"Future Considerations For PK/PD Research": Terrence F. Blaschke, M.D

“FUTURE CONSIDERATIONS
FOR PK/PD RESEARCH”

Terrence F. Blaschke, M.D.
Professor of Medicine and Molecular Pharmacology
Stanford University
Issue for discussion:
Can PK/PD modeling help to devise

dosage regimens that will have better
efficacy and/or safety without adding
time/cost to drug development?
Premise:
• There is a need for alternative dose-finding
methods since all reasonable regimens cannot be
studied using the current standard of a 48 week
controlled study of efficacy and safety
– Patient resources are limited
– Time requirements would be excessive, and delay
patient access to alternative regimens
– HIV therapeutics is a fast-moving field, and approved
regimens may not be acceptable as controls to patients
or investigators
Combinatorials: the numbers problem
IF: n!
M=
p!(n-p)!
FOR: n=31 M=4495
(p=3)
n=23 M=1771
n=14 M=364
n=6 M=20
“PK/PD Modeling”
What is meant by this expression?
Pharmacokinetics (PK) describes the time
course of drug concentrations in plasma (and
sometimes in other fluids and tissues) resulting
from a particular dosing regimen
Pharmacodynamics (PD) expresses the

relationship between drug concentrations in
plasma (and sometimes in other fluids and
tissues) and a resulting pharmacological effect
A PK/PD Model combines
• A model describing drug concentrations vs.
time (PK) with
• A model describing the relationship of effect
vs. concentration (PD), and
• A statistical model describing variation in
intra- and inter-individual PK/PD models
to predict the time-course and variability of effect
vs. of time.
Note: Only mechanistic PK/PD models can be

relied upon for extrapolation (I.e., for prediction vs.
description)
Process:
• Build PK Model
• Build PD Model
• Link PK and PD models
• Simulate treatment regimens or trials for
useful predictions
An Example:
(Next few slides courtesy of Abbott
Laboratories and Pharsight Corporation)
This simple model links adherence,
pharmacokinetics, and viral pharmacodynamics to
treatment outcome in a patient population.
Antiretroviral Experience,
Disease Severity
Prescribed
PI Doses Actual Plasma
Dose Pharmaco- Conc
Adherence Pharmaco- Viral
kinetics dynamics Load
Data MEMS data, Two multiple-dose In-vitro data,

Source Public literature Phase I studies,
One Phase II study
Model Random, Two one-comp. Standard two-strain

(beta distribution) PK models with viral model
fractional adherence rate enzyme inhibition
and induction
Pharmacokinetic Modeling: The PK model accounts for
dose-dependent bioavailability, competitive inhibition, and
exposure-dependent enzyme induction.
Enzyme
induction
when
Fraction
applicable
Absorption Time
Elimination
PI Absorbed
When Site
Plasma
Applicable
Competitive
Enzyme
Inhibition
Fraction Absorption
RTV Absorbed
Site Plasma
Enzyme
Time Induction
Pharmacodynamic Modeling
The model was previously published.# This simple PD model includes two
viral strains (wild type and a pre-existing mutant), long-lived infected and
actively infected cells, and different sites of action by PIs and NRTIs.
r. t. r. t.
inhibitors inhibitors
infect mutate: mutate: infect V2
V1
T T
m1 m2
virus: virus:
1 = wild-type release 1–m1 1–m2 release 2 = mutant
protease protease
TA1 actively infected TA2
inhibitors inhibitors
TL1 long-lived cells TL2
#
Hsu A, Wada DR, Liu M et al., PK/PD Modeling of ABT378/Ritonavir Clinical Trials,
Including an Adherence Factor. Seventh European Conference on Clinical Aspects and
Treatment of HIV Infection, 1999, Oct 23-27.
Simulation
– For assessing the effect of PK and adherence variability,

400 subjects were simulated for 48 weeks for each of
the six regimens, for a dose-time perturbation of 1.6 hr.
Adherences with a beta distribution and with a mean of
81% and SD of 0.20 were used for BID regimens, and a
mean of 84% and SD of 0.19 were used for QD
regimens.
Abbott used this approach to compare various
combinations PI dosing regimens which
included low and moderate dose ritonavir and
were able to predict:
• The range of peak and trough concentrations for
each of the PI’s in the regimen, and the ratio of
trough concentrations to IC50 values
• The effect of varying degrees of nonadherence on
the fraction of patients who were likely to experience
virological failure
The PK/PD model and the simulations done with

it were observed to be consistent with data from
several actual trials carried out by Abbott
Building and Evaluating PK/PD Models
• PK models
– As part of conventional PK studies,
information on inter- and intra-subject
variability is needed
– For drug combinations, interactions should
be evaluated at steady-state with dose
regimens that include/bracket those likely to
be used
– Consider measuring binding proteins such as
1 acid glycoprotein and unbound drug
concentrations
Prescribed
Dose Pharmaco- Conc
Model Single-coin model, Two one-comp. Standard two-strain

beta distribution PK models with viral model
of fractional adherence enzyme inhibition
and induction
Antiretroviral
Experience,
Disease Severity
Data MEMS data, Two multiple-dose
Source Public literature Phase I studies, In-vitro data,
One Phase II study
DATA NEEDED TO CREATE PK/PD MODELS

