DEVELOPMENT OF AN INTEGRATED POPULATION PHARMACOKINETIC MODEL FOR IMMEDIATE RELEASE AND CONTROLLED RELEASE FORMULATIONS OF AN INVESTIGATIONAL COMPOUND IN HEALTHY SUBJECTS AND SCHIZOPHRENIA PATIENTS Vikas Kumar*1, Kevin Sweeney1, Diane Mould2, Jing

1
DEVELOPMENT OF AN INTEGRATED POPULATION
PHARMACOKINETIC MODEL FOR IMMEDIATE RELEASE AND
CONTROLLED RELEASE FORMULATIONS OF AN
INVESTIGATIONAL COMPOUND IN HEALTHY SUBJECTS AND
SCHIZOPHRENIA PATIENTS Vikas Kumar1, Kevin
Sweeney1, Diane Mould2, Jing Liu11Pfizer Global
Research and Development, Groton/New London, CT
06320, 2Projections Research Inc., Phoenixville,
PA
RESULTS
RESULTS
INTRODUCTION

•  
• Schizophrenia is a severe, chronic mental illness
  and ranked as fifth for the leading cause of
  years lived with a disability by WHO
• Available treatments for schizophrenia are often
  only partially effective residual symptoms are
  present in the majority of stabilized patients
• PF-XYZ is being developed to treat negative and
  cognitive symptoms in adjunctive treatment of
  patients with schizophrenia
• PF-XYZ is currently in Phase-II development for
  schizophrenia
• Currently, both immediate release (IR) and
  controlled release (CR) formulations are used for
  the development of PF-XYZ
• Data from six studies (FIH to Phase-IIa stage) is
  used for the development of PopPK model

Individual Model Predicted Clearance vs Patient
Status (Left) and CYP2D6 Metabolizer Status
(Right)
Population PK Parameter Estimates from Final Model
Pharmacokinetic Parameter (Unit) Estimate ( RSE) 95 CI
Ka for IR formulation (Hr-1) 1.67 (6.7) 1.45, 1.89
MTT for CR formulation (Hr) 8.29 (2.6) 7.86, 8.73
CL/F (2D6 EM) (L/Hr/70 Kg) 127 (4.4) 116, 138
CYP2D6 IM ( Reduction) 21.2 (49) 1.60, 40.8
Female ( Reduction) 35.5 (30) 13.9, 57.1
Vc/F (L/70 Kg) 558 (3.7) 518, 598
Vp/F (L/70 Kg) 176 (6.4) 154, 198
Q/F (L/Hr/70 Kg ) 27.1 (11) 21.4, 32.8
Tlag for IR formulation (Hr) 0.281 (14) 0.202, 0.359
Variance Variance Variance
w2Ka 0.58 (22) 0.33, 0.83
w2CL/F 0.44 (16) 0.31, 0.57
w2Q/F 0.29 (46) 0.04, 0.56
Residual Variance 0.34 (4.2) 0.31, 0.37
OBJECTIVES

•  
• To develop an integrated population PK model for
  immediate release and controlled release
  formulations of PF-XYZ
• To describe PF-XYZ pharmacokinetics in healthy
  subjects and stable chronic schizophrenia
  patients on background therapy of second
  generation of antipsychotics
• To evaluate intrinsic and extrinsic covariates
  that may be important determinants of PF-XYZ
  exposure
• o provide post-hoc predictions from the PopPK
  model that will be used in sequential PK/PD
  analyses

• Food was estimated to increase the
  bioavailability of CR formulation by 18
• High correlation (91) was observed between
  random effects of CL/F and Vc/F (Figure below)
  therefore shared eta was used in final model for
  parsimonious ? structure
• No difference in CL/F was observed between HV and
  patient population

STUDIES INCLUDED FOR ANALYSIS
PHARMACOKINETIC MODEL
DIAGNOSTIC PLOTS
VISUAL PREDICTIVE CHECK
METHODS MODELING STRATEGY
Visual Predictive Check using Observed
Concentrations from One Dose (symbols) and 90
Prediction Interval (shaded area)
Goodness of Fit Plots Observed vs Predicted in
Normal Scale (Left) and Log Scale (Right) Final
Model
The population PK model was developed by pooling
the data from four phase I studies and two
studies in schizophrenia patients.
Pharmacokinetic models were fit to the data
using First Order Conditional Estimation (FOCE)
method in NONMEM version 7. Both one- and
two-compartment models were evaluated. Absorption
profiles obtained from IR and CR formulations
were modeled simultaneously. First order
absorption with or without lag time was explored
for IR formulation and a transit compartment
model was used for the CR formulation. As PF-XYZ
is primarily metabolized by CYP2D6, the effect of
CYP2D6 phenotype was added in the base model.
For the final model development, various
covariates-parameter were explored graphically
and then added to the final model with care to
avoid co-linearity in predictors. In the final
model, one dichotomous covariate (gender) was
included to quantify the impact on CL/F. Also, an
allometric model with weight normalized to 70 kg
was used for the estimation of CL/F, Vc/F, Vp/F
and Q/F. Proportional or additive proportional
error models for both normal and log transformed
data were explored for residual variability. Log
normal distributions were used to characterize
the inter-individual variability of
pharmacokinetic parameters. Selection of the
appropriate structural, variance, and error
models was based on the change in the objective
function value, visual inspection of goodness of
fit plots, precision of the parameter estimates,
as well as decreases in both between-subject
variability and residual variability. The final
population PK model was evaluated using visual
predictive check.
Goodness of Fit Plots CWRES vs Time (Left Final
Model) Correlation of ETAs (CL/F vs Vc/F)
(Right Base Model)
CONCLUSIONS

• Overall, the final population PK model provided a
  good description of the IR and CR data
• No differences were observed in the PK of healthy
  subjects and patient population
• CYP2D6 phenotype and gender were found to be
  significant covariates for oral clearance
• Food increases the bioavailability of PF-XYZ CR
  formulation by 18
• Predicted concentrations from the final PopPK
  model were used to build sequential PK-PD model