrogate endpoint.
 P38
MAPK: Characterize an experimental model of acute
inflammation for anti-TNF response.
 Avitriptan:
 Pop
Characterize safety profile (BP and heart rate).
PK/PD approach in Linezolid bridging program.
IL12: An example of complex
PK/PD relationship
IL12
A 70 kDa heterodimer cytokine (35+40 kDa subunits).
 Enhances T helper 1-type immunity.
 Potentiates secretion of IFNg by, and the cytolytic
activity of, NK cells and CTLs.
 IL12-induced secretion of IFNg is required for activity.
 mIL12 has potent antitumor& antimetastatic activity in
murine tumor models.
 Under development for cancer and infectious diseases.

Phase I Study Design
 Open
label dose-escalation study in cancer
patients.
 A single dose of rhIL12 followed by cycles of
5 consecutive daily iv injection at the same
dose every 3 weeks.
Days 1
 MTD
study
2 weeks washout
15
16
17
18
19
Repeat every 3 weeks
of 500 ng/kg was established in this
Atkins et al,Clin Cancer Res. 1997
Phase II Study Design
 Open
label repeat-dose efficacy study in patients
with advanced renal cell carcinoma.
 Cycles of 5 consecutive daily iv injection at MTD
(500 ng/kg) dose every 3 weeks.
Days 1 2 3 4
5
3 weeks washout
27 28 29 30
31
Repeat every
3 weeks
Leonard et al., Blood, 1997
Phase II Study Results
 Treatment
was associated with unexpected serious
adverse events.
 Most of the patients experienced serious AEs after
2nd and 3rd doses.
 Two patients died and no one entered the 2nd cycle
due to drug related toxicity such as GI bleeding.
 PK profiles for IL12 were comparable to those
observed in Phase I study.
Leonard et al., Blood, 1997
Reason for unexpected toxicity:
A four-fold
higher trough
IFNg concentrations in Phase
II may have caused the serious
toxicity.
Leonard et al., Blood, 1997
Summary
 If
IFNg concentrations were used as a safety biomarker,
it would have been possible to avoid serious AEs by
stopping after 2nd dose in Phase II study.
 A single dose of IL12 causes tolerance in its ability to
induce IFNg production upon further dosing.
 IL12 produces tolerance rapidly (3-4 days) during
multiple dosing which lasts for a relatively long time
period (14 days) in humans.
 PK/PD modeling to characterize schedule-dependent
IL12-induced IFNg production is crucial for designing
safe and effective dosing regimens.
Comparative PD of Anti-CD4 mAbs
in Transgenic Mice
Sharma et al., JPET, 2000
Anti-CD4 mAbs
 Mediate
their immunomodulatory effects via
indirect response mechanisms:
– removal of CD4+ T cells via effector mechanism;
– down-modulation of cell surface CD4 via internalization or
stripping and/or
– inhibition of CD4-MHC II interactions.
 Under
development for autoimmune disorder such
as rheumatoid arthritis.
Anti-CD4 mAbs
Clenoliximab
Keliximab
Cynomolgus Macaque
V-domain
Human C l-domain
VL
VH
VH
VH
VH
CH1 C H1 V H
H
H
CH2 CH2
Human g1 CH-domains
VL
VL
CH3 CH3
• Primate/human chimeric CD4 mAb of
IgG1 isotype.
• Does not mediate complement
dependent cytotoxicity.
• Exhibits efficient binding to human
IgG Fc receptors and can cause
depletion of CD4+ cells.
Pro
Cys 227
Pro
Ser
Cys 230
VH
VH
CH1 CH1
H
H
CH2 CH2
CH3 CH3
V L Cynomolgus Macaque
V-domain
VH
Human Cl-domain
235 Phe
Leu
Gly
Gly
Pro
240 Ser
Glu
Human g4 CH-domains
• IgG4 derivative of Keliximab.
• Does not mediate complement
dependent cytotoxicity.
• Does not exhibit efficient binding to
human IgG Fc receptors.
Reddy et al. J Immun, 2000
FcR and CD4 Mediated Cell Adhesion
mAb Binding to FcR g
(% Adhesion of THP-1 Cells)
25
20
Keliximab
Keliximab
Keliximab + sCD4
20
Clenoliximab
Keliximab F(ab') 2
15
15
10
10
5
5
0
0
0.1
1
10
100
1000
0.1
1
10
100
1000
mAb (ng/mL)
Reddy et al. J Immun, 2000
Study Design
 Male
transgenic mice (n=10-13 per group) bearing
human CD4 in place of the mouse CD4.
 Three dose levels (5, 25 & 125 mg/kg).
 PK: unbound plasma mAb concentrations.
 PD: CD4+ T cells; number of CD4 epitopes on the
surface of T cells and CD8+ T cells.
Preclinical Species
Plasma Keliximab Concentration (ug/mL)
Target-mediated Disposition
1000
hCD4+ Transgenic
CD4 knock-out
1 mg/kg
1 mg/kg
10 mg/kg
30 mg/kg
100
10
1
Davis et al., Drug Metab Disp, 1996
0.1
0.01
0
20
40
60
80
Time (hours)
100
120
140
PK Model for Anti-CD4 mAbs
Dose
kPT
Plasma
(CP)
Tissue
(CT)
V max . C P
Km + CP
dC p
dt
V max . C T
Km + CT
= -
V max. C p
Km+ Cp
- k .C p
PT
dC T
V max . C T
= k .CpPT
dt
Km+ CT
IC: Cp = Dose/Vc; CT = 0
Sharma et al., JPET, 2000
Mean Plasma Concentration (ng/mL)
Pharmacokinetics of Anti-CD4 mAbs
Clenoliximab
5mg/kg
25mg/kg
125mg/kg
1e+6
Keliximab
5mg/kg
25mg/kg
125mg/kg
1e+5
Parameter (unit)
Estimate
890
Vmax (mg/mL/h)
1e+4
Km (ng/mL)
1e+3
5249
Vc (mL)
2.5
VT (mL)
25.6
kPT (day-1)
0.15
1e+2
0
100
200
300
TIME (hours)
400
500
Sharma et al., JPET, 2000
PD Model for Anti-CD4 mAbs
koin
kout
CD4+ cell
SC50
Smax
dR
dt
= k in - k out . S(t) . R
S max . Cp
S(t) = 1 +
SC 50 + Cp
At a very high dose:
Smax = (Ro - Rmax) / Rmax
IC: Ro = kin/kout
Sharma et al., JPET, 2000
Sharma & Jusko, Br J Clin Pharmaco, 1998
PK/PD of Anti-CD4 mAbs
60
Keliximab
60
5 mg/kg
25 mg/kg
125 mg/kg
40
40
20
20
Clenoliximab
25 mg/kg
125 mg/kg
0
0
0
400
800
1200
1600
0
400
800
1200
1600
Time (hour)
Sharma et al., JPET, 2000
PD Parameters of Circulating
CD4+ T Cell Number
Treatment
Keliximab
Clenoliximab
0.035 (11%)
0.032
28.2 (18%)
16.2
SC50 (ng/mL)
37500 (54%)
419000
Ro (% lymphocytes)
34.1 (7.9%)
34.1
between-animal variability in R
13% (48%)
13%
proportional residual error
29% (20%)
26%
Kin (% lymphocytes/hr)
Smax
Variances
Summary
 Clenoliximab
is less potent and efficient
than keliximab in causing depletion of
circulating CD4+ T cells.
 The results of this study are similar to those
from clinical trials at comparable doses.
 This study validates the transgenic mice as
an appropriate model for preclinical PK/PD
evaluation of anti-CD4 mAbs.