Transcript ACPS- clinical pharmacology subcommittee meeting

Transporters and Their Role in
Drug Interactions
1
Outline
• Messages of the draft drug interaction
guidance (September 2006)
- Outline of CYP- vs. transporter- based
interaction evaluation
• Proposed methods to evaluate transporterbased interaction
- Current labeling examples
• Questions for the committee
2
Discussions on Drug Interactions
• Publications of in vitro and in vivo drug
interaction guidance documents
- http://www.fda.gov/cder/guidance/clin3.pdf (1997)
- http://www.fda.gov/cder/guidance/2635fnl.pdf (1999)
• Advisory Committee meetings
-April 20, 2003 (CYP3A inhibitor classification and P-gp
inhibition)
-November 18, 2003 (CYP2B6 and CYP2C8- related interactions)
-November 3, 2004 (relevant principles of drug interactions)
Concept paper published- October 2004
3
Guidance for Industry:
Drug Interaction Studies —
Study Design, Data Analysis,
and Implications for
Dosing and Labeling
Draft published for public comment
September 11, 2006
http://www.fda.gov/cder/guidance/6695dft.pdf
4
Key messages:
1. Metabolism, transport, drug-interaction info
key to benefit/risk assessment
2. Integrated approach (in vitro and in vivo )
may reduce number of unnecessary studies and
optimize knowledge
3. Study design/data analysis key to important
information for proper labeling
5
Key messages (continued):
4. Clinical significance of a PK-based
interaction needs to be interpreted based on
exposure-response data/analyses
5. Classification of CYP inhibitors and
substrates can aid in study design and
labeling
6. Labeling language needs to be useful and
consistent (new labeling rule, June 2006)
6
What’s
New?
CYP Enzymes
Major CYPs
-specific substrates
-specific inhibitors
-inducers
In vitro and in vivo
Transporters
P-gp
- specific substrate
- general inhibitors
- inducers
in vitro and in vivo
Others transporters:
OATP, BCRP, MRP2,
OATs, OCTs
-general substrates,
inhibitors, inducers
(in vitro/in vivo)
< http://www.fda.gov/Cder/drug/drugInteractions/default.htm
7
What’s CYP Enzymes
New? A decision tree --- when
in vivo studies are
recommended
per in vitro data
- substrate
- inhibitor (I/Ki > 0.1)
- inducer (40% control)
Classification of
-inhibitors
-substrates
Transporters (P-gp)
Decision trees-- when
in vivo studies are
recommended
per in vitro data
- substrate (flux ratio)
- inhibitor (I/Ki)
- (inducer)
No classification
system
8
What’s
New?
Others:
• protocol restriction (juice,
dietary supplement use)
• multiple- inhibitor study
• cocktail approach
9
Why Study Transporters?
10
Liver Sinusoidal Hepatic
Uptake: OCT1, OATP-C,
OATP-B, OATP8, NTCP, OAT2
Secretion: MRP1, MRP3
Brain Transporters:
P-gp (MDR1), OAT3, OATP-A,
MRP1, MRP3
Liver Canalicular
Biliary Excretion:
P-gp, MRP2, BCRP, MDR3
Intestinal Luminal
Absorption: PEPT1
Secretary: P-gp, OATP3
Kidney Basolateral:
OCT1, OCT2, OAT1, OAT2, OAT3,
MRP1
Kidney Apical
Renal Secretion: P-gp, OAT4
Reabsorption: PEPT2
<Zhang L et al, Mol Pharm. 2006; 3(1), 62-69, Epub Jan 4 2006 >
11
The role of P-gp transporter?
