Drug–Drug Interaction Studies
Peter Stopfer
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
General DDI Considerations Inclusive Comparison of the DDI
Guidelines EMA/FDA/PMDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2
Nonclinical Assessment of DDI by In Vitro Investigations: Determination if a
Drug Is a Victim or Perpetrator of a Potential DDI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Metabolism-Based DDIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Transporter-Based DDIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4
4
6
General Strategies for the Planning and Conduct of DDI Trials . . . . . . . . . . . . . . . . . . . .
6
Practical Considerations for DDI Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Choice of Substrate and Interacting Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Complex Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Route of Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Dose Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Statistical Considerations, Clinical Relevance, and Sample Size . . . . . . . . . . . . . . . . . . . . . . . .
Cocktail Approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Pharmacogenomic Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
DDI as Part of Pop PK in Phase II and Phase III Trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
9
10
11
14
16
16
16
17
17
18
18
DDI Considerations for NBEs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
References and Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
P. Stopfer (*)
Boehringer Ingelheim Pharma GmbH & Co. KG,
Ingelheim, Germany
e-mail: peter.stopfer@boehringer-ingelheim.com
# Springer International Publishing AG 2018
F.J. Hock, M.R. Gralinski (eds.), Drug Discovery and Evaluation: Methods in Clinical Pharmacology,
https://doi.org/10.1007/978-3-319-56637-5_13-1
1
2
P. Stopfer
Abbreviations
ABC
AhR
AUC
ATP-binding cassette
Aryl hydrocarbon receptor
Area under the plasma concentrationtime curve
BCRP Breast cancer resistance protein
BSEP Bile salt export pump
CAR
Constitutive androstane receptor
CYP
Cytochrome P450
FMO Flavin monooxygenase
MAO Monoamine oxidase
MATE Multidrug and toxin extrusion
MRP
Multidrug resistance-associated
protein
NTR
Narrow therapeutic range
OAT
Organic anion transporter
OATP Organic anion transporting
polypeptide
OCT
Organic cation transporter
PBPK Physiologically-based
pharmacokinetic
PD
Pharmacodynamics
P-gp
P- glycoprotein
PK
Pharmacokinetics
PXR
Pregnane X receptor
SLC
Solute carrier
TDI
Time dependent inhibition
UGT
Uridine diphosphate (UDP)glucuronosyl transferase
XO
Xanthine oxidase
Introduction
Drug drug interaction (DDI) can result when one
drug alters the pharmacokinetics of another drug
or its metabolites. The assessment of pharmacokinetic DDIs during clinical development is a part
of the general clinical pharmacology and safety
assessment of a new investigational compound.
Market withdrawals of drugs were frequently
caused by DDIs which underlines the importance
of addressing these issues during drug development. This is also reflected by the latest DDI
(DDI) guidelines from European Medicines
Agency EMA (2012), Food and Drug Administration (FDA) (2012), and Pharmaceuticals and
Medical Devices Agency (2014). The details of
all aspects which have to be considered in the
design of DDI studies are outlined in the respective guidelines from EMA (2012), FDA (2012),
and PMDA (2014). This section is aiming to give
a summary of the respective considerations of
these guidelines for the design of DDI studies
and also contains many aspects of the respective
guidelines including the most relevant decision
trees and tables.
This chapter:
• Describes how an evaluation of DDI is
performed from in vitro to in vivo studies
within clinical development
• Reflects recent recommendations by authorities as regards the design, conduct, and
reporting of DDI studies
• Presents the requirement to assess the clinical
significance of DDIs
General DDI Considerations Inclusive
Comparison of the DDI Guidelines
EMA/FDA/PMDA
The main focus of this chapter is on pharmacokinetic DDIs. The understanding of the nature and
magnitude of DDI is important for several reasons. Concomitant medications, dietary supplements, and some foods, such as grapefruit juice,
may alter metabolism and/or drug transport
abruptly in individuals who previously had been
receiving and tolerating a particular dose of a
drug. A respective alteration in metabolism or
transport can change the known safety and efficacy of a drug. In a few cases, consequences of an
interaction have led to the conclusion that the drug
could not be marketed safely. Several drugs have
been withdrawn from the market because of significant DDIs that led to, e.g., QT prolongation
and Torsades de Pointes (TdP) arrhythmias, after
warnings in drug labels did not adequately manage the risk of DDIs.
The overall objective of DDI studies for a new
drug is to determine:
Drug–Drug Interaction Studies
Fig. 1 General DDI
decision tree for a drug as a
victim for a DDI (*FDA
requests the investigation
on multiple enzymes)
3
Particular pathway(s*) significantly contributes overall pharmacokinetics
(e.g. one metabolic enzyme, hepatic/biliary/renal secretion >25% of total CL)
Yes
No
Clinical DDI study
No clinical
DDI study
clinical DDI study results show significant DDI
Consider further DDI studies with other less Yes
potent inhibitor/inducer based on the
potential of concomitant use
• Whether any DDIS are sufficiently large to
necessitate a dosage adjustment of the drug
itself or of the drugs with which it might be
used
• Whether any DDI calls for additional therapeutic monitoring
• Whether there should be a contraindication to
concomitant use when lesser measures cannot
mitigate risk
Therefore, the development of an investigational drug should include identification of the
principal routes of elimination, quantitation of
the contribution by enzymes and transporters to
drug disposition, and characterization of the
mechanism of DDIs.
The study of DDIs for a new drug generally
begins with in vitro studies to determine whether a
drug is a substrate, inhibitor, or inducer of metabolizing enzymes. The results of in vitro studies
will inform the nature and extent of in vivo studies
that may be required to assess potential interactions. Along with clinical pharmacokinetic data,
results from in vitro studies may serve as a screening mechanism to rule out the need for additional
in vivo studies, or provide a mechanistic basis for
proper design of clinical studies.
Human clinical studies to assess DDIs are
either designed for a dedicated administration of
No
No further
DDI study
a perpetrator and a victim drug or may contain
simultaneous administration of a mixture of substrates of multiple CYP enzymes and transporters
in one study (i.e., a “cocktail approach”) to evaluate a drug’s inhibition or induction potential.
All three DDI Guidelines (EMA-CHMP 2012;
US-FDA 2012; PMDA. Pharmaceuticals & Medical Device Agency-Japan 2014) are displaying
general decision trees as to when a drug has to be
considered for a DDI trial, when the drug is a
victim for an enzyme or drug transporter (Fig. 1)
Additionally also decision trees can be found
in all three DDI Guidelines (EMA-CHMP 2012;
US-FDA 2012; PMDA. Pharmaceuticals & Medical Device Agency-Japan 2014) which display as
to when a drug has to be considered for a DDI
trial, when the drug is acting as a perpetrator for
an enzyme or drug transporter DDI (Fig. 2).
Additionally, complex DDIs, which can occur
in specific populations (e.g., patients with organ
impairment, and pediatric and geriatric patients),
should be considered on a case-by-case basis.
Moreover also PK modeling approaches (if well
verified for intended purposes) can be helpful to
guide the determination of the need to conduct
specific DDI studies or even to avoid respective
DDI studies in special cases.
4
P. Stopfer
Fig. 2 General DDI
decision tree for a drug
acting as a perpetrator for a
DDI
Drug or metabolites inhibit/induce the target in vitro
No
No DDI
evaluation
Yes
Basic model and Mechanistic static PK model (MSPK) (or PBPK model)
suggest the potential DDI
No
Clinical DDI study
Significant effect on
Yes
the substrate?
