Henri CAPLAIN, MD, MSc
President
‘Association Française de PharmacologieTranslationnelle
– Le Club Phase 1’
October 17, 2018GMP 2018 - Institut Pasteur - Paris1
Transporter-mediated Drug Interaction :
Are They Clinically Relevant ?
Known Drug-drug Interaction (DDI)
Which Really Matters
October 17, 2018GMP 2018 - Institut Pasteur - Paris2
Classical Example of DDI with
Harmful Clinical Consequences
October 17, 2018GMP 2018 - Institut Pasteur - Paris3
The first case of well documented DDI with
harmful clinical consequences was that of the
potentially lethal arrhythmia, torsades de pointes,
occurring in association with terfenadine
(Seldane) use in a young woman.
This ECG is a classic example of torsades de
pointes, which is French for "twisting of the
points“. Torsades is a form of ventricular
tachycardia that can most often be due to
medications. The QRS complexes during this
rhythm tend to show a series of "points up"
followed by "points down" often with a narrow
waist between. Recognition and reporting of this
arrhythmia in association with terfenadine,
astemizole (Hismanal), cisapride (Propulsid),
grepafloxacin (Raxar), and mibefradil (Posicor)
ultimately led to the removal of these medications
from the market.
Identifying Drug-drug Interaction (DDI) in
Drug Development and in Post-Marketing
October 17, 2018GMP 2018 - Institut Pasteur - Paris4
Selected Highly Significant PK
Drug-Drug Interactions
October 17, 2018GMP 2018 - Institut Pasteur - Paris5
Victim drugs Perpetrator drugs PK Clinical
consequence
Tryptans MAO-A inhibitors AUC raised up to 7-
fold
Cardiovascular
ADRs
Ramelteon Strong CYP1A2
inhibitors
AUC raised up to
190-fold
CNS ADRs
Tizanidine CYP1A2 inhibitors AUC raised up to 10-
fold
Hypotonia
Lova-
/Simvastatin
CYP3A4 inhibitors AUC raised up to 20-
fold
Rhabdomyolysis
Irinotecan CYP3A4 inhibitors AUC raised 2-fold Cytotoxicity
Ergot alkaloids CYP3A4 inducers Vasoconstriction,
necrosis
(ergotism)
Protease
inhibitors
Strong CYP3A4
inducers
AUC decreased by
80%
Lack of efficacy
Atazanavir Proton pump
inhibitors
AUC decreased by
60%
Lack of efficacy
Phansalkar S et al. J Am Med Inform Assoc
2012;19:735-43
What about drug-drug interactions
mediated by transporters?
Selected Highly Significant PD
Drug-Drug Interactions
October 17, 2018GMP 2018 - Institut Pasteur - Paris6
PD DDI Drug #1 Drug#2 Clinical consequence
Additive Liraglutide Insulin determir Glucose lowered
Additive Phenprocoumon NSAIDS Additive anticoagulant
effect
Synergistic Diphenhydramin
e
Ethanol Enhanced impairment
Synergistic Tramadol Acetaminophen Enhanced pain reduction
Competitive
antagonistic
Naloxone Opioids Dampening of opioid
effects
Noncompetiti
ve allosteric
antagonists
Ruthenium red Capsaicin Reduce irritant effect of
capsaicinRoberts AG et al. Clin Pharmacol. 2018;10:123-
134
What about drug-drug interactions
mediated by transporters?
Drug Transport Proteins:
Gatekeepers of the Body
October 17, 2018GMP 2018 - Institut Pasteur - Paris7
> 400 membrane
transport proteins
in human
genome
ABC
transporters
SLC transporters
~30 drug
transporters
(efficacy/safety of
drugs)
Zhang L et al. Clin Pharmacol Ther. 2011;89:481-4
Drug-drug interaction potential
!
