A Population PK/PD Model Assessing the Pharmacodynamics of a Rapid-acting Recombinant FVIIa Analogue, NN1731, in Healthy Male Subjects .

1
A Population PK/PD Model Assessing the
Pharmacodynamics of a Rapid-acting Recombinant
FVIIa Analogue, NN1731, in Healthy Male Subjects
.

• Andreas Groth1, Judi Møss2, Tine Møller3, Steen
  H. Ingwersen11Biomodelling, 2Medical and
  Science, NovoSeven Key Projects, 3Biostatistics,
  Novo Nordisk A/S, Copenhagen, Denmark
  avg_at_novonordisk.com

Conclusions An appreciable dose-concentration-resp
onse relationship between NN1731 and F12 was
expressed in a population PK/PD model. Since F12
appearance traces the formation of thrombin, this
relationship supports the possibility of using
F12 as a biomarker for haemostatic agents.
Aims To explore the potential of prothrombin
fragments 12 (F12) as a biomarker for
haemostatic agents with a model of the effects of
the FVIIa analogue NN1731. Background Haemophilic
patients suffer a defect in blood coagulation
due to lack of either coagulation factor VIII or
IX. In some patients, replacement therapy with
the lacking coagulation factor eventually results
in the formation of antibodies (inhibitors).
Inhibitor patients may be treated with by-passing
agents such as activated human coagulation factor
FVII (FVIIa, NovoSeven?). NN1731 is a FVIIa
analogue that in vitro has shown increased
activity in stimulating the cleavage of
prothrombin to thrombin and F12, a key step in
the coagulatory pathway1. F12 was measured in
the first clinical trial with NN1731, a dose
escalation trial with 4 dosing arms. NN1731 and
F12 plasma concentrations were related to NN1731
doses to establish a population PK/PD model
treating F12 as a PD biomarker.
References 1 E. Persson et al, Proc Natl Acad Sci
U S A, 9613583,2001
A sketch of the pro-coagulatory actions of
thrombin, also known as coagulation factor IIa.
Thrombin activates several coagulatory proteins
and these actions cascade down eventually leading
to the formation of cross-linked fibrin (CLIa)
which forms the actual blood clot.
Methods

• Strategy
• Develop PK-model from NN1731 plasma concentration
  data.
• Develop PD-model from individual post-hoc PK
  model parameters and F12 plasma concentration
  data.
• Data source (3 pre- and 10 post-dose PK samples
  1 pre- and 5 post-dose PD samples) ? 6 healthy
  subjects ? 4 active (non-zero) dose levels. Dose
  range 5 µg/kg-30 µg/kg
• Modelling PK and PD in man was modelled
  sequentially using NONMEM V with FOCE. Regarding
  inter-individual variability (i.i.v.) on model
  parameters, log-normal distributions were tested
  for significance against the hypotheses of zero
  i.i.v on that parameter (which is why the
  geometric, rather than the arithmetic, post-hoc
  estimate means are displayed on fig. 4).

Results
Figure 1. Structure of PK/PD model
Figure 2. Fit of PK/PD model
PK/PD model parameters
10 ?g/kg
5 ?g/kg
Model parameter V1 V2 CL Q B kout E
Unit ml/kg ml/kg ml/kg/h ml/kg/h pM 1/h pM/h/IU/ml)
Estimate 59.6 78.0 (14) 120 (14) 38.6 132 (29) 0.346 0.164 (46)
S.E. of estimate 2.2 4.0 4.5 2.0 11 0.048 0.042
The PK/PD model predictions of the F12 time
profiles for each trial subject as well as for
the typical subject are shown along with the
observations and their means for each dose level.

V1, V2 central peripheral volumes of
distribution, CL clearance, Q
intercompartmental clearance, B baseline F12
level, kout rate constant for F12, E NN1731
efficacy Values in parenthesis Coefficients of
Variation (CVs) regarding i.i.v. for each
parameter.
30 ?g/kg
20 ?g/kg
The resulting PK model was a standard
two-compartment model with inter-individual
variability (i.i.v.) on CL and V2. The PD model
was a linear indirect response model with the
plasma concentration of NN1731 affecting the
formation of F12 , incorporating i.i.v. on
baseline F12 levels (B) and the efficacy
parameter (E) . The F12 formation rate at the
baseline state Cp0 equals B ? kout .
Figure 3. Dose-independence check of PK model
Figure 4. Dose-independence check of PD model
B (pM)
V2 (ml/kg)
E pM/h/(IU/ml)
CL ml/kg//h
o Individual post-hoc estimates Geometric
mean of individual post-hoc estimates
NN1731 dose (µg/kg)
NN1731 dose (µg/kg)
NN1731 dose (µg/kg)
NN1731 dose (µg/kg)
o Individual post-hoc estimates Geometric
mean of individual post-hoc estimates
The individual post-hoc parameter estimates in
the PD model were also checked for dependence on
NN1731 dose. The result is less clear-cut than
that of the PK parameters (fig. 3), but since the
ranges of values for the lowest and the highest
dose are quite similar for the efficacy parameter
E, it is concluded that the NN1731
concentration-PD response relationship is well
described.
Post-hoc parameter estimates of CL and V2 were
checked for dose independence. Such a dependence
appears to be absent for both parameters,
indicating that the PK model is valid over the
studied dose-range.