Yes
Consider further DDI study
with based on the potential
of concomitant use/narrow
therapeutic range
Nonclinical Assessment of DDI by In
Vitro Investigations: Determination if
a Drug Is a Victim or Perpetrator of a
Potential DDI
The drug development process should include
evaluation of a new drug’s potential to affect the
metabolism or transport of other drugs and the
potential for the new drug’s metabolism or transport to be affected by other drugs. Use of in vitro
tools to determine whether a drug is a substrate,
inhibitor, or inducer of metabolizing enzymes or
drug transporters, followed by in vivo interaction
studies to assess potential interactions, has
become an integral part of drug development and
regulatory review. These results will be the basis
for the determination of a clinical DDI study is
needed or not. Authorities may consider in vitro
data sufficient to exclude DDI liabilities if there is
a clear indication from parameters outlined in
regulatory documents (e.g., [I]/Ki for CYP-based
interactions in the absence of liver partitioning) of
little or no DDI potential. These negative in vitro
data can obviate the need for further in vivo clinical activities considering the pathways that were
excluded from being clinically meaningful.
This section will separately discuss in vitro
investigations at the levels of metabolizing
enzymes and transporters. Also general considerations for situations when complex or multiple
DDI mechanisms will be presented will be briefly
described.
No
No clinical DDI study
No further DDI study
Metabolism-Based DDIs
Hepatic metabolism occurs primarily through the
cytochrome P450 family (CYP) of enzymes
located in the hepatic endoplasmic reticulum, but
may also occur through non-CYP enzyme systems, such as glucuronosyl- and sulfo-transferases, which can, in general, inactivate a drug and
increase its renal elimination. Some drug metabolizing enzymes are present in the gut wall and
other extrahepatic tissues, in addition to the liver.
Many metabolic routes of elimination can be
inhibited or induced by concomitant drug treatment. Metabolic DDIs can cause substantial
changes (an order of magnitude or more decrease
or increase in the blood and tissue concentrations
of a drug or metabolite) and can also significantly
affect the extent to which toxic or active metabolites are formed. These large changes in exposure
can alter the safety and efficacy profile of a drug
and its active metabolites, regardless of whether
the drug has a narrow therapeutic range (NTR).
Nonclinical in vitro experiments provide data
on DDI potentially mediated by CYP enzymes (or
others like (Uridyl diphosphate (UDP))glucuronosyltransferases) using systems such as
human liver microsomes, expressed human
recombinant enzymes, and hepatocytes. These
data are used in order to determine the substrate
specificity of an NCE for a specific metabolic
enzyme, the inhibitory potential (half maximal
inhibitory concentration (IC50), inhibition
Drug–Drug Interaction Studies
5
Table 1 Targets to be examined: whether the drug is a substrate or not
Metabolic enzymes
CYPs
[recommendation]
UGTs
Others
[recommendation]
Transporters
Gut and systemic
Hepatic
(CLH > 25% of
CLtot)
Renal
(CLR, secretion > 25%
of CLtot)
FDA
EMA
PMDA
CYP1A2, 2B6, 2C8, 2C9,
2C19, 2D6, 3A
[2A5, 2 J12,4F2, 2E1]
UGT1A1, 1A3, 1A4, 1A6,
1A9, 2B7, 2B15b
MAO, FMO, XO, ALDH,
ADH
CYP1A2, 2B5, 2C8, 2C9,
2C19, 2D6, 3A
CYP1A2, 2B5, 2C8, 2C9,
2C19, 2D6, 3A
[2A5, 2 J12,4F2, 2E1]
UGT1A1, 1A3, 1A4, 1A5,
1A9, 2B7, 2B15b
MAO, FMO, XO, AO,
ALDH, ADH
Not specified
Not specified
P-gp, BCRP
Not specified
CATP1B1/1B3a
P-gp, BCRP
OCT2, OAT1/3
Not specified
OCT2, OAT1/3, MATE1/2K
a
In case the autoradiography (ARG) in animal shows significant accumulation in the liver (PMDA)
Require the identification of UGT subtype
c
In case the drug is not metabolized by major CYPs
b
Table 2 Targets to be examined: whether a drug is an inhibitor or not
Metabolic enzymes
CYPs
UGTs
Transporters
Gut and systemic
Hepatic
(CLH > 25% of CLtot)
[recommendation]
Renal
(CLR, secretion > 25% of
CLtot)
[recommendation]
FDA
EMA
PMDA
CYP1A2, 2B6, 2C8, 2C9,
2C19, 2D6, 3A
UGT1A1, 1A3, 1A4, 1A6,
1A9, 2B7, 2B15
CYP1A2, 2B6, 2C8, 2C9,
2C19, 2D6, 3A*
UGT1A1, 2B7
CYP1A2, 2B6, 2C8, 2C9,
2C19, 2D6, 3A*
UGT1A1, 2B7
P-gp, BCRP
OA1P1B1/1B3
[MRPs, BSEP]
OATP1B1/1B3,
[BSEP, OCT1]
OATP1B1/1B3,
[MRP2, BSEP, OCT1]
OC12, OAT1/3
[MRPs, MA1E1/2-K]
OCT2,OAT1/3
[MATE1/2-K]
OCT2,OAT1/3, MATE1/
2-K,
[MRP2, 4]
For CYP3A4, investigation with multiple substrate with different binding site are required
constant (Ki) for competitive inhibitors, and rate
of enzyme inactivation (kinact) for mechanismbased inhibitors) or induction in case of enzyme
inducers (rate of metabolism). The evaluation of
CYP enzyme induction may begin with studies of
CYP1A2, CYP2B6, and CYP3A in vitro. If the in
vitro induction results are positive according to
predefined thresholds using basic models, the
investigational drug is considered an enzyme
inducer and further in vivo evaluation may be
warranted
An overview as regards which metabolic
enzymes to be examined based on FDA, EMA,
and PMDA guideline, e.g., whether a drug is a
substrate, inhibitor, or inducer or not is given in
Tables 1, 2, and 3.
6
P. Stopfer
Table 3 Targets to be examined: whether the drug is an inducer or not
FDA
Metabolic enzymes
Enzyme
CYP3A4/5 (PXR),[if positive, CYP2C8,
(transcriptional
2C9, 2C19]CYP1A2 (AhR),CYP2B6
factor)
(CAR)
BVIA
PMDA
CYP3A4/5 (PXR),
CYP1A2 (AhR),
CYP2B6 (CAR)
CYP3A4/5 (PXR),[if
positive, CYP2C9 e t
al]
CYP1A2 (AhR),
CYP2B6 (CAR)
P-gp
(in case PXR and/or CAR
mediated induction
observed)
Not mentioned
Transporter
“Methods for in vitro evaluation are not
well understood”
“Should consult with FDA about studying
induction in vivo”
Transporter-Based DDIs
Although less well-recognized than metabolizing
enzymes, membrane transporters can have important effects on pharmacokinetics and drug exposure. To date, most identified transporters belong
to one of two superfamilies: ATP-binding cassette
(ABC) and solute carrier (SLC). Transporters
govern the transport of solutes (e.g., drugs and
other xenobiotics) in and out of cells. In contrast
to metabolizing enzymes, which are largely concentrated in the liver and intestine, transporters are
present with varying abundance in all tissues in
the body and play important roles in drug distribution, tissue-specific drug targeting, drug
absorption, and elimination. Transporters can
also work in concert with metabolizing enzymes
(see also ▶ “Complex DDI Interactions”)
A number of transporter-based interactions
have been documented in recent years. Analogous
to drug interactions mediated by P450 enzymes,
coadministration of a drug that is an inhibitor or an
inducer of a drug transporter may affect the pharmacokinetics of a drug that is a substrate for that
transporter. Transporters can affect the safety profile of a drug by affecting the concentration of a
drug or its metabolites in various tissues. Transporter-based drug interactions and the potential
effect of drug transporters on safety make it
important to determine whether transporters affect
the absorption and disposition of an investigational drug and whether the investigational drug
can affect the absorption and disposition of other
drugs through an effect on transporters.