12
Number of published papers/patents
600
MDR1
500
400
300
BCRP
OCT
MRP2
200
100
OAT
OATP1B1
0
76
81
86
91
Year
<Survey via Biovista; courtesy: Aris Persidis>
96
'01
'06
13
Proposed decision trees to
evaluate transporterbased interactions
14
Figure 1. Decision tree to determine whether an investigational drug
is an inhibitor for P-gp and whether an in vivo drug
interaction study with a P-gp substrate is needed
Bi-directional transport assay
Net flux with
concn of drug
Net flux with
concn of drug
Determine Ki or IC50
[I]/IC50 (or Ki) > 0.1
An in vivo interaction study
With a P-gp substrate
(e.g., digoxin) is recommended
Poor or non-inhibitor
[I]/IC50 (or Ki) < 0.1
An in vivo interaction study
With a P-gp substrate
is not needed
15
Digoxin plasma AUC or Css
(co-administration)
If a NME is an inhibitor of P-gp in vitro,
in vivo study using digoxin may be appropriate
2.5
2
1.5
1
0.5
0
Huang, S-M, ACPS presentation, , http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4079s1.htm
16
Figure 2. Decision tree to determine whether an investigational drug
is a substrate for P-gp and whether an in vivo drug
interaction study with a P-gp inhibitor is needed
Alternatively, use a %
value (relative to a
probe substrate)
Bi-directional transport assay
Net flux ratio < 2
Net flux Ratio > 2
Is efflux significantly inhibited
by 1 or more P-gp inhibitors
YES
Likely a P-gp substrate
An in vivo interaction study
With a P-gp inhibitor Note
may be
warranted
exceptions
Poor or non-substrate
NO
Other efflux transporters are responsible
Further in vivo to determine
which efflux transporters are
involved may be warranted 17
If a NME is a substrate for P-gp in vitro:
an in vivo study with a P-gp- inhibitor
(e.g., ritonavir, cyclosporine, verapamil) may
be appropriate
18
Cyclosporine affects multiple
transporters, including OATP1B1
Fold AUC change
With cyclosporine
8
7
6
5
4
3
2
1
0
<Data from Table in Shitara and Sugiyama, Pharmacol Ther 112, 2006>
19
If a NME is a substrate for P-gp and CYP3A
-> a clinical study with a strong inhibitor
for both (e.g., ritonavir) may be appropriate
20
Vardenafil AUC
(Fold-change)
Ritonavir affects multiple pathways
(enzymes and transporters)
50
45
40
35
30
25
20
15
10
5
0
Huang, S-M, ACPS presentation, , http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4079s1.htm
21
How do we label
transporter-based
interactions?
22
“Class” labeling of drugs
that are substrates of
CYP3A
[proposed in the 2006 draft
guidance on
“drug interactions”]
23
Labeling example - CYP3A substrate
Eletriptan
AUC Cmax
Ketoconazole
8x
4x
Should not be used within at least 72 hours
with strong CYP3A inhibitors….
Ketoconazole,
itraconazole, ritonavir,
nelfinavir, nefazodone,
clarithromycin.
Not studied
<(Relpax (eletriptan) PDR labeling May 2005>
24
“Class” labeling of drugs
that are inhibitors of
CYP3A
[proposed in the 2006 draft
guidance on
“drug interactions”]
25
Labeling example- CYP3A inhibitor
Telithromycin
Midazolam
AUC
6x
• Telithromycin is a strong inhibitor of the
cytochrome P450 3A4 system
• Use of simvastatin, lovastatin, or
atorvastatin concomitantly with
KETEK should be avoided
Not studied
• The use of KETEK is contraindicated with
cisapride, pimozide
<Physicians’ Desk Reference at http://pdrel.thomsonhc.com/pdrel/librarian >
26
Do we have sufficient data
or understanding for a
similar “class” labeling of
drugs that are inhibitors or
substrates of transporters?
27
Labeling examples
28
Eplerenone
Eplerenone is not a substrate or an
inhibitor of P-glycoprotein at
clinically relevant doses
No clinically significant drug-drug
pharmacokinetic interactions were
observed when eplerenone was
administered with digoxin
http://www.fda.gov/cder/foi/label/2003/21437se1-002_inspra_lbl.pdff
29
Pramipexole
Cimetidine: Cimetidine, a known inhibitor
of renal tubular secretion of organic bases
via the cationic transport system, caused a
50% increase in pramipexole AUC and a
40% increase in half-life (N=12).
Probenecid: Probenecid, a known inhibitor
of renal tubular secretion of organic acids
via the anionic transporter, did not
noticeably influence pramipexole
pharmacokinetics (N=12).
http://pdrel.thomsonhc.com/pdrel/librarian/PFDefaultActionId/pdrcommon.IndexSearchTranslator#PDRP 30
RE01el/2004/21704lbl.pdf
Varenicline- in vitro
• In vitro studies demonstrated that varenicline does
not inhibit human renal transport proteins at
therapeutic concentrations. Therefore, drugs that
are cleared by renal secretion (e.g. metformin -see
below) are unlikely to be affected by varenicline.