Absorptio
n
Uptake for metabolism and
excretionDisposition Excretion
Expression of Transporters
in Major Human Organs
October 17, 2018GMP 2018 - Institut Pasteur - Paris8
Coordinated
operation of
transporters
Zamek-Gliszczynski MJ et al. Clin Pharmacol Ther. 2018;Aug 8
Drug Transporters – Clinical
Relevance (1/2)
October 17, 2018GMP 2018 - Institut Pasteur - Paris9
Clinical relevance
• P-gp and BCRP limit
oral bioavailability of
drug substrates
• Inhibition of P-gp or
BCRP increased
substrate
bioavailability
• High gut
concentrations of
inhibitors lead to max.
transport inhibition
Hillgren KM et al. Clin Pharmacol Ther
2013;94:52-63
Clinical relevance
• P-gp (and BCRP)
constitute BBB for
substrate drugs
• Transport inhibition
potential CNS ADRs
• Unbound concentrations
of marketed inhibitors at
BBB < in vitro IC50 of
transport
Low risk for relevant
DDI
Kalvass JC et al. Clin Pharmacol Ther.
2013;94:80-84
Drug Transporters – Clinical
Relevance (2/2)
October 17, 2018GMP 2018 - Institut Pasteur - Paris10
Clinical relevance
• Liver uptake transport
basis for subsequent
drug metabolism
• Inhibition of liver
uptake increased
plasma exposure of
substrate
• Drug inhibition of
MRP or BSEP DILI
risk
• Canalicular MRP with
sinusoidal salvage
Hillgren KM et al. Clin Pharmacol Ther 2013;94:52-63 Kalvass JC et al. Clin Pharmacol Ther.
2013;94:80-84
Clinical relevance
• Renal drug clearance
= glomerular filtration
+ tubular secretion –
tubular re-absorption
• Drugs with high
tubular secretion at
risk for renal transport
DDIs
• Uptake inhibition may
prevent nephrotoxicity
Other Localizations of Transporters
October 17, 2018GMP 2018 - Institut Pasteur - Paris11
Lee J et al. Drug Metabolism and Disposition 2016, 44 (10)
1675-1681
Cardiomycocyt
es
Ciliary
body
Ocular anterior
globePlacental barrier
Zha W. J Food Drug Anal. 2018;26(2S):S32-S44
Examples of Pharmacokinetically
Drug Transporter Mediated DDIs
October 17, 2018GMP 2018 - Institut Pasteur - Paris12
ADME Protein Victim
drug
Perpetrator
drug
DDI PK effect
Intestinal
absorptio
n
P-gp Talinolol Erythromycin Inhibition AUC▲
Cmax▲
F▲
Intestinal
absortion
P-gp Talinolol Rifampicin Induction AUC▼35%
Cmax▼ 38%
F▼ 35%
Intestinal
absorptio
n
BCRP Rosuvastat
in
Fostamatinib Inhibition AUC▲ 196%
Cmax▲188%
F▲
Intestinal
absorptio
n
OATP1A
2
Fexofenadi
ne
Naringin Inhibition AUC▼22%
Cmax▼ 18%
F▼
BBB
distributio
n
P-gp Verapamil Tariquidar Inhibition VT,brain ▲
Placental
distributio
n
P-gp Felodipine Intraconazole Inhibition VT,fetus ▲Roberts AG et al. Clin Pharmacol.
2018;10:123-134
US FDA approved drugs from 2013
to 2016 : PK DDIs in NDAs
October 17, 2018GMP 2018 - Institut Pasteur - Paris13
103 NDAs including 14 combination drugs
NMEs = 107
CYP3A = approximately 2/3 of all DDIs
Transporters (alone or with enzymes) = about 1/2 of all DDIs Weak-to-moderate interactions (as victims or penetrators)
Victims : 8 NMEs sensitive substrates of CYP3A4, 2 for CYP1A2, 1 for
CYP2C8, 1 for CYP2D6 1 NME = sensitive substrate of OATP1B1/3:
Grazoprevir with changes in exposure greater than 5-fold when co-
administered with a strong inhibitor 75% of identified CYP3A4 substrates were also substrates of P-gp
Yu et al. Drug Metab Dispos. 2018;46(6): 835-845
US FDA Approved Drugs from 2013
to 2016 : PK DDIs in NDAs (2/2)
October 17, 2018GMP 2018 - Institut Pasteur - Paris14
Penetrators :
Most clinical DDIs involved weak-to-moderate inhibition or
induction
Only 1 NME showed a strong inhibition of CYP3A and 1 NME
behaved as a strong CYP3A inducer
Among drugs with large changes in exposure (≥ 5-
fold), whether as victim or perpetrator, the most
represented classes were antivirals and oncology
drugs, suggestion a significant risk of clinical DDIs in
these patient populations.
