Modeling & Simulation Toolkit

Inside
2 Introduction Modeling and simulation have become indispensable in drug
development and of increased interest by global regulatory authorities
3 Quick Guide: Types of Modeling and potential investors. With modeling and simulation, your existing
& Simulation data can answer many important drug development questions and
potentially save your program significant time and money.
10 Blog: What is the Difference Between
PBPK & PopPK Modeling? Existing and prospectively collected data from your compound, as well
as literature data on similar compounds, can be leveraged to provide
14 Blog: How to Avoid Clinical Trials important insights on product safety and effectiveness due to variability
Using Modeling & Simulation in drug concentrations. These insights can also be used to select dose
regimens to optimize benefit-risk ratio, assess the need to adjust the
20 Additional Resources dose for intrinsic and extrinsic factors, inform clinical trial design,
predict trial outcomes, and more.

Use this toolkit to learn how modeling and simulation can make
clinical trials more efficient and even be used to potentially avoid
certain clinical trials completely. We hope that you find this
information helpful to your program’s overall development strategy.

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 Quick Guide:
Types of Modeling & Simulation

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Quick Guide: Types of Modeling & Simulation
INTRODUCTION
This is a quick guide to modeling and simulation in drug development.
First, we will briefly cover model-informed drug development as an
overall drug development strategy. Next, we will review four major
types of modeling to support a model-informed drug development
strategy which are quantitative systems pharmacology, population
pharmacokinetics, physiologically-based pharmacokinetics, and
exposure-response. Lastly, we will summarize three specialized types
of modeling that are used to address specific questions which include:
allometric scaling, concentration-QT analysis, and in vitro in vivo
correlation.
MODEL-INFORMED DRUG DEVELOPMENT AS AN
OVERALL STRATEGY
MIDD is useful at any stage of development but is most beneficial
when it is integrated early and continuously to help guide effective pro-
gram decisions. Some decisions that MIDD can inform along product
development include:
• Selecting the optimal dose for Phase 1-3 clinical trials and the
product label
• Understanding factors that may contribute to variability in
safety, efficacy, and pharmacokinetics (PK)
• Predicting exposure relative to safety and toxicology thresholds
• Optimizing the design of Phase 2/3 clinical trails
• Bridging between formulations, populations, or indications
• Likelihood of meeting the target product profile

Model-informed drug development (MIDD), previously referred to • Mechanistic understanding

as model-based drug development (MBDD), is a process whereby
key program decisions are supported by mathematical models and
simulations that predict the likelihood of success for the drug in the
treatment of a particular disease using the optimum dose.
The concept of a MIDD paradigm as defined by the most recent FDA
guidance states, “MIDD approaches use a variety of quantitative
methods to help balance the risks and benefits of drug products in
development. When successfully applied, MIDD approaches can
improve clinical trial efficiency, increase the probability of regulatory
success, and optimize drug dosing/therapeutic individualization in the
absence of dedicated trials.”