The effect of a compound on drug transporter
function will be investigated, e.g., in bidirectional
transport experiments in tissue cultures. Results of
these experiments show whether the investigated
compound is a drug transporter substrate (by
determining the net transport rate, efflux ratio, or
Michaelis constant (Km)) or an inhibitor of the
transporter (by IC50 or Ki values). Because of the
lack of a validated in vitro system to study transporter induction, the definitive determination of
induction potential of an investigational drug on
transporters is based on in vivo induction studies.
An overview as regards which drugs transporters to be examined based on FDA, EMA and
PMDA guideline, e.g., whether a drug is a substrate, inhibitor, or inducer or not is given in
Tables 1, 2, and 3.
General Strategies for the Planning
and Conduct of DDI Trials
The evaluation of a DDI potential for a compound
is at first based on all in vitro data collected for a
compound to whether the drug is a substrate,
inhibitor, or inducer or a metabolic enzyme or
drug transporter in relation to the (expected) in
vivo plasma concentrations (e.g., maximum
plasma concentrations). The respective cut offs,
which have to be considered, are given based on a
“basic model” for reversible, time-dependent inhibition and also induction. Respective overviews
as regards specific recommendations (e.g., use of
unbound or total drug concentrations) and cut off
values (as to whether a clinical DDI trial needs to
Drug–Drug Interaction Studies
7
Table 4 Basic model: for reversible inhibition (R = 1 þ [I]/Ki or IC50)
FDA
EMA
Metabolic enzyme: Reversible inhibition
Systemic
[I] = total Cmax
[I] = unbound Cmax
R > 1.1
R 1.02
Gut
[l]G = Dose/250 mL, R > () 11
Transporter: Reversible inhibition
Systemic
P-gp, BCRP
[I] = total Cmax
[I] = unbound Cmax
R 1.1
R 1.02
[I] = unbound Cmax
CAT1,3, OCT2
[I] = unbound Cmax
MATE1, 2-K(PMDA)
R 1.1
R 1.02
[I] = unbound Cmax, inleta
CA7P1B1,3
[I] = total Cmax
R 1.1 and
R 1.04
[I] = unbound Cmax, inleta
R 1.25
Gut
P-gp, BCRP
[I]G = Dose/250 mL, R > () 11
a
PMDA
[I] = total Cmax
R > 1.1
[I] = total Cmax
R 1.1
[I] = unbound Cmax
R 1.25
[I] = unbound Cmax, inleta
R 1.25
Cmax,inlet is calculated as fu,b x ([I]max,b þ Fa x Fg x ka x Dose/Qh)
Table 5 Basic model: time-dependent inhibition (TDI)
FDA
Time dependent inhibition (TDI)
Systemic
[I] = total Cmax
R > 1.1
Gut
[l]G = Dose/250 mL
R > 11
EMA
PMDA
[I] = unbound Cmax
R 1.25
[I]G = Dose/250 mL
R 1.25
[I] = total Cmax
R > 1.1
[I]G = Dose/250 mL
R > 11
Table 6 Basic model: induction [R = 1 þ Emax [I]/(EC50 þ [I])]
FDA
Metabolic enzyme induction
mRNA change > predefined threshold
Cut off value
[I] = total Cmax
R < 0.9
Transporter induction
Not mentioned
EMA
PMDA
>2-fold (concentration dependent increase) or 20% increase of the
increase in positive controla
[I] = unbound Cmax
[I] = total Cmax
R: Not defined
R < 0.9
a
It is acceptable to use the enzyme activity as a measure, in case that the inhibition of enzyme can be clearly denied
(PMDA)
be performed) of the guidelines from different
authorities are given in Tables 4, 5, and 6.
Mechansitic static models and/or more comprehensive dynamic models (e.g., physiologically
based PK (PBPK) models) may be used additionally, and specific recommendations can be found
in the guidelines from FDA, EMA, and PMDA. It
should be noted that currently only the FDA provides a dedicated flowchart how to explore DDI
potential with PBPK models. The recommended
cases to use PBPK (EMA/FDA) are to predict
DDI’s worst case scenarios (additive “multiple
DDI mechanisms” combined with, e.g., organ
impairment), dose-dependent DDIs, the effect of
a less potent inhibitor, or the impact of a DDI in
subpopulations.
The initial approach to assessing clinical DDIs
is the evaluation of underlying mechanisms with
8
P. Stopfer
Table 7 Overview as regards inhibitor, inducer, and substrate lists provided by authorities
Metabolic enzyme (in vitro/in vivo)
Inhibitor
Inducer
Substrate
Transporter (in vitro/in vivo)
Inhibitor
Inducer
Substrate
FDA
EMA
PMDA
/◎
◎/◎
/○
○/◎
/
○/○
○/◎
○/◎
○/◎
/○
/○
/○
/
/
/
◎/○
◎/○
◎/○
◎: listed with intensity for each drug (i.e., classification [weak, moderate, or strong] or Ki value), ○: listed, : not listed
probe compounds. Examples of appropriate probe
compounds that are considered to be specific and
representative for a defined metabolic pathway or
drug transporter are defined in current regulatory
guidelines (e.g., (1,2,3)). A brief overview, which
inhibitors, inducers, and substrates are specified in
the respective guidelines, can be found in Table 7.
If a clinical relevant DDI cannot be excluded
through screening with a probe compound, further
clinical DDI evaluations may become necessary
(see Figs. 1 and 2). The demonstration of a relevant DDI in a study with a probe compound can
result in the need of further studies with concomitant medications for the NME (Figs. 1 and 2) to
determine:
1. Whether additional studies are needed to better
quantify the effect and to examine the effects of
weaker inhibitors (early studies usually examine strong inhibitors) on the investigational
drugs as substrates and effects of investigational drugs (as inhibitors) on a range of
substrates.
2. Whether dosage adjustments or other prescribing modifications (e.g., additional safety monitoring or contraindications) are needed based
on the identified interaction(s) to avoid
undesired consequences. Drug interaction
information is used along with information
about exposure-response relationships in the
general population and specific populations,
to help predict the clinical consequences of
DDIs.
Should in vitro data show that a drugis an
inhibitor or inducer of enzymes, it may be
recommended to conduct a DDI study as early as
possible in clinical development in order to
exclude any possible liability of this interaction.
For substrates of specific drug metabolizing or
drug transporter pathways, the timing of DDI in
vivo clinical studies depends on the safety range
and on the frequency of co-medications that
would act as inhibitor on the compound especially
during Phase II or III.
Independently of underlying mechanisms for
potential DDIs, it has to be evaluated whether
compounds with narrow therapeutic windows
(relevant co-medications) in the targeted therapeutic area need to be evaluated in addition to
the before mentioned studies which use probe
drugs. It should be noted that DDI studies with
specific co-medications might be necessary in
order to have a specific label of no clinically
relevant DDI.
In general, the described principles of nonclinical and clinical assessment of DDI are also
valid for oncological NCEs. However, studies in
healthy volunteers might not be possible due to
low tolerability of the compound. Furthermore,
study design options might be limited due to a
reduced clinical state of the patients. In general, all
“combination trials” of standard chemotherapy
together with a NME should be designed to investigate possible DDIs between the different compounds in light of this document (approaches to be
discussed on a case-by-case basis).