Yu et al. Drug Metab Dispos. 2018;46(6): 835-845
US FDA Approved Drugs in 2017:
PK DDIs in NDAs
October 17, 2018GMP 2018 - Institut Pasteur - Paris15
46 drugs
34 NDAs including 3 combination drugs
9 cancer treatments and 8 anti-infective agents
All the NDAs were systematically evaluated for metabolism- and transport-mediated DDI and similar trends were observed compared with drugs approved 2013-2016
CYP3A was confirmed as the predominant enzyme responsible for clinically significant drug interactions involving both inhibition and induction
Inhibition of OATP1B1/1B3 is emerging as a significant mechanism of DDIs, leading to large changes in exposure of victim drugs (antivirals, statins)
In addition to clinical trials, PBPK simulations continue to develop at a clinical tool to support dose recommendations
Most Significant Clinical Inhibitions:
max AUC ratios ≥ 5 in 2017 NDAs Review
October 17, 2018GMP 2018 - Institut Pasteur - Paris16
Most Significant Clinical Inductions:
max AUC ratio ≤ 0.2 in 2017 NDAs Review
October 17, 2018GMP 2018 - Institut Pasteur - Paris17
Most Pronounced Clinical Inhibitions:
Literature 2017-2018 (Top 10)
October 17, 2018GMP 2018 - Institut Pasteur - Paris18
Most Pronounced Clinical Inductions:
Literature 2017-2018 (Top 10)
October 17, 2018GMP 2018 - Institut Pasteur - Paris19
EU EMA EPAR New Approved Drugs
Review from 2017 to Now
October 17, 2018GMP 2018 - Institut Pasteur - Paris20
72 EPARs including 10 combinations
15 cancer drugs, 10 anti-infective agents, Immunosuppressants
27 drugs with possibly affected transporters
Labelling considerations: 4.4 Special warnings and precautions for use
4.5 Interactions with other medicinal products and other forms of interaction
4.3 Contraindications in the SmPc : 3 DRUGS+++
No RMP activities beyond routine: assessment or minimization measures
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (1/12)
October 17, 2018GMP 2018 - Institut Pasteur - Paris21
Drug Therapeutic
group
MOA Transporters
possibly affected
Clinical impact Labelling considerations
Encorafenib
BRAFTOVI
Antineoplastics Blocking
BRAF
protein
Substrate P-gp No impact None
Inhibitor OAT1,
OAT3, OAT2
Increase exposure
substrates
Caution with furosemide,
penicillin
Inhibitor OATP1B1,
OATP1B3, OCT1
Increase exposure
substrates
Caution with atorvastatin,
bosentan
Inhibitor BCRP Increase exposure
substrates
Caution with methotrexate,
rosuvastatin
Inhibitor P-gp Increase exposure
substrates
Caution with posaconazole
Binimetinib
MEKTOVI
Antineoplastics Blocking
MEK
protein
Substrate P-gp and
BCRP
Low impact None
Inhibitor OAT3 Increase exposure
substrates
Caution with pravastatin or
ciprofloxacin
Neratinib
NERLYNX
Antineoplastics Tyrosine
kinase
inhibitor
blocking
EGFR,
HER2 and
HER4
Inhibitor BCRP Increase exposure
substrates
Cautious monitoring with
rosuvastatin, sulfasalazine
Inhibitor P-gp Increase digoxin AUC
32% and Cmax 54%
Cautious monitoring with
dabigatran, digoxin and
fexofenadine
Inhibitor OCT1 Low impact None
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (2/12)
October 17, 2018GMP 2018 - Institut Pasteur - Paris22
Drug Therapeuti
c group
MOA Transporters possibly
affected