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Major Types of Modeling
1. QUANTITATIVE SYSTEMS PHARMACOLOGY
Quantitative systems pharmacology (QSP) is an exciting and powerful
convergence of biological pathways, pharmacology, and mathematical
models for drug development. Individually, the concepts and com-
ponents of QSP (understanding the interaction of drugs in biological
systems) are not new. However, merging these disciplines has the
potential to significantly impact modern medicine by facilitating the
discovery and utilization of newly identified molecular pathways and
drug targets, especially in the pursuit of new therapeutics and individu-
alized medicine.
QSP is a computational method that mechanistically describes the
interaction of the drug in the body. QSP models can be informed by in
vitro data (e.g., receptor interaction), animal models (biomarker re-
sponse in animal models of disease), and clinical endpoints in patients.
Utilizing big data (i.e., genomics, proteomics, metabolomics), QSP can
help guide appropriate study design or suggest additional experiments
to make more informed drug development decisions. Similarly, QSP
can significantly reduce missteps that might prolong the drug develop-
ment process or even result in an unnecessary failure.
QSP can be leveraged to identify novel therapeutic targets, verify
new therapeutic approaches to current targets, design virtual patient
populations, and predict clinical exposure-response and efficacy out-
comes for the design of early clinical trials. QSP has benefited from
the insights gained in developing physiological based pharmacokinetic
(PBPK) models (ex. predicting PK outcomes by differences in physio-
logical variables) and has truly taken the power of systems biology and
pharmacodynamics (PD) to a new level.
The key difference between QSP and PBPK is that PBPK is most
frequently intended to predict PK outcomes in patient populations,
whereas QSP focuses on prediction of PD and clinical efficacy out-
comes in these patients. QSP involves development of mathematical
models (e.g. ordinary differential equations) to describe biological
systems relevant to a specific therapeutic target and to understand the
mechanism(s) of action. These models are then used to predict clini-
cally relevant PD responses (i.e. predicting heart-rate changes, muscle
growth rate, etc.). The QSP approach can be particularly useful during
early development when attempting to predict pharmacodynamic
effects in humans based on early nonclinical in vitro and in vivo data.
Ideally, QSP is applied throughout the drug development process,
from preclinical through clinical development, to harness its true
power and capacity. For example, in programs where the first clinical
study will be in a patient population such as in a rare disease or in cell
and gene therapies, the need to predict a therapeutic dose for the first
in human dose is crucial. QSP offers the ability to help make these
critical and ethical decisions with more confidence.
QSP can incorporate evolving nonclinical and clinical data to better
inform development decisions such as identification of novel indica-
tions, selection of doses, and evaluation of a drug’s potential to have a
clinically meaningful impact for patients. QSP can be employed at all
stages of drug development (preclinical to Phase 3). Nuventra’s consul-
tants have many years of experience designing quantitative and trans-
lational pharmacology strategy.
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Major Types of Modeling
2. POPULATION PHARMACOKINETICS
Population pharmacokinetics, also referred to as population PK or
popPK, seeks to understand the variability in drug concentrations
among individuals in a group of interest (i.e. the “population”)
receiving clinically relevant doses of a drug.
Because patient characteristics (“covariates”), such as age, disease state,
demographics, sex, concomitant medications, or presence of renal or
hepatic impairment, can affect drug PK, understanding this variability
can help characterize a robust PK profile and inform safe and effective
dosing regimens.
Population PK analysis involves collecting rich PK samples from some
subjects (like in Phase 1 and 2 studies) and sparse PK samples from
many patients often across multiple clinical studies (like in some Phase
2 and 3 studies), and then building mathematical models to describe
those data. With appropriate sampling design and model selection, the
resulting PK data can be pooled and analyzed to support conclusions
about PK variability and the influence of covariates.
PopPK analyses are a crucial aspect of almost all drug development
programs. Because of the growing emphasis placed on popPK analyses
by regulatory authorities, and the wealth of information that these
analyses provide, it is more important than ever to consider how
popPK fits into your own drug development program.
3. PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING
Typical popPK models describe concentrations over time using empir-
ic models. In contrast, PBPK modeling is a compartment and flow-
based type of PK modeling and relatively easy to conceptualize. In
PBPK models, each compartment represents a physiologically discrete
entity, such as an organ or tissue, and mass [drug] transfer is described
using the blood flow into and out of those entities. In theory, if a PBPK
model contained a compartment for each organ in the body, it could
facilitate the simultaneous description of drug concentration changes
over time in each organ.
Because PBPK models are constructed with such granular detail, they
can help answer very specific questions. For example, the molecular
signature of a disease can be incorporated into a PBPK model by
altering key parameters to help predict how drug concentration will
change in a specific patient population. This type of prediction can
help inform dosing recommendations or influence the design of clinical
trials when evaluating a drug for a new indication.
PBPK models will have many more assumptions than an empiric pop-
PK model. Therefore, it is key to discuss your objectives for the model
before deciding whether to use a popPK model or a PBPK model. A
pharmacometrics expert can discuss the options with you and help
guide you on which is more appropriate depending on your objec-
tives. Read more about PBPK and the differences between PBPK and
popPK modeling in the next section of this toolkit: What is the Difference
Between PBPK and PopPK Modeling?
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Major Types of Modeling
4. EXPOSURE-RESPONSE MODELING
For a drug to show efficacy or toxicity, it has to reach the organ of
interest (e.g., site of action). However, for most drugs, we cannot
measure drug concentrations at the site of action directly (e.g., CNS,
muscle tissue). Instead, we measure plasma drug exposure and clinical
endpoints and develop a model to correlate plasma drug exposure to
the response endpoints. The exposure-response model can be as simple
as a linear, Emax, or logistic model to correlate steady-state AUC/
Cmax to the response endpoints, or can be as complicated as a full
