PKPD Modeling of Preclinical Data: Using a Surrogate Antibody to ...

AAPS Symposium
Mechanism-based PKPD Modeling: its Role in Discovery and Early Development of Biologics
PKPD Modeling of Preclinical Data: Using
a Surrogate Antibody to Underwrite
Toxicology Safety Study
Rong Deng Ph.D.
Genentech Inc
November 11, 2009

Outline
• Efalizumab and its murine surrogate, muM17
• Pharmacokinetics (PK)/Pharmacodynamics (PD)
relationship of efalizumab in human and muM17 in
mice
• Mechanism-based PK/PD modeling and simulations
for muM17 in mice to support safety studies
• Conclusions

Efalizumab
• Humanized IgG1 mAb
• Binds to the CD11a chain of
leukocyte function antigen-1 (LFA-1)
• Blocks interaction between LFA-1 on
T-cell and intracellular adhesion
molecule (ICAM) on APC, endothelia
cells and keratinocytes
• Efalizumab was approved in the
United States and Europe for
treatment of moderate to severe
plaque psoriasis in 2003
Werther WA, et al. J Immunol. 1996;157:4986-4995.
Krueger JG. J Am Acad Dermatol. 2002;46:1-23.

Challenges for Efalizumab Development
• Efalizumab is specific for chimpanzee and human
CD11a but does not recognize CD11a from other nonhuman
primates
• Since efalizumab modulates immune responses and
given its target population, reproductive toxicity
studies were essential
• A chimeric rat anti-mouse CD11a antibody, muM17,
was developed and evaluated as a species-specific
surrogate molecule for efalizumab

muM17 has Comparable in vitro
Pharmacological Activity to Efalizumab
Efalizumab
muM17
istotype
binding domain
Humanized full-length mAb
IgG1
I domain of human CD11a
(AA 193-207)
Chimeric rat /mouse IgG2a
I domain of mouse CD11a
(AA 126-129)
Binding affinity to blood
leukocytes
3.0 1.5nM 2.7 1.2nM
Mixed lymphocyte
response
IC50 0.06-0.09 µg/mL
IC50 0.1-0.3 µg/mL

muM17 has Comparable in vivo
Pharmacological Activity to Efalizumab
Efalizumab
muM17
Pharmacological activity in
vivo
PD effects
PK/PD relationship
Safety profiles
Tissue cross-reactivity
Placental transfer
Demonstrated activity in
patients with psoriasis
Demonstrated activity in delayed
type hypersensitivity (DTH) study
similar
muM17 in female CD-1 mice is proposed to be a suitable surrogate molecule for
testing selected pharmacological and toxicological activities of efalizumab in human

What is the clinically relevant dose of
the surrogate molecule muM17 for
efalizumab toxicology studies

Efalizumab PK and PD Profiles Following 1 mg/kg/wk for 12 Weeks in
Patients with Moderate to Severe Psoriasis
•Within 24 h after efalizumab dosing in humans, maximum PD effects (>80%
CD11a down modulation) were observed.
•The maximum PD effects were maintained until efalizumab concentrations
in the circulation decreased to ~1 µg/mL

MuM17 PK and PD Profiles Following Single SC
Administration in CD-1 Mice
• Dose-dependent plasma elimination of
muM17 and duration of CD11a down
modulation.
• muM17 rapid elimination occurred when
concentrations fell below 10 µg/mL
• Maximum down modulation of CD11a
expression (

Dose Equivalency of Efalizumab in
Human and muM17 in Mice
Is it possible that dose equivalency of efalizumab in human and
muM17 in mice could be determined based on PK profiles
Yes
AUC, Cmax, or time above
threshold concentration
etc
PD
NO
•The capacities of the target
receptor (CD11a on T-
lymphocytes) in mice and
humans are different
visual inspection SD SC data
of muM17 in mice
modeling and
simulation approach
3 mg/kg muM17 is the minimum dose to maximally
down modulate CD11a expression for at least 1 week

Mechanism-based PK/PD Model of muM17
1,
• IV and SC single-dose PK/PD data are simultaneously fitted by
NONMEM
• The PK/PD model for muM17 was validated by visual comparison of
simulated versus observed data from an external PK/PD dataset

The Proposed Receptor-mediated PK/PD Model Described both
the PK and PD of muM17 well after Single Dose in CD-1 Mice
Table 1. PK/PD parameters of muM17 and Efalizumab
Estimated Using Nonlinear Mixed-Effect Model
5 mg/kg
3 mg/kg
10 mg/kg
Parameter muM17 Efalizumab a
V c (mL/kg) 44.5 20.0 71.6 5.8
K 12 (1/day) 56.1 70.1 0.283 0.060
K 21 (1/day) 59.9 29.3 0.506 0.037
K 01 (1/day) 1.53 0.135 N/A
K 10 (1/day) 0.162 0.072 0.0992 0.0107
V max1 (µg/kg/day/%CD11a) 27.4 3.24 1.47 0.19
V max2 (1/day) 13.2 1.19 1.34 0.36
K mc (µg/mL) 9.38 1.81 0.248 0.079
K 03 (%CD11a/day) 79.8 10.3 43.5 15.7
K 30 ( 1/day) 0.890 0.137 0.467 0.173
F (%) 84.0 0.0287 NA
3 mg/kg
5 mg/kg
Values given as mean SE
NA, Not estimated
a
Values obtained from published data (Bauer R.J., JPB,1999,27:397)
10 mg/kg

The Model Described the PK and PD of muM17 well after Multiple Doses
3 mg/kg SC weekly X2
The mechanistic-based PK/PD model was validated using an external sparse data set

Model-simulated Mouse versus Observed Human CD11a Expression
on T-lymphocyte-time Profiles Following 12 weekly SC Doses
•CD11a expression after a dose of 1 mg/kg/week muM17 was approximately
60% of baseline during the dosing period, whereas maximum CD11a down
modulation (

Conclusions
• A PD marker was used to select the relevant dose for
toxicology studies in mice
• A mechanism-based PK/PD model helped confirm
the PD-based dose equivalency of muM17 in mice
and efalizumab in humans
• This approach may be helpful in finding the clinically
relevant dose of a surrogate molecule for toxicology
studies of other protein therapeutics

Acknowledgments
All my colleagues in Dev Sci at Genentech!!!

References
• Wu B, Joshi A, Ren S, Ng C. The application of mechanism-based PK/PD modeling
in pharmacodynamic-based dose selection of muM17, a surrogate monoclonal
antibody for efalizumab. J Pharm Sci. 2006,95:1258-1268
• Clarke J, Leach W, Pippig S, Joshi A, Wu BM, House R, Beyer J. Evaluation of a
surrogate antibody for preclinical safety testing of an anti-CD11a monoclonal
antibody. Regul Toxicol Pharmacol. 2004, 40: 219-226.
• Bauer RJ, Dedrick RL, White ML, Murray MJ, Garovoy MR. Population
pharmacokinetics and pharmacodynamics of the anti-CD11a antibody hu1124 in
human subjects with psoriasis. J Pharmacokinet Biopharm 1999, 27: 397-420
• Werther WA, Gonzalez TN, O'Connor SJ, McCabe S, Chan B, Hotaling T, Champe
M, Fox JA, Jardieu PM, Berman PW, Presta LG. Humanization of an anti-lymphocyte
function-associated antigen (LFA)-1 monoclonal antibody and reengineering of the
humanized antibody for binding to rhesus LFA-1. J Immunol. 1996,157(11):4986-95