Drug–Drug Interaction Studies
9
Practical Considerations for DDI Trials
When testing an investigational drug for the possibility that its metabolism is inhibited or induced
(i.e., as a substrate), selection of the interacting
drugs should be based on in vitro or in vivo
studies identifying the enzyme systems that
metabolize the investigational drug. The choice
of the interacting drug can then be based on
known, important inhibitors and inducers of the
pathway under investigation. Strong inhibitors
and inducers provide the most sensitive assessment and should generally be tested first
Study Design
In vivo DDI studies generally are designed to
compare substrate concentrations with and without the interacting drug. Because a specific study
can address a number of questions and clinical
objectives, many study designs for investigating
DDI can be considered. In general, crossover
designs in which the same subjects receive substrate with and without the interacting drug are
more efficient. A study can use a randomized
crossover (e.g., Substrate (S) followed by Sþ
Inhibitor (I), S þ I followed by S), one-sequence
crossover (e.g., S followed by S þ I), or a parallel
(S in one group of subjects and S þ I in another
group) design, and there may be reasons to have
another period when the I is removed to assess
effect duration. The following possible dosing
regimen combinations for a substrate and
interacting drug can also be used: single dose/
single dose, single dose/multiple dose, multiple
dose/single dose, and multiple dose/multiple
dose. Additional factors include consideration of
the sequence of administration and the time interval between dosing of substrate and inhibitor/
inducer. The selection of a study design depends
on a number of factors for both the substrate and
interacting drug, including:
1. Whether the substrate and/or interacting drug
is used acutely or chronically
2. Safety considerations, including whether a
substrate is a NTR drug (NTR drugs are
3.
4.
5.
6.
defined as those drugs for which there is little
separation between therapeutic and toxic doses
or the associated blood or plasma concentrations) or non-NTR drug
Pharmacokinetic and pharmacodynamic characteristics of the substrate and interacting
drugs
Whether there is a desire to assess induction as
well as inhibition
Whether the inhibition is delayed
Whether there is a need to assess persistence of
inhibition or induction after withdrawal of the
interacting drug
The interacting drugs and the substrates should
be dosed so that the exposures of both drugs are
relevant to their clinical use, including the highest
doses likely to be used in clinical practice, and
plasma levels of both drugs should be obtained to
show this. The following considerations may be
useful:
• When attainment of steady state is important
(especially for the drug being the perpetrator
drug), and either the substrate or interacting
drug or their metabolites have long half-lives,
one or both periods of a crossover study should
be long, but several other approaches can be
considered, depending on pharmacokinetic
characteristics of the drug and metabolites.
For example, if the substrate has a long halflife, a loading dose could be used to reach
steady-state concentrations earlier in a onesequence crossover followed by an S þ I
period long enough to allow I to reach steady
state (here too, using a loading dose could
shorten that period).
• When it is important that a substrate and/or an
interacting drug be studied at steady state for a
long duration because the effect of an
interacting drug is delayed, as is the case for
inducers and time-dependent imhibition (TDI),
documentation that near steady state has been
attained for the pertinent substrate drug and
metabolites as well as the interacting drug is
critical, and both S and I should be present long
enough to allow the full effect to be seen. This
documentation can be accomplished by
10
•
•
•
•
P. Stopfer
sampling over several days prior to the periods
when test samples are collected. This information is important for metabolites and the parent
drug, particularly when the half-life of the
metabolite is longer than the parent. It is also
important when the interacting drug and
metabolites both are metabolic inhibitors (or
inducers). Finally, it is critical to evaluate the
time it takes for the enzyme activities to return
to normal when induction or TDI is involved
so that a third crossover period in which the
interacting drug (I) is removed will generally
be recommended.
Studies can usually be open label (unblinded),
unless pharmacodynamic endpoints (e.g.,
adverse events that are subject to bias) are
critical to the assessment of the interaction.
For a rapidly reversible inhibitor, administration of the interacting drug either just before or
simultaneously with the substrate on the test
day might increase sensitivity by ensuring
maximum exposure to the two drugs together.
For a mechanism-based inhibitor (a drug that
requires metabolism before it can inactivate the
enzyme; an example is erythromycin), administration of the inhibitor prior to the administration of the substrate drug can maximize the
effect. If the absorption of an interacting drug
may be affected by other factors (e.g., the gastric pH), it may be appropriate to control the
variables or confirm the absorption through
plasma level measurements of the interacting
drug.
Timing of administration may be critical in
situations of concurrent inhibition and induction. For example, if the investigational drug is
a substrate for both enzymes and OATP, and
rifampin is used as an enzyme inducer, the
simultaneous administration of the drug with
rifampin (an OATP inhibitor) may underestimate enzyme induction, so delayed administration of the substrate is recommended. The
optimal delayed time should be determined.
In addition, it is critical to evaluate the duration
of the interaction effect after the interacting
drug has been removed.
When the effects of two drugs on one another
are of interest, the potential for interactions can
be evaluated in a single study or two separate
studies. Some design options are randomized
three-period crossover, parallel group, and
one-sequence crossover.
• To avoid variable study results because of
uncontrolled use of dietary/nutritional supplements, tobacco, alcohol, juices, or other foods
that may affect various metabolizing enzymes
and transporters during in vivo studies, it is
important to exclude, when appropriate, subjects who used prescription or over-the-counter
medications, dietary/nutritional supplements,
tobacco, or alcohol within 1 week prior to
enrollment. In addition, investigators should
explain to subjects that for at least 1 week
prior to the start of the study until its
conclusion.
• Because interactions might differ in subgroups
of different pharmacogenetic genotypes,
genotyping for the enzymes and transporters
involved in the interaction should be carried
out when appropriate.
• Detailed information on the dose given and
time of administration should be documented
for the coadministered drugs.
Study Population
In most situations, clinical DDI studies can be
performed using healthy volunteers, and findings
in healthy volunteers will predict findings in the
patient population for which the drug is intended.
Safety considerations, however, may preclude the
use of healthy subjects in studies of certain drugs.
In addition, there are circumstances in which subjects drawn from the intended patient population
offer advantages, including the opportunity to
study pharmacodynamic endpoints not present in
or relevant to healthy subjects. The extent of drug
interactions (inhibition or induction) may be different depending on the subjects’ genotype for the
specific enzyme or transporter being evaluated.
For example, subjects lacking the major polymorphic clearance pathway will show reduced total
metabolism or transport. However, alternative
pathways can become quantitatively more
Drug–Drug Interaction Studies
important in these subjects. In such cases, the
alternative pathways should be understood and
studied appropriately. Thus, phenotype or genotype determinations to identify genetically determined metabolic or transporter polymorphisms
are important when evaluating effects on enzymes
or transporters with polymorphisms, such as
CYP2D6, CYP2C19, CYP2C9, UGT1A1, and
OATP1B1 (SLCO1B1). In addition, it is valuable
to specify the need for stratifying the population
based on genotype while conducting the DDI
studies. Another alternative is to consider
powering the study for the genotype status that is
likely to have the highest potential for interaction.
Choice of Substrate and Interacting
Drugs
CYP-Mediated Interactions
The Investigational Drug as a Substrate of
CYP Enzymes – Effect of Other Drugs on
Investigational Drugs
When testing an investigational drug for the possibility that its metabolism is inhibited or induced
(i.e., being the victim drug of a DDI as a substrate), selection of the interacting drug can then
be based on known, important inhibitors and
inducers of the pathway under investigation.
Strong inhibitors and inducers provide the most
sensitive assessment and should generally be
tested first. Consider, for example, an investigational drug metabolized by CYP3A with the contribution of this enzyme to the overall elimination
of this drug that is either substantial ( 25% of the
clearance pathway) or unknown. In this case, the
inhibitor and inducer can be itraconazole and
rifampin, a strong inhibitor and a strong inducer,
respectively. Respective strong inhibitors or
inducers should be looked after in the respective
sections of the guidelines from FDA, EMA, and
PMDA or in the most current literature. If the
study results are negative, then absence of a clinically important DDI for the metabolic pathway is
demonstrated. If the clinical study of the strong
inhibitor or inducer is positive, effects through in
vivo studies of other less potent specific inhibitors
11
or inducers may be needed to be evaluated. If the
investigational drug is metabolized by CYP3A
and its plasma AUC (Area under the plasma concentration time curve) is increased fivefold or
higher by strong CYP3A inhibitors, it is considered a sensitive substrate of CYP3A. The labeling
would indicate that the drug is a “sensitive
CYP3A substrate” and that its use with strong or
moderate inhibitors may call for caution,
depending on the drug’s exposure-response
relationship.
