Modelling of PK/Efficacy/Toxicity in rats to help
design a FHD for a Cell Cycle Inhibitor X
Celine Pitou, PharmD1; Sophie Glatt, PhD3;Inaki Troconiz, PhD2
1, PK/PD/TS dpt, Eli Lilly and Co, UK; 2, School of Pharmacy, University of Navarra, Spain; 3, former Lilly employee, currently at UCB Celltech Ltd, UK
OBJECTIVES
The primary objective of PK/PD modelling in preparation of the FHD study was to estimate a pharmacologically effective and safe dose range in humans, based on
preclinical data. In addition, doses and administration schedules for this compound were optimized in order to minimise the duration of neutropenia.
METHODS
 The PK model was built using both oral and IV rat data from 12 studies over a total dose range of 0.5 to 60mpk dosed QD.
Drug
 The PK/efficacy model was developed using rat HCT116 xenograft data by means of a modified Gompertz model (1) where
compound LY is assumed to act as a cytotoxic agent by increasing the rate of cell death. This model was built using IV rat data
over a total dose range of 10 to 30mpk dosed weekly.
This model is described by several parameters: TS0, tumour size at the start of the experiment; Kgw1, rate constant controlling
the cell proliferation with an exponential rate; Kgw2, rate constant controlling the cell proliferation with a linear rate; Kdth,
rate constant controlling the cell death; Ktr, first order rate of transition.
Kprol
(=kgrw1, kgrw2)
+
kdth
TS
feedback=(Circ0/circ)
Kprol=(ktr)
 The PK/Tox model was developed using neutrophil count data obtained in nude rats from 5 pharmacology
studies over a total dose range of 9 to 60 dosed QD, Q2D, Q3D or Q7D.
The model (2) describes the time course of plasma neutrophil count is assumed to reduce the proliferation rate
or induce cell loss, which was modelled as a linear function. A time effect was also added to account for the
increase in baseline neutrophil count over time.
ktr
Prol
kdth
Damage Cells 1
Trst
1
Trst
2
ktr
ktr
ktr Trst
3
Neu
kCirc(=ktr)
Drug Effect
MTT
 Allometric Scaling approach was performed to predict human PK parameters using mouse, rat, dog and monkey IV PK data (2 cpt model was assumed for all species).
MODELLING RESULTS
 Allometric Scaling Results: The estimated median and 90% CI for human Cl, V1 and V2 were 8.50L/h (4.61-15.42), 121.55L (35.86-391.76) and 36.61L (19.4868.41), respectively. Inter-individual variability in humans was assumed to be 30% for CL, V1 and V2.
 Rat PK data are described adequately with a two cpt model with first order
250
200
150
5000
600
400
100
200
50
0
0
0
4
8
12
16
20
0
24
4
8
12
21.7
9.57
5th
95th
median
actual data
Dose of 0.5mpk IV
w
0.784 (88.5%)
V3
0.0148 (12.2%)
22
140
34.9
additive error
0.44
Dose = 20 mg
100
80
60
Dose = 30 mg
2000
2500
2000
1500
1000
40
0.155 (12.5%)
2.11 (35.3%)
Dose = 25 mg
5000
3000
120
2
14
2
0
14
Time (days)
500
20
multiplicative error
additive error
w2 Kgw1
0
0
4
8
12
16
20
24
0
4
8
12
time (hr)
median
5th
95th
16
20
24
Placebo group
time (hr)
actual data
median
5th
95th
actual data
Rat PK/Tox model describes the data with a reasonable uncertainty.
A time effect for the baseline was added in the model due to the experimental
data as shown below. This was also described and modelled in literature (3).
It’s important to note that the rats were immunosuppressed which explain the
low Circ0 value.
