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Introduksjon
Legemiddelinteraksjoner –
også et problem med
biologiske legemidler
• En rekke legemidler trukket fra markedet grunnet
legemiddelinteraksjoner (dødsfall)
– Mibefradil, cerivastatin, terfenadin
• Biologiske legemidler ble antatt å være frie for
farmakokinetisk interaksjonsproblematikk
Hege Christensen
Farmasøytisk institutt
Seksjon for farmasøytisk biovitenskap
Universitetet i Oslo
[email protected]
Farmakokinetikk
Renal utskillelse
Utskillelse galle
Biologiske
legemidler
Introduksjon
Vanlige
legemidler
Renal utskillelse
• 1990-tallet: En rekke legemidler trukket fra
markedet grunnet interaksjoner (dødsfall)
– Mibefradil, cerivastatin, terfenadin
Uspesifikk clearance
(proteolyse)
Reseptor-mediert clearance
(internalisering, proteolyse)
Høy MW
Parenteral administrasjon
Lavt V d
Proteinbinding lite betydning
t1/2 lang (dager, uker)
Transport
(P-gp)
Metabolisme
(CYP)
Lav MW
Oral administrasjon
Distribueres til vev
Proteinbinding kan være viktig
t1/2 kort (timer)
• Biologiske legemidler ble antatt å være frie for
farmakokinetisk interaksjonsproblematikk
• Endret immunologisk aktivitet fører til endret nivå
av legemiddelmetaboliserende enzymer og
transportører
Synergisme i tarm og lever
CYP3A4 og P-glykoprotein
Variasjon i farmakokinetiske prosesser
Plasma konsentrasjon
Biotilgjengelighet
- Begrenser biotilgjengelighet
Dose· F
AUC =
Cl
Enterocytter
Lever
CYP3A4
AUC
Clearance
CYP3A4
Metabolitt
Biotilgjenge li g
dose
Legemiddel
Opptakspumpe
P-glykoprotein
P-glykoprotein
Tid
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Interindividuell variabilitet i evne til å
metabolisere/transportere vanlige
legemidler
Immunologisk respons og CYP-metabolisme
• Akutt øvre luftveisinfeksjon i astmatiske barn ga
↑t1/2 (60% ↓ Cl) for teofyllin under infeksjonen i
forhold til 1 mnd. etter (teofyllinintoksikasjon)
• Genetisk polymorfisme
• Miljømessige årsaker
– Legemiddelinteraksjoner
– Sigarettrøyk, grapefruktjuice, johannesurt
• Sykdomsrelaterte faktorer
• Antatt at virusinfeksjonen påvirket enzymer
involvert i teofyllin metabolisme (nedregulert
CYP1A2)
– Immunologisk respons og frisetting av cytokiner
Chang KC. et al. Lancet 1978; 1132-33.
Inflammatorisk sykdom - RA
80 mg verapamil Isoptin®
N=8
RA pasienter
AUC ca. 4-ganger høyere
HIV-pasienter
CYP3A4
• Lavere Cl/F
• Høyere biotilgjengelighet
• Lavere CYP3A4 aktivitet
7 ganger økt IL-6
Friske, frivillige personer
CYP2D6
• Genotypet som EM,
fenotypet som PM ved
høy sykdomsaktivitet
( Jones
AE. et al. 2010; 66: 475-485)
Mayo PR. et al. Br J Clin Pharmacol 2000; 50, 605-613.
Pasienter med alvorlig kreft
IL-6 og endring i cyclosporin PK
Endogen IL-6
Nedsatt
CYP3A4
aktivitet
Årsak til intraindividuell
variabilitet i
CsA PK
•
37% CYP2C19 PM status i pasienter med normal genotype
metabolismekapasitet i kreftpasienter
Helsby NA et al. Br J Cancer 2008; 99, 1251-55.
Chen et a. Clin Pharmacol Ther 1994; 55: 649.
