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Inter-species comparison of semi-physiological pre-clinical
PK/PD models to better predict the time course of
myelosuppression in human: application to a novel
vectorized epipodophyllotoxin (F14512)
A. Petain (1), B. Gomes (1), D. Tierny (2), A. Bidaut (1), P. Ferre (1) and L. Nguyen (1)
(1) Institut de Recherche Pierre Fabre, Research & Development center, Toulouse, France
(2) Oncovet Clinical research, Villeneuve d’Ascq, France
Background
Simulation in human
Objectives
The aim of the present study was to retrospectively assess the human
predictability of semi-physiological leukopenia PK/PD models built on
rats, Beagle laboratory dogs and pet dogs.
Data
Studies
Rats
Beagle dogs
Pet dogs
1 PK/PD
3 toxicity
1 clinical
SD and repeated doses
(2/weeks)
QD for 3 days every 2
weeks
iv bolus
iv infusion (3h)
From 0.03 to 0.85
From 0.05 to 0.085
Schedule
QD : once a day ; BID : twice daily ; SD : single
dose
SD
QD
Administration route
BID
iv bolus
Doses (mg/kg)
1; 2; 3
0.4 ; 0.7
0.4 ; 0.7
Number of animals
84
46
23
Number of observations
364
189
405
Ratio of unbound fraction
human / animal
0.264
0.291
0.291
Ratio of IC90
animal/human *
0.594
0.232
0.232
* Results of an in vitro evaluation of F14512 haematotoxicity on CFU-GM hematopoietic progenitor
• Observed WBC counts in 11 patients included in a phase I ovarian cancer study
where F14512 was administered as a 3h infusion once daily for 3 days
Simulations were performed considering
- data from the 11 patients included in the ovarian cancer study:
-Individual baseline values of WBC
-Individual PK parameters (EBE obtained with the post hoc options)
-System related parameters of the PK/PD models previously established:
-MTT=125 h (IIV,CV=26 %) and γ=0.17 [4]
-Slopes estimated with PK/PD modeling in animals (IIV,CV=45%) and adjusted with the
unbound fraction but without considering the inter-species in vitro sensivity results
fuhuman /
fu animal
Fu corrected
predicted Slope in
human
(L/mg)
IC90animal
/IC90human
Fu and sensivity
corrected
predicted Slope
in human
(L/mg)
5.12
0.264
1.35
0.594
0.817
Beagle dog
59.3
0.291
17.3
0.232
4.01
Pet dog
48.1
0.291
14.0
0.232
3.24
Human
21.4
-
21.4
-
21.4
Models
Estimated
Slope from
Animal
(L/mg)
Rat
Protein binding
study
5 mg/m2/QD for 3 days
in vitro stem
cells study
10 mg/m2/QD for 3 days
Simulation with
rat slope
-F14512, a polyamine-vectorized anti-cancer drug which combines an
epipodophyllotoxin core targeting topoisomerase II with a spermine moiety as a tumor
cell-delivery vector [1].
-Currently in clinical phase II study in combination with aracytine for patients with acute
myeloid leukemia, F14512 was also investigated in ovarian cancer patients.
-In parallel, F14512 is tested in pet dogs with naturally occuring lymphoma [2].
A same semi-physiological PK/PD model of leukopenia was used to fit the data of the 3
groups of animals (rat, beagle dogs and pet dogs) separately. [3]

Structure of the PK-PD model
describing chemotherapy induced
myelosuppression
WBC0
WBC Circulating
Kprol
Proliferating
Progenitors
cells
ktr
ktr
Transit
Transit
ktr
Transit
ktr
Circulating
WBC
Effect = Slope x Conc
Kcirc
System (physiological) parameters :
- MTT = 4/ktr (Kprol=kcirc=ktr)
- WBC0=baseline of WBC
- γ=Feed back
Drug dependant parameter :
- Slope
F14512 PK model
Estimate (RSE %)
Rat
PK/PD sequential strategy :
Population PK parameters for
rat and beagle dogs models
Individual PK parameters for
Pet Dog model
Nonmem 7.2
FOCE method
Observations
100
150
200
0
100
Time
200
300
10.9 (9 %)
MTT (h)
γ
Slope (L/mg)
74.7 (10 %)
77.1 (4 %)
63.6 (6 %)
0.149 FIX [4]
0.2 FIX
0.15 (13 %)
5.12 (7%)
59.3 (10 %)
48.1 (14 %)
Inter individual variabilities , CV (%)
WBC0
MTT
Slope
18.5 % (21%) 15.5 % (58 %)
Admin days : 1–5–25-29-33
Doses : 0.1-0.35-0.03-0.6-0.85 mg/kg
Admin days : 1–5–15
Dose 0.5 mg/kg
SD
Doses : 0.1 and 0.35 mg/kg
2 / week
Doses : 0.03; 0.1; 0.35
400
BID (0.4 & 0.7 mg/kg)
Observations
Observations
10
200
7.51 (3 %)
Time
Once daily (0.4 & 0.7 mg/kg)
100
14.8 (2 %)
10
Time
0
WBC0 (x 109/L)
300
400
32 % (28 %)
-
-
12.4 % (57 %)
-
-
52.4 % (33 %)
VPC – Beagle dog model
SDDU (1,2&3 mg/kg)
Observations
50
Typical values
Prop. PD error 18.1 % (10%) 25.2 % (20%) 44.2 % (12 %)
VPCRUN-214Rat model
0
Pet Dogs
Residual variability, CV%
Log transformed data
Control
Beagle dog
Simulation with
Pet dog slope
Feedback loop =
Simulation with
Beagle dog slope
Model building
VPC – Pet dog model
Median
of simulations
P5, P95
of simulations
0
100
200
300
400
Time
Prediction interval of simulations in black
Observed values in blue
Median of
observations
Conclusion
- Actual myelosuppression in human was considerably under-estimated by the rat model
- Both Pet / Beagle dogs models with fu correction provided a good prediction of human leukopenia
induced by F14512
- Considering correction for inter species differences in bone marrow sensitivity would have resulted
in a large under-prediction of the human myelosuppression
- PK/PD models based on larger species such as pet dogs may be a useful translational tool and its
application in better predicting hematotoxicity in FIH trials can be valuable.
References
[1] Barret JM et al. Cancer Res. 2008 Dec 1;68(23):9845-53.
[2] Tierny F et al. Submitted in Clinical Cancer Research- Under review.
[3] Friberg LE et al. 2010 Dec;28(6):744-53..
[4] Friberg LE et al 2002 Dec 15;20(24):4713-21.
10
Observed
data