population PK/PD model that correlates plasma concentration-time
data to the response endpoints. Further, there could either be a direct
relationship between exposure and response or a delayed or indirect
relationship between exposure and response. Different exposure-
response models can be set up depending on the biological mechanism
of action.
For many drugs, it may be difficult (e.g., GI drugs) or impossible (e.g.,
dermatology drugs) to evaluate the relationship between exposure and
response. It is also important to understand issues around the schedule
for collection of the endpoints and any plasma concentrations. For
example, if you have too few samples, you may not be able to model
exposure-response. In contrast, if an endpoint is collected six or more
times in a subject, then you may be able to use a longitudinal exposure-
response model, which can be very informative for many drug
development questions. When exposure-response models are available,
efficacy and safety data may be extrapolated to new dosing regimens,
new populations, or dosage forms through clinical trial simulations,
without doing a clinical efficacy and safety study.
If an exposure-response model is attempted but cannot be developed
because an exposure-response relationship is not apparent, this just
means that if you change the dosing regimen, you need to confirm that
the change is appropriate by conducting a clinical trial.
The FDA’s exposure-response guidance states that “exposure-response
information can support the primary evidence of safety and/or
efficacy.” In some circumstances, exposure-response information can
provide important insights that can allow a better understanding of
the clinical trial data (e.g., in explaining a marginal result on the basis
of knowledge of systemic concentration-response relationships and
achieved concentrations). The guidance also allows for the use of dose
as a measure of exposure, when PK data are not available.
This part of the guidance is especially important for rare diseases
where it is difficult to conduct efficacy trials (particularly after a
treatment has been shown in one study to be efficacious). Another area
that exposure-response models may be used as confirmatory evidence
of effectiveness is for drugs where the mechanism of action is well
known and the safety has been well characterized in other indications.
Talk with a pharmacometrician to find out how exposure-response
can serve as primary evidence of effectiveness or add to the weight of
evidence for effectiveness.
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Specialty Types of Modeling
1. ALLOMETRIC SCALING
Allometric scaling is one of the tools that drug developers use to pre-
dict human PK based upon animal data prior to a first time in human
(FTIH) study. Methods like allometric scaling provide a prediction
of how a drug might behave in humans before any clinical studies
are conducted by accounting for differences in the pharmacokinetic
parameters (clearance, volume) based on species-dependent differences
in body weight. This is important information for both drug developers
and regulators (like FDA) because it provides a data-driven foundation
for establishing a conservative starting dose in humans.
Predictions from allometric scaling allow go/no go decisions about
drug candidates, support selection of safe FTIH doses and allow hu-
man studies to be effectively designed to obtain safety and PK infor-
mation. Allometric scaling can also be used to predict the right dose by
scaling data from adults to pediatrics and vice versa.
Overall, allometric scaling is frequently used in drug development to
inform strategies including:
• Understanding the doses needed in toxicology studies
• Selecting a starting dose and designing dose escalation strategies for
FTIH studies
• Predicting the minimally anticipated biological effect level
(MABEL) dose used to select your FTIH dose
• Evaluating the therapeutic index early in drug development
• Predicting drug exposure and toxicity for early phase studies
• Designing a blood sample collection schedule to calculate PK and
other parameters
• Finding the best dose to study in pediatric patients
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Specialty Types of Modeling
2. CONCENTRATION-QT ANALYSIS
An internationally accepted modeling and simulation approach
called concentration-QT (C-QT) analysis can help establish the risk
of prolonging the QT interval and can possibly be used to avoid
conducting a full thorough QT (TQT) study completely. C-QT
analysis is a PK/PD modeling and simulation technique and a low-cost/
efficient analysis compared to running a full TQT study.
In a C-QT analysis, PK data (concentration of a drug over time) is
time matched with electrocardiogram (ECG) data to create a measure
of exposure and response. PK and ECG data that have already been
collected in standard clinical studies, including: FTIH, single ascending
dose, multiple ascending dose, proof of concept Phase 2, or any combi-
nation may be used in C-QT analyses. There is also the possibility to
plan for appropriate data collection in an upcoming study in order to
conduct a C-QT study.
More information on C-QT analysis and how it can be used in lieu
of a TQT study can be found in the blog: How to Avoid Clinical Trials
Using Modeling & Simulation further down in this toolkit.
3. IN VITRO IN VIVO CORRELATION
An in vitro in vivo correlation (IVIVC) is a predictive mathematical
model that describes the relationship between drug release in a
dissolution apparatus and how that translates to the amount of drug
that enters the bloodstream following administration. This type of
relationship is likely to exist when a drug has high solubility and when
dissolution is the rate limiting factor in the process of drug absorption.
An IVIVC model is recommended by regulatory authorities for most
modified release dosage forms. The main advantage of IVIVC is that it
provides a mechanism for evaluating the change in in vivo absorption
based on in vitro dissolution changes when there are small changes in
a formulation. Once a validated IVIVC model has been established, it
can be used to predict bioavailability/bioequivalence (BA/BE) based on
in vitro data that are already available. In such cases, dissolution test
results can be used to provide the desired information without the need
for any human BE studies.
Another advantage of IVIVC is that it conveys a better understanding
of the drug product itself. This may allow for setting wider drug prod-
uct acceptance criteria, formulation stability, and can be especially
useful for predicting the in vivo effects of changes to the manufacturing
process, site of manufacture, or formulation components. In addition,
IVIVC can be used to support a biowaiver, which allows sponsors to
waive an in vivo BA and/or BE study requirement. When requesting
biowaivers for drug manufacturing changes, IVIVC can be used in
lieu of certain otherwise required in vivo studies if sufficient safety and
efficacy have been established.
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 Blog: What is the Difference
Between PBPK & PopPK Modeling?