Dose of 15mpk weekly
6
Parameters
Circ0 (106/mL)
MTT (h)
GAM
slope (mL/ng)
time effect
Estimates
1.2
49.7
0.469
0.00182
0.00112
%SEE
7.98
2.56
6.12
11.5
27.7
9
8
5
7
neutrophil counts (109/L)
27
actual data
2000
4
3
2
6
5
4
3
2
1
1
0
0
0
168
336
504
672
0
168
5th
95th
0.106 (32.6%)
0.889 (94.3%)
additive error
multiplicative error
0.46
61.40%
28
60
504
672
504
672
time (hr)
actual data
median
Dose 30mpk weekly
w2 Circ0
w2 slope
336
time (hr)
median
5th
95th
actual data
Dose of 45mpk weekly
10
12
9
10
8
7
Neutrophil counts (109/L)
28.5
95th
neutrophil counts (109/L)
433
0.109 (33%)
0.599 (77.4%)
2
5th
%SEE
5.46
12.4
7.03
11
3500
plasma concentration (ng/mL)
0.0166 (12.9%)
w2V2
plasma concentration (ng/mL)
w2Ka
24
Estimates
0.196
220
60.9
0.00503
Dose of 10mpk IV
160
w2CL
20
Parameters
Kgw1, zero order (/day)
Kgw2, first order (mg/day)
TS0 (mg)
Kdth (mL/h/ng)
neutrophil counts (109/L)
0.378
0.465
16
time (hr)
time (hr)
median
Ka (h-1)
F
Dose = 15 mg
800
Tumor Size (mg)
plasma concentration (ng/mL)
plasma concentration (ng/mL)
% SEE
6.22
18.9
18.5
16.6
14
Dose = 10 mg
1000
300
Estimates
0.613
2.7
2.21
2.19
2
Control
1200
350
Parameters
CL (L/h)
V2(L)
Q (L/h)
V3 (L)
 Rat PK/efficacy model was better define with a modified Gompertz model
Dose of 30mpk PO
Dose of 10mpk PO
absorption
6
5
4
8
6
4
3
2
2
1
0
0
0
168
336
504
672
0
168
336
time (hr)
median
5th
95th
time (hr)
actual data
median
5th
95th
actual data
RAT SIMULATION RESULTS
Rat Simulation: exploratory relationship
weekly dosing Q7d*3 at 15, 20, 30, 40mpk IV 1hr infusion
1.45
15
1.40
fold decrease from baseline
(neutrophils account)
1.35
11
1.30
1.25
9
1.20
7
1.15
5
1.10
fold decrease from placebo on D28 (tumor
size)
13
In order to correlate the efficacy and the myelosuppression rat models, some simulations were performed at several doses.
The figure below represents in function of AUC(0-168h), the fold decrease of tumour volume and the fold decrease of
neutrophil count. In this figure, the curve of the toxicity is following the curve of the tumour growth decrease.
Based on this, the starting targeted efficacious exposure in rats is 5700ng*h/mL.
3
1.05
1.00
0
2000
4000
6000
8000
10000
12000
14000
1
16000
predicted AUCweekly (ng*h/mL)
PD neutrophils
HUMAN SIMULATION RESULTS
Efficacy
Human PK and PD simulations in terms of neutrophil count were generated after adaptation of the rat PD parameters from literature data.
It was performed following one or two injections per 21-day cycle for the same total dose per cycle.
Human median Neutrophil account simulations
at several doses twice per cycle D1 and D8 over 2 cycles (21days)
5.5
Human median Neutrophil account simulations
at several doses once per cycle over 2 cycles (21days)
5.0
6.0
4.5
5.5
Neutrophil count (109/L)
4.5
4.0
3.5
3.0
2.5
2.0
1.5
grade 2
1.0
grade 3
0.5
Compound X given twice per cycle gave a more prolonged nadir
compare to a single administration over the cycle. This has been noticed
for 5-FU in literature (4). These two sets of simulations suggested that,
upon one dose every 21 days, a dose range of A to E should be required
to reach efficacy and to have a manageable neutropenia.
grade 4
Neutrophil Count (109/L)
4.0
5.0
3.5
3.0
2.5
2.0
1.5
grade 2
1.0
grade 3
0.5
grade 4
0.0
0
0.0
0
168
Amg median
336
Bmg median
504
time (hr)
Cmg median
Dmg median
672
840
Emg median
168
336
1008
504
672
840
1008
time (hr)
Amg median
Time of the Dose
Bmg median
Cmg median
Dmg median
Emg median
CONCLUSIONS
This modelling study combined both efficacy and toxicity rat data within one fully integrated mechanistic model.
This integrated model described the rat data adequately and helped connect efficacy and toxicity outcomes.
The model was translated to human to derive an efficacious and safe dose range for the FHD study.
References: 1. Simeoni et al, Cancer Res 2004;64:1094-1101, 2. Friberg LE et al, J Clin Oncol 2002;20: 4713-4721. 3. Segura et al, Pharm Res 2004:21:567-572, 4.
Friberg LE et al, J Pharmacol Exp Ther 2000;295:734-740
Time of Dose