For further information as regards the labeling
of respective DDI effects, please look at the
respective section of the DDI guidelines from
EMA, FDA, and PMDA.
If a drug is metabolized by a polymorphic
enzyme (such as CYP2D6, CYP2C9, 1327
CYP2C19, or UGT1A1), the comparison of pharmacokinetic parameters of this drug in poor metabolizers and extensive metabolizers may
substitute for an interaction study for that particular pathway, as the PK in the poor metabolizers
will indicate the effect of a strong inhibitor. When
the study suggests the presence of a significant
interaction with strong inhibitors or in poor metabolizers, further clinical DDI evaluation, e.g.,
with weaker inhibitors or intermediate metabolizers, may be recommended (additionally also
mechansitic modeling approaches may be used
supporting respective investigantions).
The Investigational Drug as an Inhibitor or
an Inducer of CYP Enzymes: Effect of
Investigational Drugs on Other Drugs
When studying an investigational drug as the
interacting drug (being the perpetrator drug), the
choice of substrates (approved drugs) for initial in
vivo studies depends on the P450 enzymes
affected by the interacting drug. When testing
inhibition, the substrate selected should generally
be one whose pharmacokinetics are markedly
altered by the coadministration of known specific
inhibitors of the enzyme systems (sensitive substrates) to see the largest impact of the interacting
investigational drug. Examples of such substrates
include (refer also to the respective section in the
EMA, FDA, and PMDA DDI guidelines and most
recent literature):
12
P. Stopfer
1.
2.
3.
4.
5.
investigational drug, when given at the highest
dose and shortest dosing interval, increases the
AUC of oral midazolam or other sensitive
CYP3A substrates by between 1.25- and 2-fold
(1.25- and <2-fold), it can be considered a weak
CYP3A inhibitor.
When an in vitro evaluation does not rule out
the possibility that an investigational drug is an
inducer of CYP3A, an in vivo evaluation can
be conducted using the most sensitive substrate
(e.g., oral midazolam). When midazolam, is
coadministered orally following the administration of multiple doses of the investigational
drug, and there is no interaction, it can be concluded that the investigational drug is not an
inducer of CYP3A (in addition to the conclusion
that it is not an inhibitor of CYP3A). A caveat to
this interpretation is that if the investigational drug
is both an inducer and inhibitor of CYP3A, such
as ritonavir, the net effect at any time it is introduced may vary. In this case, the net effect of the
drug on CYP3A function may be time dependent.
In vivo induction evaluations have often been
conducted using oral contraceptives as the substrate. However, oral contraceptives are not the
most sensitive substrates for CYP3A, so a negative result does not exclude the possibility that the
investigational drug is an inducer of CYP3A.
Some compounds listed as sensitive substrates
for the other enzymes can also be used as substrates with the investigational drug as an inducer.
For example, omeprazole and repaglinide are
CYP2C19 and CYP2C8 substrates, respectively,
but they are also metabolized by CYP3A. If
omeprazole is used as a substrate to study
CYP2C19 induction, measurement of its metabolites (CYP2C191397-mediated hydroxy-omeprazole and CYP3A4-mediated omeprazole sulfone)
will be recommended for the interpretation of the
study results.
Midazolam for CYP3A
Theophylline for CYP1A2
Bupropion for CYP2B6
Repaglinide for CYP2C8
Warfarin for CYP2C9 (with the evaluation of
S-warfarin)
6. Omeprazole for CYP2C19
7. Desipramine for CYP2D6
If the initial study determines that an investigational drug either inhibits or induces metabolism of sensitive substrates, further studies using
other substrates, representing a range of therapeutic classes, based on the likelihood of
coadministration, may be useful. If the initial
study with the most sensitive substrates is negative, it can be presumed that less sensitive substrates also will be unaffected. It should be noted
that several of the substrates recommended for
drug interaction studies are not specific because
they are substrates for more than one CYP enzyme
or may be substrates for drug transporters. While a
given substrate may not be metabolized by a single enzyme (e.g., dextromethorphan elimination
is carried out primarily by CYP2D6 but other
enzymes also contribute in a minor way), its use
in an interaction study is appropriate if the inhibitor (the investigational drug) to be evaluated is
selective for the CYP enzyme of interest. If an
investigational drug is a CYP inhibitor, it may be
classified as a strong, moderate, or weak inhibitor
based on its effect on a sensitive CYP substrate.
For example, CYP3A inhibitors can be classified
based on the magnitude of the change in plasma
AUC of oral midazolam or other CYP3A substrates that are similar in characteristics (e.g., fm
(%clearance contributed by CYP3A), half-life,
not subject to transporter effect) as midazolam,
when the substrate is given concomitantly with
the inhibitor. If the investigational drug increases
the AUC of oral midazolam or other CYP3A
substrate by fivefold or higher ( fivefold), it
can be considered a strong CYP3A inhibitor. If
the investigational drug, when given at its highest
dose, increases the AUC of oral midazolam or
other sensitive CYP3A substrates by between
two- and fivefold ( two- and <fivefold), it can
be considered a moderate CYP3A inhibitor. If the
Transporter-Mediated Interactions
Similar to CYP enzymes, transporters may be
inhibited or induced. Inhibition of transporters
by interacting drugs can lead to altered exposure
of other drugs that are substrates of transporters.
Therefore, the potential for an investigational
drug as a substrate, inhibitor, or inducer for
Drug–Drug Interaction Studies
transporters should be evaluated during drug
development.
In the most recent guidances from EMA, FDA,
and PMDA, BCRP, OATP, OATs, and OCTs are
considered important transporters (see also Tables
1, 2, and 3) in addition to P-gp and should be
routinely evaluated. Because the field of transporter pharmacology is rapidly evolving, other
transporters (e.g., multidrug resistance-associated
proteins (MRPs), multidrug and toxin extrusion
(MATE) transporters, and bile salt export pump
(BSEP) transporters) should be considered when
appropriate.
The Investigational Drug as a Substrate of
Transporters – The Effect of Other Drugs on
an Investigational Drug
When testing an investigational drug for the possibility that its transport is inhibited or induced (i.
e., as a substrate), selection of the interacting
drugs should be based on in vitro or in vivo
studies identifying the transporters that are
involved in the absorption and disposition of the
investigational drug (e.g., absorption and efflux in
the gastrointestinal tract, uptake and secretion in
the liver, and the secretion and reabsorption in the
kidney). The choice of the interacting drug should
be based on known, important inhibitors of the
pathway under investigation. Strong inhibitors
provide the most sensitive assessment and should
generally be tested first. As there is overlapping
selectivity in substrate and inhibitor among transporters, negative results from a study using a
broad inhibitor may rule out the possibility for
drug interaction mediated by multiple pathways.
For example, it may be appropriate to use an
inhibitor of many transporters (e.g., cyclosporine,
which inhibits P-gp, OATP, and BCRP) to study
its effect on a drug that may be a substrate for
these transporters. A negative result rules out the
involvement of these transporters in the drug’s
disposition. However, if the result is positive, it
will be difficult to determine the relative contribution of each transporter to the disposition of the
substrate drug. In contrast, if the goal of the study
is to determine the role of a specific pathway in the
13
PK of a substrate drug, then a selective and potent
inhibitor for that transporter should be used. As an
alternative, comparative PK of an investigational
drug in subjects with different genotypes of specific transporters can be evaluated to determine
the importance of a specific transporter in the
clearance pathway for the drug. On the other
hand, polymorphism data on P-gp is controversial
and may not be used to determine the role of P-gp
in the disposition of investigational drugs that are
substrates of P-gp.