Clinical impact Labelling considerations
Lesonurad
+Allopurinol
DUZALLO
Antigout URAT1
inhibitor +
xanthine-
oxidase
inhibitor
L substrate OATP1B1,
OAT1, OAT3, OCT1
No impact None
L inhibitor OATP1B1,
OAT1nOAT3, OAT4, OCT1
No impact None
Bictegravie +
Tenofovir
alafenamide
+
Emtricitabine
BIKTARVY
Anti-
infectives
Integrase
inhibitor + 2
nucleoside
reverse
transcriptas
e inhibitors
B substrate P-gp, BCRP Not established Caution with inhibitors of P-
gp and/or BCRP
B inhibitor OCT2, MATE1 None None
TA substrate P-gp, BCRP Loss of activity
with P-gp
inductors
Co-administration of
product that induce P-gp
activity may lead to loss of
therapeutic effect and
development of resistance
Increase
concentration
with inhibitors
None
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (3/12)
October 17, 2018GMP 2018 - Institut Pasteur - Paris23
Drug Therapeutic
group
MOA Transporters
possibly affected
Clinical impact Labelling considerations
Rucaparib
RUBRACA
Antineoplasti
cs
Inhibitor of
PARP
enzymes
Substrate P-gp,
BCRP
Not established Caution with strong inhibitors of
P-gp
Inhibitor MATE1,
MATE2-K, OCT1,
OCT2
Increase metformin renal
elimination and decrease
liver uptake of metformin
Caution with metformin
Inhibitor of BCRP Increase exposure
substrate
Caution with rosuvastatin
Dolutegrav
ir +
Rilpivirine
JULUCA
Anti-
infectives
Integrase
inhibitor +
non-
nucleoside
reverse
transcripta
se inhibitor
D substrate P-gp,
BCRP
Loss of activity with
inducerss
None
Increase absorption and
plasma concentration with
inhibitors
None
D inhibitor OCT2
and MATE1
Increase concentration
dofetilide, metformin (risk
for lactic acidosis)
Contraindication with dofetilide
Dose adjustment of metformin
D inhibitor OAT1,
OAT3
Increase concentration
substrates
None
R inhibitor P-gp Can increase the exposure
of the most sensitive
substrates as dabigatran
None
R inhibitor MATE-
2K
Unknown None
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (4/12)
October 17, 2018GMP 2018 - Institut Pasteur - Paris24
Drug Therapeuti
c group
MOA Transporters
possibly affected
Clinical impact Labelling
considerations
Gemtuzuma
b +
Ozogamicin
MYLOTARG
Antineoplast
ics
MAB anti
CD33 +
cytotoxic
O inhibitor P-gp,
BCRP, BSEP,
MRP2, MATE1,
MATE2K, OAT1,
OAT3, OCT1,
OCT2, OATP1B1,
OATP1B3
Low potential None
Ertugliflozin
+ Sitagliptin
STEGLUJAN
Diabetes SGLT2
inhibitor +
DPP-4
inhibitor
E substrate P-gp
and BCRP
None None
Ertugliflozin
+ Metformin
SEGLUROM
ET
Diabetes SGLT2
inhibitor +
antihyperglyca
emic agent
(glucose
tolerance)
M substrate of
OCT1, OCT2
Inhibitor OCT1 Dose adjustment may
be considered (reduce
efficacy)
Inducers OCT1: may
increase absorption and
efficacy of metformin
Caution with renal
impairment
Inhibitors OCT2: may
decrease the renal
elimination of metformin and
thus lead to an increase in
metformin plasma
concentration
Caution in patients with
renal impairment
Inhibitors OCT1 and OCT2:
alter efficacy and renal
elimination
Dose adjustment may
be considered
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (5/12)
October 17, 2018GMP 2018 - Institut Pasteur - Paris25
Drug Therapeuti
c group
MOA Transporters possibly
affected
Clinical impact Labelling considerations
Baricitinib
