OBJECTIVES

1
Modelling of PK/Efficacy/Toxicity in rats to help
design a FHD for a Cell Cycle Inhibitor X Celine
Pitou, PharmD1 Sophie Glatt, PhD3Inaki
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.

• 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.

• 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.

• 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
  (19.48-68.41), 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 absorption

• Rat PK/efficacy model was better define with a
  modified Gompertz model

• 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). Its important to note that the rats were
  immunosuppressed which explain the low Circ0
  value.

RAT SIMULATION RESULTS
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 5700ngh/mL.
HUMAN SIMULATION RESULTS
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.
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.
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
2004641094-1101, 2. Friberg LE et al, J Clin
Oncol 200220 4713-4721. 3. Segura et al, Pharm
Res 200421567-572, 4. Friberg LE et al, J
Pharmacol Exp Ther 2000295734-740