The Investigational Drug as an Inhibitor or
an Inducer of Transporters – Effect of the
Investigational Drugs on Other Drugs
When studying an investigational drug as the
interacting drug, the choice of substrates for initial
in vivo studies depends on the transport pathway
that may be affected by the interacting drug. In
general, when testing inhibition, the substrate
selected should be one whose pharmacokinetics
are markedly altered by coadministration of
known specific inhibitors of the transporter pathway to see the largest impact of the interacting
investigational drug. The choice of substrates can
also be determined by the therapeutic area of the
investigational drug and the probable
coadministered drugs that are known substrates
for transporters (respective lists of selected substrates for transporters can be found in the respective guidelines of the EMA, FDA and PMDA
guideline and most recent literature). However,
because many drugs are substrates of multiple
transporters or enzymes, specific substrates for
each transporter are not available. The observed
clinical interactions may be a result of inhibition
of multiple pathways if the investigational drug is
also an inhibitor for the same multiple pathways.
Because of the lack of a validated in vitro
system to study transporter induction, the definitive determination of induction potential of an
investigator on transporters is based on in vivo
induction studies. For example, because of similarities in the mechanisms of CYP3A and P-gp
induction, information from the testing of CYP3A
inducibility can inform decisions about P-gp. If an
14
investigational drug is found not to induce
CYP3A in vitro, no further tests of CYP3A and
P-gp induction in vivo are necessary. If a study of
the investigational drug’s effect on CYP3A activity in vivo is indicated from a positive in vitro
screen, but the drug is shown not to induce
CYP3A in vivo, then no further test of P-gp
induction in vivo is necessary. However, if the in
vivo CYP3A induction test is positive, then an
additional study of the investigational drug’s
effect on a P-gp probe substrate is recommended.
If the drug is also an inhibitor for P-gp, then the
induction study can be conducted with the inhibitor study using a multiple-dose design.
EMA, FDA, and PMDA DDI guidelines contain valuable information regarding the classification of in vivo inhibitors or inducers for CYP
enzymes, examples of sensitive in vivo CYP substrates and CYP substrates with narrow therapeutic ranges, examples of in vivo inhibitors and
inducers of selected transporters, examples of in
vivo substrates of selected transporters and examples of in vivo CYP3A and P-gp inhibitors and
their relative potency.
Complex Drug Interactions
The above sections separately discussed DDIs
related to effects on enzymes and transporters,
but drug interactions for a specific drug may
occur based on a combination of mechanism and
have to be taken in consideration, when a clinical
DDI trial needs to be designed.
Such “complex drug interaction” scenarios
include, but are not limited to:
• Concurrent inhibition and induction of one
enzyme or concurrent inhibition of enzyme
and transporter by a drug
• Increased inhibition of drug elimination by the
use of more than one inhibitor of the same
enzyme that metabolizes the drug
• Increased inhibition of drug elimination by use
of inhibitors of more than one enzyme that
metabolizes the drug
P. Stopfer
• Inhibition by a drug and its metabolite or
metabolites, both of which inhibit the enzyme
that metabolizes the substrate drug
• Inhibition of an enzyme other than the genetic
polymorphic enzyme in poor metabolizers taking substrate that is metabolized by both
enzymes
Multiple CYP Inhibitors
There may be situations when an evaluation of the
effect of multiple CYP inhibitors on the drug can
be informative. For example, it may be appropriate to conduct a DDI study with more than one
inhibitor simultaneously if all of the following
conditions are met:
1. The drug exhibits blood concentration-dependent important safety concerns.
2. Multiple CYP enzymes are responsible for the
metabolic clearance of the drug.
3. The predicted residual or noninhibitable drug
clearance is low.
Under these conditions, the effect of multiple
CYP-selective inhibitors on the investigational
drug’s blood AUC may be much greater than
when the inhibitors are given individually with
the drug, and more than the product of changes
in AUC observed with each individual inhibitor.
The magnitude of the combined effect will depend
on the residual fractional clearance (the smaller
the fraction, the greater the concern) and the relative fractional clearances of the inhibited pathways. Modeling and simulation approaches can
help to project the magnitude of the effect based
on single pair drug interaction studies. If results
from a study with a single inhibitor have already
triggered a major safety concern (i.e., a contraindication), multiple inhibitor studies are unlikely to
add value.
Enzyme/Transporter Interplay
There is an overlap in enzyme and transporter
specificity. For example, there is considerable
overlap between CYP3A and P-gp inhibitors and
inducers. Itraconazole inhibits CYP3A and P-gp
and rifampin induces CYP3A and P-gp. However,
dual inhibitors for CYP3A and P-gp do not
Drug–Drug Interaction Studies
necessarily have similar inhibition potency on
CYP3A and P-gp. To assess the worst case scenario for a dual CYP3A and P-gp substrate, inhibition should be studied using an inhibitor that
shows strong inhibition for both P-gp and
CYP3A, e.g., such as itraconazole. However,
under this condition, if the result is positive, specific attribution of an AUC change to P-gp or
CYP3A4 may not be possible. If the goal is to
determine the specific contribution of CYP3A or
P-gp on the AUC change, then a strong inhibitor
for CYP3A only or a potent inhibitor for P-gp
only should be selected to discern the effect of
CYP3A versus P-gp.
In addition to the possibility that a drug is an
inhibitor or inducer of multiple enzymes/transporters, a drug can be an inhibitor of one
enzyme/transporter and inducer of another
enzyme/transporter. For example, rifampin, an
established inducer of multiple CYP enzymes
and transporters, was recently found to be an
inhibitor of the uptake transporter OATP1B1 and
may inhibit the uptake of an investigational drug
that is a substrate of OATP1B1. Accordingly, if a
drug is a CYP enzyme substrate and an OATP1B1
substrate, an induction study with rifampin should
be designed and interpreted carefully. The net
steady-state effect may vary depending on the
relative size of the individual effect on transporter
and enzyme activities. Timing of administration
may become critical in situations when both
enzymes and transporters can be affected. These
overlapping selectivities contribute to complex
drug interactions and make the prediction of in
vivo outcome based on in vitro evaluation challenging or impossible (Zhang et al. 2009a, b). The
implications of simultaneous inhibition of a dominant CYP enzyme(s) and an uptake or efflux
transporter that controls the availability of the
drug to CYP enzymes can be just as profound as
that of multiple CYP inhibition. For example, the
large effect of coadministration of itraconazole
and gemfibrozil on the systemic exposure (AUC)
of repaglinide may be attributed to collective
inhibitory effects on both the enzyme (CYP2C8)
15
and transporters (OATP1B1) by itraconazole and
gemfibrozil and their respective metabolites.
Effect of Organ Impairment
Another type of complex drug interaction is the
coadministration of substrate and enzyme/transporter inhibitor in subjects with organ impairment. For example, if a substrate drug is
eliminated through both hepatic metabolism and
renal secretion/filtration, the use of an enzyme
inhibitor in subjects with renal impairment may
cause a more than projected increase in exposure
of substrate drug based on individual effect alone.
Unfortunately, current knowledge does not permit
the presentation of specific guidance for studying
some of these complex drug interaction scenarios
because dedicated in vivo studies in humans may
not be feasible or may raise ethical and practical
considerations. Modeling and simulation
approaches integrating prior in vitro and in vivo
ADME and drug interaction data may be useful for
evaluating complex drug interactions. For example, results from dedicated single pair drug interaction studies and separate pharmacokinetic
evaluation in subjects with organ impairment may
provide useful information to strengthen the model
for the evaluation of complex drug interactions.
Pediatrics and Geriatrics
Age-related changes in physiological processes
governing drug disposition and drug effect have
been investigated. In some cases, disproportional
alterations in binding proteins, drug metabolizing
enzymes and/or transporters, and renal filtration/
secretion caused by developmental changes have
been known to result in different drug disposition
characteristics in pediatric and geriatric
populations. However, dedicated drug interaction
studies in these populations may not be feasible.
