transporter-mediated drug interaction : are they ... · adme protein victim drug perpetrator drug...

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


Classical Example of DDI with

Harmful Clinical Consequences


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


Selected Highly Significant PK

Drug-Drug Interactions


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


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


> 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


Coordinated

operation of

transporters

Zamek-Gliszczynski MJ et al. Clin Pharmacol Ther. 2018;Aug 8

Drug Transporters – Clinical

Relevance (1/2)


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)


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


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


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


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)


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


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


Most Significant Clinical Inductions:

max AUC ratio ≤ 0.2 in 2017 NDAs Review


Most Pronounced Clinical Inhibitions:

Literature 2017-2018 (Top 10)


Most Pronounced Clinical Inductions:

Literature 2017-2018 (Top 10)


EU EMA EPAR New Approved Drugs

Review from 2017 to Now


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


Review from 2017 to Now (1/12)


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




Drug Therapeuti

c group

MOA Transporters possibly

affected


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




Drug Therapeutic

group

MOA Transporters

possibly affected


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


substrates

None

R inhibitor P-gp Can increase the exposure

of the most sensitive

substrates as dabigatran

None

R inhibitor MATE-

2K

Unknown None




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




Drug Therapeuti

c group


affected


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




Drug Therapeutic

group

MOA Transporters

possibly affected


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




Drug Therapeutic

axis

MOA Transporters

possibly affected


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


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




Drug Therapeutic

group


affected


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




Drug Therapeuti

c group


affected


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


several products

G substrate OATP1B1/3 Increase

exposure of G by

inhibitors of

OATP1B1/3

None




Drug Therapeuti

c group


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


moderate P-gp inducers

Ve/Vo substrates

OATP1B1/OATP1B3

Increase

concentration

with OATP1B

inhibitors, not for

the others


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




Drug Therapeuti

c group


affected


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




Drug Therapeutic

group


affected


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


inducers of P-gp

Increase

concentration

with inhibitors


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


• 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


• 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


BACK-UP




Drug Therapeutic

group

MOA Transporters

involved


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




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





involved


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





involved


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




Drug Therapeutic

group

MOA Transporters

involved


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

transporter-mediated drug interaction : are they ... · adme protein victim drug perpetrator drug...

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