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Fenokonversjon av
legemiddelmetaboliserende enzymer
- NAT2, CYP1A2, 2C8, 2C9, 2C19, 3A4, 2E1 og 2D6
•
•
•
•
•
•
•
Krefttilstander
HIV-infeksjon
Akutte infeksjoner
Hjertesvikt, nyresvikt, leversvikt
Transplanterte pasienter
Sepsis
Inflammatoriske lidelser
– RA, SLE, sykelig overvekt ….
Proteinuttrykk av CYP3A4 i sykelig
overvektige pasienter
Invers sammenheng mellom BMI og uttrykk av
CYP3A4
Ulvestad et al. Clin Pharm Ther 2013; 93: 275-282
Shah RR and Smith RL. DMD 2015; 43: 400-410.
Biologiske
legemidler i
Norge
Virkestoff
Indikasjoner
Cytokiner
Interferon alfa-2a
Hepatitt, kreft
Interferon alfa-2b
Hepatitt, cancer
Interferon beta-1a
Multippel sklerose
Interferon beta-1b
Multippel sklerose
Interferon gamma-1b
Kronisk granulomatøs sykdom
Peginterferon alfa-2b
Hepatitt
Peginterferon alfa-2a
Hepatitt
Anticytokiner, interleukinhemmere
Anakinra
Revmatoid artritt
Basiliksimab
Organtransplantasjon
Canakinumab
Div. syndromer, urinsyregikt
Tocilizumab
Revmatoid artritt
Ustekinumab
Psoriasis
Interferon-α
• IFN-α til 5 pasienter med kronisk hepatitt B
– Cl for teofyllin ↓ 30-80 %
Williams SJ et al. Lancet 1987; 330: 939.
• IFN-α-2b til 17 pasienter med melanom
− 60% ↓ CYP1A2 aktivitet (koffein som probe)
− 40% ↓ CYP2C19 aktivitet (mephenytoin som probe)
Islam M et al. Clin Cancer Res 2002; 8: 2480.
Anticytokiner, TNF-alfa hemmere
Adalimumab
Revmatoid artritt
Certolizumab
Revmatoid artritt
Etanercept
Revmatoid artritt
Golimumab
Revmatoid artritt
Infliksimab
Revmatoid artritt, ulcerøs kolitt, psoriasis
IFN-α-2a (Roceron )
50% ↓ clearance av teofyllin (interaksjonsavsnitt Felleskatalogen)
Hermann M. et al. Norsk Farmasøytisk Tidsskrift 2015 (in press)
Monoklonale antistoffer og CYPmetabolisme
• Nedsetter konsentrasjonen av cytokiner og kan
gjenopprette CYP-aktiviteten
• Redusert plasmakonsentrasjon og mulig terapisvikt
av legemidler
• FDA forsiktighetsregel først på rilonacept (2008)
Sykdom-simvastatin-tocilizumab interaksjon
i pasienter med RA
Før tocilizumab
• Simvastatin før og etter
tocilizumab (n=12)
• 57% redusert AUC en
uke etter injeksjon
Etter tocilizumab
• Økt CYP3A4-aktivitet
• Effekten vedvarte i 4
uker
Schmitt et al. Clin Pharm Ther 2011; 89 (5).
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Tocilizumab
RoActemra
Legemiddelinteraksjoner med biologiske legemidler
Utdrag fra SPC
• Monitorere warfarin og cyclosporin ved oppstart
og seponering
Biologisk
Legemiddel
legemiddel
som påvirkes
CYP-enzym
Effekt
Interferoner (INF)
• Kan få nedsatt effekt av CYP3A4 substrater som
P-piller, statiner og kalsiumkanalblokkere
INF-alfa
Teofyllin
CYP1A2
30-80% redusert clearance
INF-beta
Teofyllin
CYP1A2
26% redusert clearance
INF-alfa
Erytromycin
CYP3A4
15% redusert CYP3A4
aktivitet
INF-alfa-2b, INF-beta
Warfarin*
CYP3A4, CYP2C9
Økt konsentrasjon
INF-alfa
Cyclofosfamid
CYP2C19, CYP3A
60% redusert clearance
INF-alfa-2b
Koffein
CYP1A2
60% redusert CYP1A2
aktivitet
Erytromycin
CYP3A4
50% redusert CYP3A4
aktivitet
Tocilizumab
Omeprazol
CYP2C19
30% redusert AUC
Tocilizumab
Simvastatin
CYP3A
60% redusert AUC
Tocilizumab
Simvastatin
CYP3A
40-60% redusert AUC
140% økt t1/2
Interleukiner
• Effekten av tocilizumab på CYP-enzym
aktiviteten kan vedvare i flere uker etter
seponering pga. lang t1/2
IL-2
Monoklonale antistoffer
Hermann et al. NFT 2015 (in press)
Mekanisme
CYP3A4 m-RNA
IL-6 og CYP3A4 aktivitet
humane hepatocytter
CYP3A4 protein
Dickman et al. DMD 2011; 39.