• In vitro studies demonstrated the active renal
secretion of varenicline is mediated by the human
organic cation transporter, OCT2. Coadministration with inhibitors of OCT2 may not
require a dose adjustment …. as the increase in
systemic exposure .. is not expected to be clinically
meaningful (see Cimetidine interaction below).
31
Varenicline (2)- in vivo
• Metformin: varenicline .. did not alter the steadystate pharmacokinetics of metformin .. which is a
substrate of OCT2. Metformin had no effect on
varenicline steady-state pharmacokinetics.
• Cimetidine: Co-administration of an OCT2
inhibitor, cimetidine … with varenicline (2 mg
single dose) … increased the systemic exposure of
varenicline by 29% .. due to a reduction in
varenicline renal clearance.
<Chantix labeling, May 2006- http://www.fda.gov/cder/foi/label/2006/021928lbl.pdf>
32
Multiple - inhibitor
interactions
33
Repaglinide AUC
(fold-change)
Combination of CYP and transporter
interactions
20
18
16
14
12
10
8
6
4
2
0
< Data from Neuvonen: Niemi M et al, Diabetologia. 2003 Mar;46(3):347-51>
34
Repaglinide
Caution should be used in patients already on
PRANDIN and gemfibrozil - blood glucose levels
should be monitored and PRANDIN dose
adjustment may be needed. Rare postmarketing
events of serious hypoglycemia have been
reported in patients taking PRANDIN and
gemfibrozil together. Gemfibrozil and
itraconazole had a synergistic metabolic
inhibitory effect on PRANDIN. Therefore,
patients taking PRANDIN and gemfibrozil
should not take itraconazole.
PDR on Orandin, December 2004
35
Summary
36
P-gp- based interactions
• Most well developed
• Information increasingly included in labeling
• To determine when to evaluate in vivo:
need agreed-upon criteria to evaluate
in vitro (preclinical) data- presented in the
September 2006 draft guidance
• Digoxin a clinically relevant substrate
• Proposed general transporter inhibitors
• Other issues
37
Other transporter- based
interactions
• In vitro methodologies being developed
• Some information has been included in labeling
• Need standardized procedures; need probe
substrates/inhibitors
• Short-term recommendations may be drugor “therapeutic class-” specific
38
Questions for the
Committee
39
1. Are the criteria for determining
whether an investigational drug is an
inhibitor of P-gp and whether an in
vivo drug interaction study is needed,
as described in the following figure,
are appropriate?
40
Figure 1. Decision tree to determine whether an investigational drug
is an inhibitor for P-gp and whether an in vivo drug
interaction study with a P-gp substrate is needed
Bi-directional transport assay
Net flux with
concn of drug
Net flux with
concn of drug
Determine Ki or IC50
[I]/IC50 (or Ki) > 0.1
An in vivo interaction study
With a P-gp substrate
(e.g., digoxin) is recommended
Poor or non-inhibitor
[I]/IC50 (or Ki) < 0.1
An in vivo interaction study
With a P-gp substrate
is not needed
41
2. Are the criteria for determining
whether an investigational drug is an
substrate of P-gp and whether an in
vivo drug interaction study is needed,
as described in the following figure,
are appropriate?
42
Figure 2. Decision tree to determine whether an investigational drug
is a substrate for P-gp and whether an in vivo drug
interaction study with a P-gp inhibitor is needed
Alternatively, use a %
value (relative to a
probe substrate)
Bi-directional transport assay
Net flux ratio < 2
Net flux Ratio > 2
Is efflux significantly inhibited
by 1 or more P-gp inhibitors
YES
Likely a P-gp substrate
An in vivo interaction study
With a P-gp inhibitor Note
may be
warranted
exceptions
Poor or non-substrate
NO
Other efflux transporters are responsible
Further in vivo to determine
which efflux transporters are
involved may be warranted 43
3. If a NME is a P-gp substrate and an
in vivo interaction study is indicated,
are the inhibitors listed in page 11 (i.e.,
ritonavir, cyclosporine, verapamil)
appropriate?
-- 3a. Should different inhibitors be
considered, if NME is also a substrate
for CYP3A? For example, a strong dual
inhibitor of P-gp and CYP3A (e.g.,
ritonavir)
44
4. Does the current knowledge base
support the recommendation of drug
interaction studies for other
transporters such as OATP1B1, MRP2,
BCRP, OCTs and OATs?
45