OLUMIAN
T
Immunosup
pressants
Inhibitor
JAK1 and
JAK2
Substrate OAT3, P-gp,
BCRP, MATE2-K
OAT3 inhibitor AUC 2-
fold increase
Dose adjustment
Caution with leflunomide or
teriflunomide
Inhibitor OCT1 Unknown None
Letermovie
PREVYMI
S
Anti-
infectives
Inhibit CMV
DNA
terminal
complex
Substrate OATP1B1/3 Increase concentration
with inhibitors
Dose adjustment with
cyclosporine
Caution if other inhibitors
added to L + cyclosporine
Substrate P-gp, BCRP None Caution if inhibitors added
to L + cyclosporine
Inhibitor BCRP,
OATP2B1, OAT3
Unknown, OAT3
increase concentration
substrates
Additional monitoring
Inhibitor OATP1B1/3 Increase concentration
substrates particularly
with cyclosporine
Consideration when the L
regimen is changed during
treatment with substrate
Inducer P-gp Decrease concentration
substrates
Should be taking account
for substrates P-gp as
dabigatran and sofosbuvir
Inducer BCRP,
OATP2B1
Unknown Additional monitoring
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (6/12)
October 17, 2018GMP 2018 - Institut Pasteur - Paris26
Drug Therapeutic
group
MOA Transporters
possibly affected
Clinical impact Labelling
considerations
Niraparib
ZEJULA
Antineoplasti
cs
Inhibitor of PARP-1
and PARP-2
Substrate P-gp,
BCRP, MATE1/2
None None
Inhibition P-gp,
BRCP, BSEP
P-gp and BCRP :
very weakly and weak
Caution in combination
with BCRP substrates
Inhibitor MATE1/2 Increase
concentration
substrates of these
transporters :
metformin
None
Inhibit OCT1 Weak Caution with products
transported by OCT1 as
metformin
Fluticason
e furoate +
Umeclidini
um
bromide +
Vilanterol
ELEBRAT
O/
TRELEGY
ELLIPTA
Obstructive
airway
diseases
Corticosteroids +
muscarinic
receptor antagonist + β2-adrenergic
agonist
F/U/V substrates P-
gp
None None
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (7/12)
October 17, 2018GMP 2018 - Institut Pasteur - Paris27
Drug Therapeutic
axis
MOA Transporters
possibly affected
Clinical impact Labelling considerations
Padeliporfin
TOOKAD
Antineoplastic
s
Sensitizers
photodynami
c/radiation
therapy
Inhibitor OATP1B1,
OATP1B3
Transient increase
concentration
substrates
Avoid substrates on the
day of administration and
at least 24 hours after
Close monitoring
Danuravie +
Cobicistat +
Tenofovir
alafenamide
+Emtricitabin
e
SYMTUZA
Anti-infectives Inhibitor HIV-
1 protease +
mechanism-
based
inhibitor of
CYP3A + 2
nucleoside
reverse
transcriptase
inhibitors
D inhibitor P-gp Increase concentration
substrates
None
C inhibitor P-gp,
BCRP, MATE1,
OATP1B1, OATP1B3
Increase concentration
substrates
None
TA substrate P-gp,
BCRP
Loss of activity with P-
gp inductors
Co-administration may
lead to loss of therapeutic
effect and development of
resistance
Increase absorption
and plasma
concentration with P-
gp inhibitors
None
TA substrate
OATP1B1, OATP1B3
Distribution of TA in
the body may be
affected by the activity
of these transporters
None
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (8/12)
October 17, 2018GMP 2018 - Institut Pasteur - Paris28
Drug Therapeutic
group
MOA Transporters possibly
affected
Clinical impact Labelling considerations
Midostaurin
RYDAPT
Antineoplasti
cs
Inhibitor
receptor
tyrosine
kinases
(FLT3, KIT)