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What is the Difference Between PBPK & PopPK Modeling?
“I suppose it is tempting, if the only tool you have is a hammer, to treat
everything as if it were a nail.” – Abraham Maslow
Modeling can save countless hours and dollars, as well as help
make decisions at critical points in the process. Modeling is a broad
methodological category with many techniques. All too often though,
modelers become enamored with specific methods and try to shoehorn
one particular method into every problem.
Each modeling method is best-suited for answering specific questions.
This post will explain the differences between two of the most widely-
used pharmacokinetic (PK) modeling methods, physiologically-based
pharmacokinetic (PBPK) modeling and population pharmacokinetic
(popPK) modeling and provide some examples of when to use each tool.
PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING
PBPK is a compartment and flow-based type of pharmacokinetic
modeling and relatively easy to conceptualize. In PBPK models, each
compartment represents a physiologically discrete entity, such as an
organ or tissue, and the blood flow into and out of those entities. For
example, a simple PBPK model might contain one compartment
representing the blood linked to two other compartments in parallel,
one that represents the liver, and one that represents the lungs. The
distribution of drug into and out of that organ will be related to the
blood flow into and out of that organ, the concentration in the blood,
and a partition coefficient.
In theory, if a PBPK model contained a compartment for each organ
in the body, it could facilitate the simultaneous description of drug
concentration changes over time in each organ. The compartments are
not limited to entire organs, and often PBPK models contain nested
compartments that represent different cell types within an organ, and
even different organelles within a cell. These levels of hierarchical
complexity permit modeling of molecularly-driven events, such as
specific metabolic pathways. Mathematically, the blood flows and
partition coefficients that link the compartments together are initially
estimated from animal and in vitro data, though clinical data can
be used when known. The parameters and compartments are then
optimized to fit the model to existing data.
Because PBPK models are constructed with such granular detail, they
can help answer very specific questions. For example, the molecular
signature of a disease can be incorporated into a PBPK model by
altering key parameters to help predict how drug concentration will
change in a specific patient population. This type of prediction can
help inform dosing recommendations or influence the design of clinical
trials when evaluating a drug for a new indication.
Similarly, drug-drug interactions (DDI) can be predicted and
simulated, given that metabolic and transport information is known for
both drugs. PBPK models are typically limited by the available level of
mechanistic knowledge. For instance, in the case of a DDI, it would be
impossible to predict the impact of concomitant drug administration if
the enzymes involved in their metabolism are not known.
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What is the Difference Between PBPK & PopPK Modeling?
Quantitative systems pharmacology (QSP) is an extension of PBPK
modeling. In addition to describing the change in drug concentration
as a function of time in specific compartments, QSP models the
pharmacodynamic effect of the drug on tissues and organs.
A limitation of PBPK models is that they are commonly so complex
(having numerous parameters, organ volumes, organ specific
blood flows, and partition coefficients) that the parameters cannot
be estimated using traditional statistical methods. Sometimes the
parameters can be fixed to data collected in vitro or preclinically,
but this requires the availability of such data (which is not typically
available during drug development). Also, it is never clear if the
parameter estimates from in vitro data or non-clinical species are the
same as human parameters. When human plasma concentration-time
data are available, the variables can be manually adjusted to improve
the model’s fit.
POPULATION PHARMACOKINETIC MODELING
PopPK modeling is also a compartment-based type of
pharmacokinetic modeling. Unlike PBPK, however, the compartments
do not necessarily have distinct physiological meaning. Rather, popPK
modeling takes all available pharmacokinetic information and builds a
model that fits the data. Thus, these models are “top down,” starting
with data observed, while PBPK models are “bottom up,” starting with
what is understood at the organ, or tissue level.
The fundamental difference between physiologically-based models and
most popPK models is that popPK models are largely empiric.
For example, a popPK model development typically starts with a very
simple model, often one compartment, linear elimination, and linear
absorption. Additional “features,” such as peripheral compartments,
absorption lag time, etc. are then added to the model, one at a time,
and tested for statistical significance. Note that these compartments are
called “central” and “peripheral,” not “plasma” and “adipose.”
Occasionally, these compartments might correspond to actual
anatomic compartments or processes. For example, large proteins are
usually restricted to the plasma volume, and aminoglycoside clearance
correlates very well with glomerular filtration rate. But, in general,
these “compartments” are just an empiric description of the behavior
of the drugs. That said, the biological plausibility of the models and
each additional “feature” is carefully considered when constructing
these models, especially when considering clearance models. For
example, we might test whether the clearance of a drug known to be
cleared renally is related to creatinine clearance or age but would be
unlikely to consider whether clearance is related to formulation, or fed/
fasted state, since the latter two are not biologically plausible.
Nuventra uses popPK models to identify the sources of variability
in a drug’s kinetic profile. This is a necessary step in any drug’s
successful clinical implementation. These sources of variability
can include both intrinsic factors (such as age, weight, and gender)
and extrinsic factors (such as food and other drugs). PopPK can
frequently describe the relationship between drug clearances
and organ function. This relationship is derived from empirical
observations – that is, from data, not a theoretical understanding of
drug clearance. But, again, these relationships must be consistent
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What is the Difference Between PBPK & PopPK Modeling?
with our understanding of the mechanisms if they are to be
extrapolated with confidence. PopPK models also estimate the
individual variability in PK parameters like clearance and volume
of distribution and residual (or unexplained) variability. This is in
contrast to PBPK models that usually describe the typical subject
without variability.
PopPK models have enormous utility in answering questions about
drug kinetics related to multifactorial variables. Importantly, they are
useful for formal testing of hypotheses, such as a relationship between
clearance and creatinine clearance. Like PBPK models, they are often
useful for prediction, even outside of the range of the available data.
The extrapolation outside the range of available data requires that the
model make biological sense. This means that if you have a model that
includes an effect of creatinine clearance on drug clearance, and you
have data in a range of creatinine clearance from 60-120 ml/min, that
a model can likely predict, with confidence, the clearance in patients
with a creatinine clearance of 30 ml/min.
PHYSIOLOGICALLY-BASED PHARMACOKINETIC VS.
POPULATION PHARMACOKINETIC MODELS
Both popPK models and PBPK models can be used to predict
exposure in pediatric patients. Empiric popPK models can predict
exposure in pediatrics down to age 2 years for most drugs. If the
enzymes responsible for metabolism are one of the common enzymes,
there are maturation models that can be added to predict exposure
in even younger pediatric subjects. The outcome is understanding the
range of potential exposures in pediatrics (conservative information).
PBPK models can predict exposure in pediatric patients regardless of
age; however, a very thorough understanding of the metabolism is
needed as well as in vitro and preclinical data to have a better chance
of successfully predicting the average exposure in pediatric patients.
Regulatory agencies are getting more interested in PBPK models,
especially for complex drug interactions with multiple substrates or
inhibitors when, traditionally, they have not advocated for popPK.
In contrast, both modeling approaches are well-suited to predict
exposure in pediatrics. Therefore, companies can make a decision
about which approach they want to take for predicting exposures in
pediatrics, depending on how much knowledge is known about how
the drug is metabolized, available in vitro and preclinical data to help
with parameter estimates in PBPK, and whether they are interested in
the average pediatric subject (which they will get from PBPK) or the
variability in pediatric exposures (which they will get from popPK).
CONCLUSIONS
PBPK and popPK modeling are complementary techniques in the
pharmacokineticist’s toolbox. They both possess powerful descriptive
and predictive potential and can help make decisions throughout the
drug development process. Importantly, PBPK and popPK methods
are not mutually exclusive. While popPK models are traditionally
described as “empiric,” we commonly include theoretical features into
these models – including those not supported by any specific data,
but rather by theoretical understanding of drug properties. Deciding
which tool (or a hybrid of the two) to use requires a careful assessment
of the specific questions to be answered and the type of data available.
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Blog: How to Avoid Clinical Trials
Using Modeling & Simulation