Cytokiner regulerer genuttrykk
The role of cyt okines in t he regulat ion of drug disposit ion: ext ended f unct ional pleiot ropism ?
Effekt av cytokiner på CYP uttrykk og
aktivitet in vitro
A. Cytokine
mediated
regulation of drug
disposition
B. PXR mediated
regulation of drug
disposition
C. Crosstalk between NF-kB
and PXR mediated regulation of
drug disposition
TNFa
IL-6
J
A
K
P
PS
IKK
P
TA
T3
P
IKK
P
P
P
STAT3
STAT3
Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Norwegian Knowledge Cntr Health Svcs on 11/03/11
For personal use only.
K
A
J
3
T
A
T
S
PXR
ligand
PXR
IKK
NF-kB
NF-kB
P
P
IkB
IkB
IkB
PXR
AP-1
NF-kB
RXR
Drug
Metabolite
CYP3A4
PXR
ABCB1
Drug
Transcription factor
binding site
CYP3A4/ABCB1
Nucleus
Liptrott
Opinand
Drug
Metab
Toxicol
2011;
341.
Figure 1. Schemat ic represent at ion of t he regulat
ion ofNJ,
drugOwen
dispositA.
ionExpert
by cyt okines
nuclear
recept
ors. A. Cyt
okine7:
may
act direct ly on genes encoding t ransport ers via immune-relat ed t ranscript ion f act ors such as AP-1. B. Induct ion of
PXR-mediat ed regulat ion of drug disposit ion in response t o a PXR ligand: ligand binds t o PXR w hich t hen t ranslocat es t o t he
cell nucleus and binds it s het erodimer part ner RXR w hich in t urn binds response element s upst ream of t ransport er and drug
met abolising enzyme genes. C. TNF-a-mediat ed regulat ion of drug disposit ion: TNF-a act ivat es NF-kB w hich t hen t ranslocat es
t o t he cell nucleus and act ivat es t arget genes w hilst also int erf ering w it h PXR--RXR complexes binding t o t heir
response element s.
AP-1: Activator protein 1; PXR: Pregnane X receptor; RXR: Retinoid-X receptor.
subsequent downregulation of expression [87] . AP-1 also has
binding motifs on several other transporters such as
ABCC2 [88] and BCRP [89] . The PI3K/Akt pathway has also
been linked to DC activation, IL-12 secretion by DC and
DC survival [90] . Furthermore, inhibition of Akt activation
hasbeen shown to reduceABCB1 and ABCC2 expression [91] .
A proposed mechanism f or direct cyt okine
regulat ion of drug t ransport ers and drug
met abolising enzymes via int racellular signalling
6.3
post-transcriptional and translational. However, there are
some data to suggest that cytokines may exert a direct effect
on expression.
Figure 1A summarises a possible mechanism for the direct
effect of cytokineson theregulation of drug disposition genes.
Here, IL-6 binds to the a-subunit of the IL-6 receptor, and
induces homo or heterodimerisation of the b-subunits [92] .