(Much of it is pre-existing scientific knowledge!)
• PD models
– Require a combination of in vitro and in vivo
data incorporated into a mechanistic model of
viral dynamics (which incorporates baseline
CD4, HIV RNA copy number, possibly prior
treatment as well)
• Relate in vitro and in vivo sensitivities using early
monotherapy data from naïve subjects with wild-type
virus
• Expand model to pretreated patients using additional
in vitro data using various resistant mutants found in
vivo
Prescribed
Dose Pharmaco- Conc

and induction
Antiretroviral
Experience,
Disease Severity
One Phase II study

In Vitro Pharmacokinetic-Pharmacodynamic System
• Evaluate PK/PD model by comparing outcome of
trial simulations to actual data from trials in
experienced patients
– Response variables: treatment failure and/or presence of
genotypic or phenotypic resistance
– Must incorporate realistic estimates of drug-taking
behavior into the simulation
• For the clinical trial used for comparison, actual
measures of adherence would be preferable since the
effect of different adherence patterns on resistance
development is not known
Prescribed
Dose Pharmaco- Conc

and induction
Antiretroviral
Experience,
Disease Severity
One Phase II study

A simple PK/PD relationship
to help understand the
potential consequences of
changes in dose regimens or
formulations
Concentration-Response Relationships for Different Quasispecies
100
90
80
70
60
50
40
30
20
10
1 10 100 1000 3000
Concentration (ng/ml)
EC50=3
100 0
90
80
Dosing Times
70 8
60
50
40 16
30
20
10 24
1 10 100 1000 3000
EC50=3
99%Inhibition @ trough
100 0
90
80
Dosing Times
70 8
60
50
40 16
30
20
10 24
1 10 100 1000 3000
EC50=3
(Note that the overall antiviral response is

the integrated response over time)
100 0
90
80
Dosing Times
70
60
12
50
40
30
20
10 24
1 10 100 1000 3000
EC50=3
100 98%Inhibition @ trough 0
90
80
Dosing Times
70
60
12
50
40
30
20
10 24
1 10 100 1000 3000
EC50=3
100 0
90
80
Dosing Times
70
60
50
40
30
20
10 24
1 10 100 1000 3000
EC50=3
100 96%Inhibition @ trough 0
90
80
Dosing Times
70
60
50
40
30
20
10 24
1 10 100 1000 3000
EC50=3
100
90
80
70
60
50
40
30
20
10
0
1 10 100 1000 3000
EC50=3 EC50=12
100 0
90
80
70
Dosing Times
8
60
50
40
16
30
20
10
0 24
1 10 100 1000 3000
EC50=3 EC50=12
100 0
90%Inhibition @ trough
90
80
70
Dosing Times
8
60
50
40
16
30
20
10
0 24
1 10 100 1000 3000
EC50=3 EC50=12
100 0
90
80
70
Dosing Times
60
50 12
40
30
20
10
0 24
1 10 100 1000 3000
EC50=3 EC50=12
100 0
90 85%Inhibition @ trough
80
70
Dosing Times
60
50 12
40
30
20
10
0 24
1 10 100 1000 3000
EC50=3 EC50=12
100 0
90
80
70
Dosing Times
60
50
40
30
20
10
0 24
1 10 100 1000 3000
EC50=3 EC50=12
100 0
90
80 72%Inhibition @ trough
70
Dosing Times
60
50
40
30
20
10
0 24
1 10 100 1000 3000
EC50=3 EC50=12
PK/PD modeling for AIDS:
Where do we stand today?
• PK models for antivirals are generally
well-defined
• Several good models of viral dynamics
have been developed
• For PIs and NNRTIs, plausible
mechanistic relationships between drug
concentrations in plasma and inhibition
of viral replication have been proposed
General PK/PD modeling:
Where do we stand today?
• Although simulations using full, mechanistic
PK/PD models are consistent with observed
data, the robustness of such models in a variety
of settings and dosing regimens has not yet
been demonstrated
• It is too soon to conclude that PK/PD modeling
can substitute for confirmatory trials
PK/PD modeling: Where do
we go from here?
• Continue to improve and refine
mechanistic PK/PD models, using in
vitro and in vivo data
– for individual drugs, in vitro data needs to be
related to in vivo data, including the effect of
protein binding, early in development when
monotherapy data are being generated
• Generate concentration-response data
in early development
we go from here?
• Use PK/PD models to plan trials, limiting
dosing regimens and drug combinations
to those likely to demonstrate acceptable
efficacy/toxicity, and be robust to non-
adherence
• Measure adherence as part of the trial
we go from here?
• Consider whether PK/PD modeling
based on short term (e.g.,  24 weeks)
studies can be used as surrogate
evidence of long term efficacy
– Differences in outcome between 24 and 48
weeks are more likely due to non-
adherence rather than regimen failure
(use-effectiveness vs. method
effectiveness)

"Future Considerations For PK/PD Research": Terrence F. Blaschke, M.D

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“FUTURE CONSIDERATIONS

FOR PK/PD RESEARCH”

Can PK/PD modeling help to devise

Pharmacodynamics (PD) expresses the

Note: Only mechanistic PK/PD models can be

Data MEMS data, Two multiple-dose In-vitro data,

Model Random, Two one-comp. Standard two-strain

TL1 long-lived cells TL2

– For assessing the effect of PK and adherence variability,

The PK/PD model and the simulations done with

Model Single-coin model, Two one-comp. Standard two-strain

DATA NEEDED TO CREATE PK/PD MODELS

Model Single-coin model, Two one-comp. Standard two-strain

DATA NEEDED TO CREATE PK/PD MODELS

Model Single-coin model, Two one-comp. Standard two-strain

DATA NEEDED TO CREATE PK/PD MODELS

(Note that the overall antiviral response is

100 98%Inhibition @ trough 0

100 96%Inhibition @ trough 0

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