Inhibitor OATP1B1,
BCRP, P-gp
Not established Caution with narrow
therapeutic range
substrates of P-gp, BCRP,
digoxin
Dose adjustment to
maintain optimal exposure
Cladribine
MAVENCLA
D
Immunosupp
ressant
Nucleoside
analogue of
deoxyadeno
sine
Inhibitor ENT1,CNT3,
BCRP
May increase the
oral bioavailability
and systemic
exposure of
substrates (20%)
None
Substrate of ENT1,
CNT3
Unknown Avoid potent ENT1, CNT3,
BCRP inhibitors during 4 to
5 day cladribine treatment
Alternative treatments
should be considered, dose
reduction , separation of
timing of administration
Careful patient monitoring
Inductor BCRP, P-gp Possible decrease
in cladribine
exposure
None
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (9/12)
October 17, 2018GMP 2018 - Institut Pasteur - Paris29
Drug Therapeuti
c group
MOA Transporters possibly
affected
Clinical impact Labelling considerations
Ribociclib
KISQALI
Antineoplas
tic
Inhibitor of
CDK
Inhibitor P-gp, BCRP,
OATP1B1/1B3, OCT1,
OCT2, MATE1, BSEP
Increase
concentration
substrates
Caution and monitoring for
toxicity with sensitive
substrates which exhibit a
narrow therapeutic index
(eg digosxin, statins,
metformin)
Glecaprevir
+
pibrentasvir
MAVIRET
Anti-
infective
2 pan-
genotypic
inhibitors
(HCV)
G/P Inhibitors P-gp, BCRP,
OATP1B1/B3
Increase
concentration
substrates
Not recommended with
several products
Contraindication with
sensitive substrates ; for
other dose adjustment may
be needed
G/P inhibitors BSEP Not established None
G/P substrate P-gp, BCRP Strong inducers
may decrease
exposure and
lead to reduce
therapeutic effect
Contraindication with P-gp
inducers
Not recommended with
several products
G substrate OATP1B1/3 Increase
exposure of G by
inhibitors of
OATP1B1/3
None
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (10/12)
October 17, 2018GMP 2018 - Institut Pasteur - Paris30
Drug Therapeuti
c group
MOA Transporters possibly
affected
Clinical
impact
Labelling
considerations
Sofosbuvir
+
Velpatasvir
+
Voxilaprevir
VOSEVI
Anti-infectives 3 Pan-
genotypic
inhibitors
(HCV)
S/Ve/Vo substrates P-gp,
BCRP
Decrease
concentration
with inducers
Contraindication with strong
P-gp inducers
Not recommended with
moderate P-gp inducers
Ve/Vo substrates
OATP1B1/OATP1B3
Increase
concentration
with OATP1B
inhibitors, not for
the others
Not recommended with
strong inhibitors of OATP1B
is not recommended
Ve/Vo inhibitors P-gp, BCRP,
OATP1B1, OATP1B3,
OATP2B1
Increase
exposure
substrates
Contraindication with
rosuvastatin or dabigatran
Edoxaban
ROTEAS
Antithromboti
cs
Factor Xa
inhibitor
Substrate P-gp Increased
concentration
with inhibitors
Dose adjustment depending
of the P-gp inhibitor
Decrease mean
AUC and
shortened half-
life with inducers
Caution with P-gp inducers
Substrate OATP1B1 None None
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (11/12)
October 17, 2018GMP 2018 - Institut Pasteur - Paris31
Drug Therapeuti
c group
MOA Transporters possibly
affected
Clinical impact Labelling considerations
Rolipitant
VARUBY
Antiemetics Antagonist
NK1
receptors
Inhibitor BCRP 2-fold increase in
Cmax and AUC
of sulfasalazine
If the combination cannot be
avoided, clinical and
biological monitoring for
ADRs must be made.