Simulations using system biology approaches
such as PBPK models may be helpful to predict
drug interaction potential when the model can be
constructed based on sufficient in vitro and clinical pharmacology and drug interaction data and
incorporates development changes.
16
Route of Administration
The route of administration chosen for a metabolic DDI study is important. For an investigational agent, the route of administration generally
should be the one planned for clinical use. When
multiple routes are being developed, the need for
metabolic DDI studies by each route depends on
the expected mechanisms of interaction and the
similarity of corresponding concentration-time
profiles for parent drug and metabolites. Sometimes certain routes of administration can reduce
the utility of information from a study. For example, intravenous administration of a substrate drug
may not reveal an interaction for substrate drugs
where intestinal CYP3A activity markedly alters
bioavailability
Dose Selection
The doses of the substrate and interacting drug
used in studies should maximize the possibility of
demonstrating an interaction. For this reason, the
maximum planned or approved dose and shortest
dosing interval of the interacting drug (as inhibitors or inducers) should be used. For example,
when using itraconazole as an inhibitor of
CYP3A, the decision whether to dose at 400 mg
QD or 200 mg BID for multiple days can be
determined based on the pharmacokinetic characteristics (e.g., the half-life) of the substrate drug
(Zhao et al. 2009). When using rifampin as an
inducer, dosing at 600 mg QD for multiple days
would be preferable to lower doses. When there
are safety concerns, doses lower than those used
clinically may be recommended for substrates. In
such instances, any limitations of the sensitivity of
the study to detect the drug-drug interaction due to
the use of lower doses should be carefully
considered.
Endpoints
Changes in pharmacokinetic parameters generally
are used to assess the clinical importance of DDIs.
Interpretation of findings (i.e., deciding whether a
P. Stopfer
given effect is clinically important) depends on a
good understanding of dose/concentration and
concentration/response relationships for both
desirable and undesirable drug effects in the general population or in specific populations. In certain instances, reliance on pharmacodynamic
endpoints in addition to pharmacokinetic measures and/or parameters may be useful. Examples
include INR measurement (e.g., when studying
warfarin
interactions)
or
QT
interval
measurements.
Pharmacokinetic Endpoints
Substrate PK exposure measures such as AUC,
Cmax, time to Cmax (Tmax), and others as appropriate should be obtained in every study. Calculation
of pharmacokinetic parameters such as clearance,
volumes of distribution, and half-lives may help
in the interpretation of the results of the trial. In
some cases, obtaining these measures for the
inhibitor or inducer may be of interest as well,
notably where the study is intended to assess
possible changes in the disposition of both study
drugs. Additional measures may help in steadystate studies (e.g., trough concentration) to demonstrate that dosing strategies were adequate to
achieve near steady state before and during the
interaction. In certain instances, an understanding
of the relationship between dose, plasma concentrations, and response may lead to a special interest in certain pharmacokinetic measures and/or
parameters. For example, if a clinical outcome is
most closely related to peak concentration (e.g.,
tachycardia with sympathomimetics), Cmax or an
early exposure measure may be most appropriate
for evaluation. Conversely, if the clinical outcome
is related more to extent of absorption, AUC
would be preferred. The frequency of sampling
should be adequate to allow accurate determination of the relevant measures and/or parameters
for the parent molecule and metabolites. For the
substrate, whether the investigational drug or the
approved drug, determination of the pharmacokinetics of relevant metabolites is important. Also,
measurement of these metabolites may be useful
to differentiate the effect of inhibitor/inducer on
pathways mediated by different CYP enzymes.
Drug–Drug Interaction Studies
Statistical Considerations, Clinical
Relevance, and Sample Size
The goal of a DDI study is to determine whether
there is any increase or decrease in exposure to the
substrate in the presence of the interacting drug. If
there is, its implications should be assessed by an
understanding of PK/PD relations both for Cmax
and AUC. Results of DDI studies should be
reported as 90% confidence intervals about the
geometric mean ratio of the observed pharmacokinetic measures with (S þ I) and without the
interacting drug (S alone). Confidence intervals
provide an estimate of the distribution of the
observed systemic exposure measure ratio of
(S þ I) versus (S alone) and convey a probability
of the magnitude of the interaction. In contrast,
tests of significance are not appropriate because
small, consistent systemic exposure differences
can be statistically significant ( p < 0.05), but
not clinically relevant.
When a DDI of potential importance is clearly
present, specific recommendations should be provided regarding the clinical significance of the
interaction based on what is known about the
dose-response and/or PK/PD relationship for the
substrate drug used in the study. This information
can form the basis for reporting study results and
for making recommendations in the labeling. It
should be recognized that dose-response and/or
PK/PD information can sometimes be incomplete
or unavailable, especially for an older approved
drug used as a substrate. If the sponsor wishes to
include a statement in the labeling that no known
DDI of clinical significance exists, the sponsor
should recommend specific no effect boundaries,
or clinical equivalence intervals, for a DDI and
should provide the scientific justification for the
recommendations. No effect boundaries represent
the interval within which a change in a systemic
exposure measure is considered not clinically
meaningful. These conclusions can be based on
dose-response data or on PK/PD modeling.
There are two approaches to defining no effect
boundaries:
Approach 1: No effect boundaries can be based on
the population (group) average dose-related
17
and/or individual concentration-response relationships derived from PK/PD models, and
other available information for the substrate
drug to define a degree of difference caused
by the interaction that is of no clinical consequence. If the 90% confidence interval for the
systemic exposure measurement change in the
DDI study falls completely within these no
effect boundaries, it can be concluded that no
clinically significant drug-drug interaction is
present.
Approach 2: In the absence of no effect boundaries defined in Approach 1, a default no effect
boundary of 80–125% can be used for both the
investigational drug and the approved drugs
used in the study. When the 90% confidence
intervals for systemic exposure ratios fall
entirely within the equivalence range of
80–125%, standard practice is to conclude
that no clinically significant differences are
present. This is, however, a very conservative
standard and a substantial number of subjects
(sample size) would need to be studied to meet
it.
The selection of the number of subjects for a
given DDI study will depend on how small an
effect is clinically important to detect or rule out
the inter- and intra-subject variability in pharmacokinetic measurements, and possibly other factors or sources of variability not well recognized.
Cocktail Approaches
Simultaneous administration of a mixture of substrates of multiple CYP enzymes and transporters
in one study (i.e., a “cocktail approach”) in human
volunteers is another way to evaluate a drug’s
inhibition or induction potential, provided that
the study is designed properly and the following
factors are present:
1. The substrates are specific for individual CYP
enzymes or transporters.
2. There are no interactions among these
substrates.
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3. The study is conducted in a sufficient number
of subjects.
Negative results from a well-conducted cocktail study can eliminate the need for further evaluation of particular CYP enzymes. However,
positive results can indicate that further in vivo
evaluation should be conducted to provide quantitative exposure changes (such as AUC, Cmax), if
the initial evaluation only assessed the changes in
the urinary parent to metabolite ratios. The data
generated from a cocktail study can supplement
data from other in vitro and in vivo studies in
assessing a drug’s potential to inhibit or induce
CYP enzymes and transporters
Negative results from a well-conducted cocktail study may eliminate the need for further evaluation of particular CYP enzymes and
transporters. However, positive results may indicate that further in vivo evaluation should be
conducted
Pharmacogenomic Considerations
When a DDI study uses a probe drug (e.g., omeprazole for CYP2C19) to evaluate the impact of the
investigational drug on a polymorphic enzyme,
individuals who have no functional enzyme activity would not be appropriate study subjects. Drug
interaction studies that evaluate enzymes or transporters with known polymorphisms should
include collection of genotype or phenotype information to allow appropriate interpretation of the
study results. In some instances, an evaluation of
the extent of drug interactions in subjects with
various genotypes may be helpful. Moreover,
DDIs can differ among individuals based on
genetic variation of a polymorphic enzyme. For
example, a strong CYP2D6 inhibitor (e.g., fluoxetine) will increase the plasma levels of a
CYP2D6 substrate (e.g., atomoxetine) in subjects
who are extensive metabolizers (EM) of
CYP2D6, but will have minimal effect in subjects
who are poor metabolizers (PM) of CYP2D6,
because these individuals have no active enzyme
to inhibit. It is noted that CYP2D6 PMs will
already have greatly increased levels of
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atomoxetine if given usual doses. There are also
situations where inhibition may have a greater
effect in PMs than EMs. If a drug is metabolized
by a minor pathway (nonpolymorphic enzyme)
and a major pathway (polymorphic enzyme), inhibition of the minor pathway will usually have
minimal effect on plasma concentrations in EMs.