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How to Avoid Clinical Trials Using Modeling & Simulation
With modeling and simulation, data can be leveraged to provide
important insights on product safety and effectiveness. Modeling and
simulation can offer a better understanding of existing clinical trial
data as well as provide supportive data for future trial designs and
decisions. Sometimes modeling and simulation can even be used to
avoid a clinical trial all together.
Modeling and simulation can be used in many different types of
situations, such as predicting the optimal dose in adult patients from
Phase 1-3 and in the product label, designing Phase 1-3 clinical trials,
assessing the probability that a new compound will have better efficacy
or safety compared to the gold standard, predicting the dose in patient
subgroups (e.g., pediatrics, elderly, renal impairment), and more.
Here we provide some examples and situations where different
types of modeling and simulation can be used to maximize clinical
trials that are already planned or completed. In some examples, we
highlight how some clinical trials can potentially be avoided by using
modeling and simulation and existing data. So, the big question
is, “how can modeling and simulation be applied to help your
development program?”
USING POPULATION PK AND EXPOSURE-RESPONSE MODELING
TO PICK THE OPTIMUM DOSE AND DESIGN FOR PHASE 2 AND 3
There are many Phase 2 and Phase 3 failures due to lack of efficacy
or too much toxicity. Many of these failures could be due to the use of
doses that are either too low to produce efficacy or too high and reduce
safety. Using population pharmacokinetic modeling (popPK) and
exposure-response to select the doses and/or dosing range to be studied
in Phase 2/3 can improve the probability of success of the trial, thereby
reducing the overall number of trials by eliminating the ones that have
a low probability of success.
Many times, a target product profile may state that DRUG X will have
better efficacy than the gold standard. A full program is developed,
but the Phase 2/3 trials fail. Before any of these studies are started,
popPK and exposure-response concepts from the gold standard or
placebo can answer whether the target product profile is even possible,
through clinical trial simulation (e.g., developing a model and then
assuming there are 100 subject per arm, simulating 1000 clinical trials,
and analyzing them as if they were “real” clinical trials to develop the
probability of success).
These “virtual” clinical trials can be run assuming a parallel study,
a placebo run-in, or a randomized withdrawal study with various
numbers of subjects for a much lower cost than actually conducting
the study. There are many examples of compounds that clinical trial
simulations have shown that the initial target product profile was not
feasible, but a different targeta (e.g., better safety profile) was feasible.
Other clinical trial simulations have shown that the initial target was
only feasible with a very different clinical trial designb/c (e.g., placebo
run-in, randomized withdrawal).
Using modeling and simulation early in drug development can thereby
avoid clinical trials that are unlikely to be successful.
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How to Avoid Clinical Trials Using Modeling & Simulation
USING POPULATION PK MODELING TO AVOID A CLINICAL
PHARMACOLOGY STUDY LIKE RENAL IMPAIRMENT
The kidneys (renal system) play a critical role in eliminating many
(but not all) drugs from the body. Therefore, it is always necessary to
consider what changes are expected in patients with renal impairment
compared to patients with normal renal function.
A standard clinical pharmacology study can be conducted in patients
with varying degrees of renal impairment or in end stage disease as per
the FDA guidance. If the drug is not excreted renally or if the disease
being treated includes many patients with renal impairment and renal
impairment will not be an exclusion criteria in the Phase 2/3 trials,
then there is a different way to get the needed information. With extra
planning, proper study design, and popPK modeling approaches, it is
possible to avoid the renal impairment clinical pharmacology study
altogether, and still have reasonable dosing recommendations for the
product label.
Using pooled, cross-study data collected during Phase 2/3 studies
from patients with varying degrees of renal impairment, popPK
modeling can be used to understand the impact of renal impairment
on drug exposure. Simulations can then be done to evaluate dosing
recommendations for patients with mild, moderate, or severe renal
impairment. If an exposure-response model for safety is available, this
data can also be simulated to strengthen dosing recommendations.
The key for this approach to successfully eliminate the need for a
renal impairment clinical pharmacology study is to understand the
epidemiology of renal impairment in the disease state, to understand
the mechanism of drug elimination and any safety implications, and to
ensure open inclusion/exclusion criteria for Phase 2/3 trials.
The same concepts can be used to eliminate the need for a separate
elderly study, obesity study, or a particular drug interaction study if
these patient populations or drug interactions are commonly found in
Phase 2/3 subjects, the Phase 2/3 inclusion/exclusion criteria are more
open, and the safety implications are well understood. It is important to
note that this streamlined approach is not for every drug program, so
prospective clinical pharmacology planning to determine the feasibility
and cost-effectiveness for your specific program is important.
CONDUCTING CONCENTRATION-QT ANALYSIS INSTEAD OF A
STANDALONE THOROUGH QT STUDY
Another example where a little bit of extra planning can help
tremendously is concentration-QT (C-QT) analysis. This type of
modeling can help you avoid a future standalone thorough QT
(TQT) trial. The FDA requires drug developers to conduct studies
to determine the risk of a drug prolonging the QT interval, and,