The lowest effective of
rosuvastatin is to be used
Inhibitor P-gp 70% increase
Cmax and 30%
increase AUC
digoxin
Clinical monitoring of ADRs
and, if possible, biological
monitoring are
recommended when R is
combined with digoxin or
other P-gp substrates, in
particular in patient with
renal impairment
Inhibitor OATP1B1,
OATP1B3
Unknown Caution with OATP1B3
substrate
Tofacitinib
XELJANZ
Immunosup
pressants
Inhibitor
JAK
Substrate MDR1 None None
Umeclidiniu
m bromide
ROLUFTA
Obstructive
airway
diseases
Muscarinic
receptor
antagonist
Substrate P-gp None None
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (12/12)
October 17, 2018GMP 2018 - Institut Pasteur - Paris32
Drug Therapeutic
group
MOA Transporters possibly
affected
Clinical impact Labelling considerations
Alectinib
ALECENSA
Antineoplasti
cs
ALK and
RET
tyrosine
kinase
inhibitor
M4 substrate P-gp None None
A/M4 inhibitors P-gp Increase
concentration
substrates
Appropriate monitoring
recommended with P-gp
substrates
A/M4 inhibitors BCRP Increase
concentration
substrates
Appropriate monitoring
recommended with BCRP
substrates
Tenofovir
alafenamid
e
VEMLIDY
Anti-
infectives
Nucleoside
reverse
transcripta
se inhibitor
(HIV)
Substrate P-gp, BCRP Decrease
concentration
with inducers
Not recommended with
inducers of P-gp
Increase
concentration
with inhibitors
Not recommended with
strong inhibitors of P-gp
Substrate OATP1B1,
OATP1B3
Distribution of TA
in the body lay
be affected by
the activity if
OATP1B1 and/or
OATP1B3
None
Summary
October 17, 2018GMP 2018 - Institut Pasteur - Paris33
• Transported-mediated DDIs may have high clinical relevance
(toxicity or loss of efficacy), but their extent is rather lower than
DDIs mediated by metabolic enzymes
• Transported-mediated DDIs are significantly more complex than
DDIs mediated by metabolic enzymes
• Transporter-mediated intestinal absorption, hepatic uptake and
renal tubular secretion are main sites of transporter-mediated
DDIs
• Clinical relevance of transporter-mediated DDIs at BBB is still
unclear
• Genetic polymorphisms and disease states can also affect
transporters function
• Emerging data on newly characterized transporters may change
mechanistic understanding of clinically relevant DDIs
• Limitations of the in vitro assays and complexity of in vivo DDIs
(differential contribution of various enzyme and transporter)
• Tissue concentration variations can be much higher than plasma
exposure particularly in comparison with DDIs mediated by
metabolic enzymes
• In- silico methods have been used in drug development to inform
study design or labelling recommendations
RELEVANC
E
Summary
October 17, 2018GMP 2018 - Institut Pasteur - Paris34
• Transporter-medicated DDIs are to be considered in drug
development as an integral part of risk assessment for the optimal
use in the intended patient population
• NMEs are recommended to be investigated as potential substrates
and/or inhibitors/inducers of relevant drug transporters according
to decision trees
• Results need to be reflected in drug labels in order to prevent
adverse drug reaction or lack of efficacy caused by transporter-
mediated DDIs
• Exposure to a clinically relevant DDI might warrant a change in
therapy, increased monitoring, and/or patient education
• Mitigate the risk of undesired clinical consequences in the presence
of concomitant medications
• Well refined PBPK modeling may enable optimal predictions of
transporter-mediated DDIs and help optimizing or even omitting
clinical trials
• Biomarkers may help elucidates the in vivo transporter in early
phase clinical studies
• No guidelines or standards for determining relevance of
interactions via consistent systematic evaluation or classification
• Clinical outcomes associated with the DDI must be determined,
including the magnitude in variability and frequency of effects
ACTIONS
October 17, 2018GMP 2018 - Institut Pasteur - Paris35
BACK-UP
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (1/5)
October 17, 2018GMP 2018 - Institut Pasteur - Paris36
Drug Therapeutic
group
MOA Transporters
involved
Clinical impact Labelling
considerations
Tildrakizumab