Stimulation of the IL-6 receptor complex activates JAK tyrosine kinases, resulting in phosphorylation of tyrosine sites on
STAT proteins [93] . The STAT proteins then homo or heter-
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Immunologisk respons og
REVI EW S
legemiddeltransport
a Intestinal epithelia
b Hepatocytes OAT2
OCT1
Blood
Intestine
P-gp i lymfocytter - pasienter med SLE og RA
OATP1B1 OATP2B1
OAT7 OATP1B3 NTCP
Blood
OATP
OCT1
M embrane transporters
Membrane-associated proteins
that govern the transport of
solutes (for example, drugs and
other xenobiotics) into and out
of cells. Transporters can play a
vital role in determining drug
concentrations in the systemic
circulation and in cells.
The two major superfamilies
of membrane transporters
are the ATP-binding cassette
(ABC) and solute carrier (SLC)
superfamilies.
The blood–brain barrier
consists of endothelial cells
connected by tight junctions.
The endothelial cells, which
are surrounded by astrocytes,
separate the circulating blood
and the brain interstitial space.
The role of the blood–brain
barrier is to protect the central
nervous system by restricting
and preventing the entry of
toxic substances including
drug molecules and bacteria
into the brain. Included in
this protective barrier are
transporters such as
P-glycoprotein.
Drug–drug interaction
(DDI). Concomitant
administration of multiple
drugs can result in altered
levels of the drugs compared
with administration of the
drugs alone. DDI can result in
higher (inhibition) or lower
(induction) levels of the drug.
For example, if drug A
(‘perpetrator’ drug) inhibits a
membrane transporter that
drug B (‘victim’ drug) uses
to enter into the cell,
administration of drug A can
lower the level of drug B in
the cell and also potentially
increase the level of drug B
in the systemic circulation.
MRP3
ASBT
MRP4
MCT1
MRP6
BSEP
BCRP
OST
–OST
P-gp
MRP2
Bile
Terapiresistens
BCRP
MRP3
P-gp
MRP2
Blood
MATE1
d Blood–brain barrier
c Kidney proximal tubules
Urine
Brain
Basolateral
OAT4
OATP4C1
Blood–brain barrier
PEPT1
OST
–OST
URAT1
OCT2
PEPT1, PEPT2
OAT1
MRP2, MRP4
OAT2
MATE1, MATE2-K
Brain capillary endothelial cells
P-gp
BCRP
MRP5
MRP4
Blood
P-gp
Apical/ luminal
OATP1A2
OATP2B1
OAT3
OCTN1, OCTN2
Figure 1 | Selected human transport proteins for drugs and endogenous substances. Transporters in plasma
membrane domains of intestinal epithelia, hepatocytes, kidney proximal tubules and
brain capillary
endothelial
cells
are
Giacomini
KM et
al. |Nature
reviews
2010: 9
Drug Discovery
presented. Those coloured in red indicate that the selected transporters are described inNature
detail Reviews
in this manuscript.
Those coloured in blue indicate that the transport proteins are of importance but are not described in this manuscript.
a | Intestinal epithelia contain in their apical (luminal) membrane several uptake transporters including one or more
members of the organic anion transporting polypeptide (OATP) family; peptide transporter 1 (PEPT1; SLC15A1); ileal
apical sodium/bile acid co-transporter (ASBT; SLC10A2); and monocarboxylic acid transporter 1 (MCT1; SLC16A1).