typically, this assessment is made by conducting a TQT clinical study.
TQT studies can cost millions of dollars and take upwards of 1 year
to complete. Using a C-QT analysis can help establish the risk of QT
prolongation and potentially avoid the expense of conducting a full
TQT study.
The biggest advantage of using C-QT analysis, besides saving
resources, is that one can predict the QTc effects early in drug
development using Phase 1 data and potentially reduce the ECG
burden later in drug development. In addition, C-QT analysis allows
one to predict QTc effects with doses and formulations that have not
been directly evaluated by clinical studies, to predict QTc effects in
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How to Avoid Clinical Trials Using Modeling & Simulation
specific populations, to predict QTc effects with drug-drug interactions,
or to clarify ambiguous results based on small numbers of subjects in
Phase 1.
There are two important documents that govern C-QT analysis: the
ICH E14 Q&A R(3) document from December 2015 and the scientific
white paper by Christine Garnett et al. Some key points to consider
when planning for a C-QT analysis include:
• Serial matched ECGs & concentrations: “rich sampling”
instead of sparse sampling
• Timing: you need samples around the time of maximum
concentration, as well as the time of maximum concentration
for metabolites (if known)
• Robust ECGs: triplicate ECGs (at baseline, at a minimum),
centrally read with manual adjudication
• Range of doses: ideally, 2x coverage of the worst-case
clinical exposure, including coverage for expected increases
in Cmax from food, drug-drug interactions, or organ
impairment (but this is not always possible)
• Placebo data: inclusion of placebo data allows for small
effect on QT to be ruled out
Single ascending dose and multiple ascending dose studies are great for
collecting data suitable for C-QT analysis. It is important to escalate
as high as possible in these studies since some of the above mentioned
requirements for a successful C-QT analysis, especially worst-case
clinical exposure, are not always known prior to starting these studies.
While C-QT analysis will never completely remove the need for you to
continue to monitor ECGs, it can reduce the level of ECG monitoring
in later studies. It is important to remember that if you have collected
the right data, C-QT analysis can be used as an alternative to
conducting a full TQT study.
MODELING FOR LABELED DOSE NOT DIRECTLY TESTED IN A
CLINICAL TRIAL
Modeling and simulation can directly impact the drug label, even
as far as labeling for dose regimens that were not directly tested in
clinical studies. Here’s a case study of a label dose coming directly from
modeling and simulation using PK and time to event modeling.
You can model the “time to an event” for any number of situations.
Some examples of time to event modeling include time to the
occurrence of a specific disease or a certain symptom, time to the
alleviation of a certain symptom, or time to the occurrence of any
other endpoint of interest.
The underlying model for time to event modeling is a hazard model
which is statistically very different from what you would apply to
other types of PK/PD modeling. In this type of modeling, the hazard
function is the potential that the event will occur per unit time, given
that the event has not occurred in the individual up to that point. Most
commonly, you would use a Cox proportional hazard or a parametric
hazard model which would calculate the likelihood of the event and
the interval of time.
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How to Avoid Clinical Trials Using Modeling & Simulation
In one example using an antiviral, the hazard of alleviation of relationship between in vitro dissolution and the in vivo input rate.
symptoms is dependent on the duration that the drug concentration Data from clinical BA studies are required to establish this relationship,
can inhibit viral replication. In this case study, time to event modeling typically from cross-over studies in the fasted state utilizing at least 2
combined with popPK modeling enabled inclusion of a dose regimen different formulations (one fast releasing formulation and one slow
on the label that was not tested in a clinical study, saving time and releasing formulation).
resources thus showing that a good model can sometimes be just as Use of an IVIVC for a biowaiver can reduce the number of BE studies
effective as conducting an entirely new study. that need to be performed during development and post-approval.
IVIVC may be sufficient for biowaivers for:
USING IN VITRO IN VIVO CORRELATION INSTEAD OF
• Manufacturing site changes
CONDUCTING A CLINICAL BIOEQUIVALENCE STUDY
• Changes in non-release and release controlling excipients
In vitro in vivo correlation (IVIVC) is a predictive mathematical
• Process changes
model that describes the relationship between an in vitro property of a
dosage formulation and a relevant in vivo exposure. IVIVC expresses • Complete removal of or replacement of non-release
the relationship between drug release in a dissolution apparatus and controlling agents
how that translates to the amount of drug that enters the bloodstream • Lower strengths that are compositionally proportional or
following administration. Further details of IVIVC modeling are found in qualitatively the same.
the Quick Guide: Types of Modeling & Simulation section of this toolkit.
Importantly, IVIVC models can be used to support a biowaiver,
which allows sponsors to waive an in vivo bioavailability and/or
bioequivalence (BA/BE) study requirement, particularly for modified
release products. In this case, the dissolution test serves as a surrogate
for human BE studies when there are manufacturing process or site
changes post-approval. IVIVC can also help pick the best modified
release formulation for progression.
Different levels of IVIVC can be established (Levels A, B, and C and
multiple Level C). A Level A relationship is required to waiver BE
studies for a modified release product. This is generally a point-to-point