ILUMETRI
Psoriasis MAB anti-IL23 None None None
Vonicog alfa
VEYVONDI
Antihemorrhagic
s
Von Willebrand factor None None None
Caplacizumab
CABLIVI
Anti-thrombotics MAB anti-Von
Willebrand
None None None
Tisagenlecleuce
l
KYMRIAH
Antineoplastics CAR T-cells None None None
Vestronidase
alfa
MEPSEVII
Metabolism Recombinant human
protein
None None None
Eravacycline
XERAVA
Anti-infectives Antibiotic
(Tetracyclines)
None None None
Metreleptin
MYALEPTA
Metabolism Leptin analogue None None None
Erenumab
AIMOVIG
Antimigraines MAB anti CGRP None None None
Inotersen
TEGSEDI
NYA Inhibitor of human
transthyretin (TTR)
None None None
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (2/5)
October 17, 2018GMP 2018 - Institut Pasteur - Paris37
Drug Therapeutic group MOA Transporters
involved
Clinical
impact
Labelling
considerations
Peramivir
ALPIVAB
Anti-infectives Inhibitor of influenza
virus neuraminidase
None None None
Darvadstrocel
ALOFISEL
NYA eASC (anal fistulas) None None None
Velmanase alfa
LAMZEDE
Metabolism Recombinant form of
alpha-mannosidase
None None None
Sodium
zirconium
LOKELMA
Hyperkalemia
/Hyperphosphatemia
Ions exchange None None None
SHINGRIX Vaccines VZV specific antigen +
adjuvant
None None None
Emicizumab
HEMLIBRA
Antihemorrhagics MAB bridges activated
factor IX and X
None None None
Burosumab
CRYSVITA
Bone diseases MAB anti FGF23 None None None
Semaglutide
OZEMPIC
Diabetes GLP-1 analogues None None None
Ocrelizumab
OCREVUS
Immunosuppressants MAB anti CD20-
expressing B cells
None None None
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (3/5)
October 17, 2018GMP 2018 - Institut Pasteur - Paris38
Drug Therapeutic group MOA Transporters
involved
Clinical impact Labelling
considerations
Benralizumab
FASENRA
Obstructive airways
diseases
MAB anti IL5 None None None
Rurictocog alfa
pegol
ADYNOVI
Antihemorrhagics Pegylated
recombinant factor
VIII
None None None
Prasterone
INTRAROSA
NYA DHEA (local) None None None
VERASEAL Antihemorrhagics Local hemostatics None None None
Guselkumab
TREMFYA
Immunosuppressant
s
MAB Anti IL23 None None None
Atezolizumab
TECENTRIQ
Antineoplastics MAB anti-PD-L1 None None None
Ertugliflozin
STEGLATRO
Diabetes Inhibitor of SGLT2 None None None
Avelumab
BAVENCIO
Antineoplastics MAB anti-PD-L1 None None None
Telotristat
XERMELO
NYA Inhibitors of L-
tryptophan
hydroxylases
(TPH1, TPH2)
None None None
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (4/5)
October 17, 2018GMP 2018 - Institut Pasteur - Paris39
Drug Therapeutic group MOA Transporters
involved
Clinical impact Labelling
considerations
Dupilumab
DUPIXENT
NYA MAB inhibitor IL4,
IL13
None None None
Patiromer
VELTASSA
Hyperkalemia Cation exchange
polymer
None None None
Brodalumab
KYNTHEUM
Immunosuppressant
s
MAB anti IL17RA None None None
SPHEROX Musculo-skeletal
disorders
ACI None None None
Cenegermin
OXERVATE
NYA Recombinant form
of NGF
None None None
Inotuzumab +
Ozogamicin
BESPONSA
Antineoplastics MAB anti CD22 +
cytotoxic
None None None
Sarilumab
KEVZARA
Immunosuppressant
s
MAB anti IL6 None None None
Nonacog beta
pegol
REFIXIA
Antihemorrhagics Recombinant
human factor IX
None None None
Nusinersen
SPINZARA
Musculo-skeletal
diseases
ASO SMN2 None None None
EU EMA EPAR New Approved Drugs
Review from 2017 to Now (5/5)
October 17, 2018GMP 2018 - Institut Pasteur - Paris40
Drug Therapeutic
group
MOA Transporters
involved
Clinical impact Labelling
considerations
Cerliponase alfa
BRINEURA
Metabolism Recombinant form of
rhTPP1
None None None
TRUMENBA Vaccines 2 recombinant lipidated
fHbp; meningococcal
bacteria
None None None
Fluciclovine
AXUMIN
Radiopharmaceutic
als
Synthetic amino acid
transported by LAT1 and
ASCT2
None None None
Dinutuximab
QARZIBA
Antineoplastics MAB anti GD2 None None None
NATPAR Hormones Recombinant PTH None None None
Simoctocog alfa
VIHUMA
Antihemorrhagics Recombinant human
factor VIII
None None None
Bezlotoxumab
ZINPLAVA
Anti-infectives MAB anti C.difficile toxin
B
None None None
Lixisenatide +
Insulin glargine
SULIQUA
Diabetes GLP1 receptor agonist +
insulin
None None None
Ionoctocog alfa
AFSTYLA
Antihemorrhagics Human factor VIII None None None