However, the minor pathway plays a greater role
in clearance of the drug in PMs of the major
pathway. Thus, inhibition of the minor pathway
in PMs of the major pathway can have a significant effect on drug clearance and resulting drug
concentrations. Therefore, studying the effect of
interactions may be recommended in subjects
with varied genotypes or phenotypes
DDI as Part of Pop PK in Phase II and
Phase III Trials
Population pharmacokinetic (PopPK) analyses of
data obtained from large-scale clinical studies that
include sparse or intensive blood sampling can
help characterize the clinical impact of known or
newly identified interactions and determine recommendations for dosage modifications for the
investigational drug as a substrate. The results of
such analyses can be informative and sometimes
conclusive when the clinical studies are adequately designed to detect significant changes in
drug exposure due to DDIs. PopPK evaluations
may also detect unsuspected DDIs, a particularly
important possibility given the complexity of the
potential interactions, not all of which are likely to
have been anticipated and studied. PopPK evaluations can also provide further evidence of the
absence of a DDI, when supported by prior evidence and mechanistic data. It is unlikely, however, that population analysis will persuasively
show the absence of an interaction that is
suggested by information from in vivo studies
specifically designed to assess a DDI. To be optimally informative, PopPK studies should have
carefully designed study procedures and sample
collection protocols. Simulations (e.g., by population-based PBPK models) can provide valuable
insight into optimizing the study design. Detailed
information on the dose given and time of
Drug–Drug Interaction Studies
administration should be documented for the
coadministered drugs. When relevant for the specific drug, the time of food consumption should be
documented. Population analyses should focus on
excluding a specific clinically meaningful PK
change. Because exposure of coadministered
drugs is not monitored in most PopPK studies,
the PopPK approach may not be useful to assess
the effect of the investigational drugs on other
drugs.
DDI Considerations for NBEs
A comparison of the most recent DDI guidelines
from EMA, FDA, and PMDA, only the guideline
FDA provides a flowchart how to evaluate DDI
for biologics (see respective part of the FDA DDI
guideline). The respective EMA guideline does
not mention about DDI of biologics. Whereas
the FDA and PMDA recommend to conduct clinical DDI study, in case the biologics are cytokine
or cytokine modulator. Additionally, FDA and
PMDA recommend to examine PK/PD, in case
the biologics is used as combination therapy with
other agents. Below, some more specific recommendations for DDI evaluations with NBEs are
given based on the FDA DDI guideline:
Therapeutic proteins (TPs) typically do not
undergo metabolism or transport as their clearance pathway, therefore the potential is limited
for small molecule drugs to affect TPs through
metabolism or transport pathways. However, a
drug may affect the clearance of TPs through the
drug’s effect on immunogenicity (e.g., methotrexate reduces the clearance of infliximab, possibly
due to methotrexate’s effect on the antibodies
formed against infliximab). In addition, TPs that
are cytokines or cytokine modulators may modify
the metabolism of drugs that are substrates for
CYP P450 enzymes through their effects on the
regulation pathways of CYP P450 enzymes. For
example, cytokines such as IL-6 can produce concentration-dependent inhibition on various CYP
isoforms at the transcription level or by alteration
of CYP enzyme stability in patients with infection
or inflammation and increase the plasma concentrations of specific CYP substrate drugs. In
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contrast, cytokine modulators such as tocilizumab
(anti-IL-6 receptor antibody) may reverse the
apparent “inhibition” effect of the cytokines on
CYP substrates, resulting in a “normalization” of
CYP activities.
Drug-TP interactions have been observed and
information about these interactions is included in
labeling and in the following some general considerations are given:
• If an investigational TP is a cytokine or cytokine modulator, studies should be conducted to
determine the TP’s effects on CYP enzymes or
transporters (Huang et al. 2010; Le Vee et al.
2009). In vitro or animal studies have limited
value in the qualitative and quantitative projection of clinical interactions because translation
of in vitro to in vivo and animal to human
results to date has been inconsistent, necessitating in vivo drug interaction studies. The in
vivo evaluations of TPs in targeted patient
populations can be conducted with individual
substrates for specific CYP enzymes and transporters, or studies can be conducted using a
“cocktail approach.”
• For TPs that will be used in combination with
other drug products (small molecule or TP) as a
combination therapy, studies should evaluate
the effect of each product on the other. The
studies should assess effects on pharmacokinetics (PK) and, when appropriate, pharmacodynamics (PD) of either drug. This evaluation
is particularly important when the drug used in
combination has a NTR (e.g., chemotherapeutic agents).
• When there are known mechanisms or prior
experience with certain PK or PD interactions,
appropriate in vitro or in vivo assessments for
possible interactions should be conducted.
Some interactions between drugs and TPs are
based on mechanisms other than CYP or transporter modulation. For example, methotrexate’s immunosuppressive effect may alter the
clearance of concomitantly administered TPs
through the reduction of antibodies formed
against TP.
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References and Further Reading
EMA-CHMP (2012) Guideline on the investigation of
drug interactions: final (CPMP/EWP/560/95/Rev. 1
corr. 2). http://www.ema.europa.eu/docs/en_GB/docu
ment_library/Scientific_guideline/2012/07/WC5001
29606.pdf. Accessed 13 Mar 2017
Huang S-M, Zhao H, Lee J, Reynolds KS, Zhang L,
Temple R, Lesko LJ (2010) Therapeutic protein drug
interactions and impacts on drug development, Clin
Pharmacol Ther 87:497–503
Le Vee M, Lecureur V, Stieger B, Fardel O (2009) Regulation of drug transporter expression in human hepatocytes exposed to the proinflammatory cytokines tumor
necrosis factor-alpha or interleukin-6, Drug Metab
Dispos 37:685–693
PMDA. Pharmaceuticals & Medical Device Agency-Japan
(2014) Drug interaction guideline for drug development and labeling recommendations (draft for public
comment)
2014.
http://www.solvobiotech.com/
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documents/Japanese_DDI_guideline_(draft)_2014Jan.
pdf. Accessed 13 Mar 2017
US-FDA (2012) Guidance for industry: drug interaction
studies – study design, data analysis, implications for
dosing, and labeling recommendations (draft guidance). http://www.fda.gov/downloads/Drugs/Guidance
rmation/Guidances/
ComplianceRegulatoryInfo
ucm292362.pdf. Accessed 13 Mar 2017
Zhang L, Zhang Y, Zhao P, Huang S-M (2009a) Predicting
drug-drug interactions: An FDA perspective, The
AAPS Journal 11(2):300–306
Zhang L, Zhang Y, Huang S-M (2009b) Scientific and
regulatory perspectives on metabolizing enzyme-transporter interplay and its role in drug interactions - challenges in predicting drug interaction, Molecular
Pharmaceutics 6(6):1766–1774
Zhao P, Ragueneau-Majlessi I, Zhang L, Strong J, Reynolds K, Levy R, Thummel K, Huang S-M (2009)
Quantitative evaluation of pharmacokinetic inhibition
of CYP3A substrates by ketoconazole – a simulation
study, J Clin Pharmacol 49(3):351–359, 2143