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How to Avoid Clinical Trials Using Modeling & Simulation
OPTIMIZING STUDY DESIGN WITH CLINICAL TRIAL
SIMULATION EXAMPLES
The goal of a clinical trial simulation is to study the effect of a drug in a simulation among their highest priorities to support efficient drug
virtual patient population to help understand the likelihood of clinical
impact of some unknown factor such as recruitment issues, dropout
rate, treatment effect, etc. The idea is to be able to increase the
efficiency across all stages of clinical development for factors such as:
• Dose and scheduling determination: What is the predicted
exposure and/or effect at different doses or regimens?
• Long-term study scenarios: What is the range of possible
outcomes prior to initiating studies that will be resource and
time intensive?
• Optimizing study design and sample size: What is the
probability of success with different numbers of subjects or
cohorts? How does that change if the dose- or concentration-
response relationship looks different?
• Impact of variability: What is the impact of missed samples,
subject drop out, or compliance on different factors?
CONCLUSIONS
Recently the FDA and EMA have both included modeling and
development and facilitate regulatory decision making. Modeling
and simulation can and should be applied throughout all stages of
development. There are many opportunities for conducting more
efficient trials or avoiding additional trials altogether.
Nuventra has an expert team of pharmacometricians who build
models tailored to guide your drug development program’s decisions.
Our team can create a custom, model-informed drug development
plan that will facilitate the selection of the optimal model for your
compound and disease area.
Contact us to learn how Nuventra’s modeling and simulation team
can help you gain insights that move your clinical development
program forward.
a
C Leonowens, J Lee, JP Therrien, C Ambery, D Quint, M Price, G Schmith. Early Clinical
Development of GSK2245035B for Dermal Application: Use of Probabilistic Risk Analysis
Approaches to Address Uncertainty. American Conference on Pharmacometrics (ACoP5). Las
Vegas Oct 12-15, 2014 Abstract M-039 [published: in press]
b
Lovern, Schmith, Dukes, McSorley PAGE 15 (2006) Abstract 978
c
https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/cpt.16
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Additional Resources