The apical ATP-dependent efflux pumps include multidrug resistance protein 2 (MRP2; ABCC2); breast cancer resistance
protein (BCRP; ABCG2); and P-glycoprotein (P-gp; MDR1, ABCB1). The basolateral membrane of intestinal epithelia
contains organic cation transporter 1 (OCT1; SLC22A1); heteromeric organic solute transporter (OSTα–OSTβ); and
MRP3 (ABCC3). b | Human hepatocyte uptake transporters in the basolateral (sinusoidal) membrane include the sodium/
taurocholate co-transporting peptide (NTCP; SLC10A1); three members of the OATPfamily (OATP1B1 (SLCO1B1),
OATP1B3 (SLCO1B3) and OATP2B1 (SLCO2B1)); organic anion transporter 2 (OAT2; SLC22A7) and OAT7 (SLC22A9); and
OCT1. Efflux pumps in the hepatocyte basolateral membrane include MRP3, MRP4 (ABCC4) and MRP6 (ABCC6). Apical
(canalicular) efflux pumps of the hepatocyte comprise P-gp; bile-salt export pump (BSEPor SPGP; ABCB11); BCRP
(ABCG2); and MRP2. In addition, multidrug and toxin extrusion protein 1 (MATE1; SLC47A1) is located in the apical
hepatocyte membrane. c | Kidney proximal tubules contain in the apical (luminal) membrane OAT4 (SLC22A11); urate
transporter 1 (URAT1; SCL22A12); PEPT1 and PEPT2 (SLC15A2); MRP2 and MRP4; MATE1 and MATE2-K (SLC47A2); P-gp;
organic cation/ergothioneine transporter (OCTN1; SLC22A4); and organic cation/carnitine transporter (OCTN2;
SLC22A5). Basolateral uptake transporters in proximal tubule epithelia include OATP4C1 (SLCO4C1); OCT2; and OAT1,
OAT2 and OAT3 (SLC22A8). d | Apical (luminal) transport proteins of brain capillary endothelial cells contributing to the
function of the blood–brain barrier include the uptake transporters OATP1A2 and OATP2B1; and the efflux pumps P-gp,
BCRP, MRP4 and MRP5 (ABCC5). Note that localization of transporters to particular membranes and tissues is sometimes
controversial; therefore, the International Transporter Consortium erred on the conservative side in only showing the
localization of transporters for which good evidence exists.
Interaksjoner mellom biologiske
legemidler og P-gp
Ts ujimura S, Tanak a Y. Clin Ex p Nephrol 2011
Interaksjoner med biologiske legemidler –
konsekvens for legemiddelutvikling
Drug-met abolizing enzymes
(DMEs). These are enzymes
responsible for chemical
modification of drugs usually
to increase rate of elimination.
The activity of these enzymes
can be altered through
inhibition or induction,
thus affecting the rate of
metabolism.
describe the selected transporters as well as other
important transporters. Note that clinical data documenting the importance of these transport proteins
with respect to drug disposition and/or toxicity continues to emerge. TABLES 1,2 include clinically relevant
information with respect to DDIs and genetic polymorphisms. Examples of clinically relevant DDIs that
can be explained, in part or in full, by modulation of
transporter activity are compiled in TABLE 3 . Below, we
present an overview of P-gp, breast cancer resistance
protein (BCRP; also known as ABCG2); organic cation
transporters (OCTs) and organic anion transporters
(OATs); and organic anion transporting polypeptides
(OATPs). For ease of reading we refer to MDR1/P-gp
• Studie i rotter (Ben reguiga M. Pharm Res 2005; 22: 1829-36)
– Interferon-α og -Υ ga økt biotilgjengelighet av
digoxin (hemmende effekt på P-gp)
NATURE REVIEWS | DRUG DISCOVERY
VOLUM E 9 | M A RCH 2010 | 217
© 20 10 Macmillan Publishers Limited. All rights reserved
• 2 studier i friske frivillige forsøkspersoner
(Zhou H et al. J Clin Pharmacol 2004; 44: 543-50 og 1244-51)
– Etanercept (Enbrel) og digoxin eller warfarin
– Ingen interaksjon
– Burde vært utført i pasienter med
inflammasjon (Huang SM. Clin Pharm Ther 2010; 87: 497-503)
Huang et al. Clin Pharm Ther 2010; 87: 497-503.
Oppsummering
• Infeksjon/inflammasjon og biologiske legemidler
(cytokiner) kan nedsette metabolisme via ulike
legemiddelmetaboliserende enzymer
• Bortfall av immunologisk stimuli (antistoffer) kan
gjenopprette metabolismekapasitet og føre til
terapisvikt av visse legemidler
• Interaksjonsstudier med biologiske legemidler bør
utføres - i pasienter
5