20
Meet Nuventra’s Modeling Team

Mark Sale, M.D. Virginia (Ginny) Schmith, Ph.D. Jie (Jessie) Zhou, Ph.D. Mark A. Bush, Ph.D. Cathrine Leonowens, Ph.D.
Sr. Vice President, Pharmacometrics Sr. Vice President, Clinical Pharmacology Director, Pharmacometrics Vice President, Clinical Pharmacology Sr. Consultant, Clinical Pharmacology
& Pharmacometrics & Pharmacokinetics & Pharmacometrics

Joanna Peng, Ph.D. Iftekhar Mahmood, Ph.D. Devin Welty, Ph.D. Damien Cronier, Ph.D. Lauren R. L. Lohmer, Ph.D.
Sr. Consultant, Clinical Pharmacology Sr. Consultant, Clinical Pharmacology Sr. Consultant, Nonclinical & Clinical Sr. Consultant, Clinical Pharmacology Principal Scientist, Clinical Pharmacology
& Pharmacometrics & Pharmacometrics Pharmacology & Quantitative Pharmacology

Jason R. Pirone, Ph.D. Vineet Goti, Ph.D. Laura Curd, M.S. Shirley Wu, Pharm.D. Celeste Vallejo, Ph.D.
Pharmacometrician II Pharmacometrician II Pharmacometrician I Pharmacometrician I Quantitative Systems Pharmacologist I 21
Featured Scientists
Mark Sale, M.D.
Sr. Vice President, Pharmacometrics
Dr. Sale received his MD in 1985 from The Ohio State University and an MS in biostatistics from
Georgetown University in 1995. Between completing his two graduate degrees, Dr. Sale completed
a Fellowship in Clinical Pharmacology at Stanford University and became an Assistant Professor of
Medicine and Pharmacology at Georgetown University. Dr. Sale has extensive experience conducting
complex population PK analyses across diverse therapeutic areas and is one of the pharmaceutical
industry’s thought leaders in modeling and simulation.

Virginia (Ginny) Schmith, Ph.D.

Sr. Vice President, Clinical Pharmacology & Pharmacometrics
30 years of leadership and experience in clinical pharmacology and pharmacometrics.
Dr. Schmith provides expert consulting in clinical development and pharmacometric strategies for
compounds from candidate selection through registration and beyond; development, implementation,
and interpretation of strategies for exposure-response and clinical trial simulations, participating in
regulatory meetings (including Advisory Committees), and evaluating the probability of successful
differentiation from competitors. Dr Schmith, a thought leader, is involved in international societies
advancing the science in clinical pharmacology and pharmacometrics.

Jie (Jessie) Zhou, Ph.D.

Director, Pharmacometrics
Dr. Zhou has more than 6 years of professional experience in clinical pharmacology, pharmacokinetics,
and pharmacometrics. Her expertise includes designing, analyzing, and interpreting clinical PK studies
and developing clinical pharmacology strategic plans. She also has experience in conducting population
PK and PK/PD analyses, authoring NDA sections and addressing responses to regulatory agencies. Jessie
received her PhD in Experimental Clinical Pharmacology from the University of Minnesota Twin Cities.
Before that, she received her Master of Science in Biomedical Engineering in Shanghai, China.
22
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Nuventra’s Modeling & Simulation Services by Phase
Additional Resources
1. Model-Based Clinical Drug Development in the Past,
Present and Future: a Commentary
2. Drug & Device Advisory Group: MBDD
3. Concepts and Challenges in Quantitative
Pharmacology & MBDD
4. Good Practices in MIDD & Development: Practice,
Application, and Documentation
5. Exposure Response Guidance
6. Model-Informed Drug Development Pilot Program
Learn More
Nuventra has an expert team of pharmacometricians who
design and implement model-informed drug development
programs. Our team uses information about your compound,
knowledge of your disease area, and regulatory strategy to
design the most optimal fit-for-purpose models to improve
decision making throughout drug development.
Learn how Nuventra’s modeling and simulation services can
help you gain insights that move your clinical development
program forward.
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CONTACT US: Contact a consultant for a complimentary 30-minute consultation
toolkit@nuventra.com | 888.615.5111 | nuventra.com/contact-us