when to conduct a renal impairment study
TRANSCRIPT
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Transporters and Their Role in Drug Interactions
2
Outline
• Messages of the draft drug interaction guidance (September 2006)
• Proposed methods to evaluate transporter- based interaction
- Outline of CYP- vs. transporter- based interaction evaluation
• Questions for the committee
- Current labeling examples
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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
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Guidance for Industry:Drug Interaction Studies —
Study Design, Data Analysis, and Implications for Dosing and Labeling
Draft published for public commentSeptember 11, 2006
http://www.fda.gov/cder/guidance/6695dft.pdf
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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
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Key messages (continued):
4. Clinical significance of a PK-based interaction needs to be interpreted based on exposure-response data/analyses
6. Labeling language needs to be useful and consistent (new labeling rule, June 2006)
5. Classification of CYP inhibitors and substrates can aid in study design and labeling
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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
What’s New?
Others transporters:
OATP, BCRP, MRP2, OATs, OCTs
-general substrates,
inhibitors, inducers
(in vitro/in vivo)< http://www.fda.gov/Cder/drug/drugInteractions/default.htm
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CYP Enzymes
A decision tree --- when
in vivo studies are recommended
per in vitro data
- substrate- inhibitor (I/Ki > 0.1)- inducer (40% control)
Transporters (P-gp)
Decision trees-- when in vivo studies are
recommended
per in vitro data
- substrate (flux ratio)
- inhibitor (I/Ki)
- (inducer)
Classification of -inhibitors-substrates
What’s New?
No classification system
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What’s New?
Others:
• protocol restriction (juice, dietary supplement use)
• multiple- inhibitor study
• cocktail approach
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Why Study Transporters?
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Kidney Basolateral: OCT1, OCT2, OAT1, OAT2, OAT3, MRP1
Kidney Apical Renal Secretion: P-gp, OAT4Reabsorption: PEPT2
Brain Transporters: P-gp (MDR1), OAT3, OATP-A, MRP1, MRP3
Liver Sinusoidal Hepatic Uptake: OCT1, OATP-C, OATP-B, OATP8, NTCP, OAT2Secretion: MRP1, MRP3
Liver Canalicular Biliary Excretion: P-gp, MRP2, BCRP, MDR3
Intestinal Luminal Absorption: PEPT1Secretary: P-gp, OATP3
<Zhang L et al, Mol Pharm. 2006; 3(1), 62-69, Epub Jan 4 2006 >
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The role of P-gp transporter?
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Number of published papers/patents
0
100
200
300
400
500
600
76 81 86 91 96 '01 '06Year
<Survey via Biovista; courtesy: Aris Persidis>
MDR1
BCRPOCTMRP2
OATOATP1B1
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Proposed decision trees to evaluate transporter-
based interactions
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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 Poor or non-inhibitor
[I]/IC50 (or Ki) > 0.1 [I]/IC50 (or Ki) < 0.1
An in vivo interaction studyWith a P-gp substrate (e.g., digoxin) is recommended
An in vivo interaction studyWith a P-gp substrate is not needed
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If a NME is an inhibitor of P-gp in vitro, in vivo study using digoxin may be appropriate
0
0.5
1
1.5
2
2.5
Quinidine
Verapamil
Grapefruit
juice Rifampin
St John’s
wort
Aprepitant
Dig
oxin
pla
sma
AU
C o
r C
ss(c
o-ad
min
istr
atio
n)
Ritonavir
Huang, S-M, ACPS presentation, , http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4079s1.htm
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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
Bi-directional transport assay
Net flux Ratio > 2 Net flux ratio < 2
Is efflux significantly inhibited by 1 or more P-gp inhibitors
Poor or non-substrate
Likely a P-gp substrate
An in vivo interaction studyWith a P-gp inhibitor may bewarranted
Further in vivo to determine which efflux transporters are involved may be warranted
YES NOOther efflux transporters are responsible
Alternatively, use a % value (relative to a probe substrate)
Note exceptions
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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
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Cyclosporine affects multiple transporters, including OATP1B1
0
1
2
3
4
5
6
7
8
pravastatin
rosuvastatin
pitavastatin
Fol
d A
UC
ch
ange
Wit
h c
yclo
spor
ine
<Data from Table in Shitara and Sugiyama, Pharmacol Ther 112, 2006>
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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
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05
10152025
3035404550
Ritonavir
Ketoconazole
200 mg
Erythromycin
Indinavir
Var
den
afil
AU
C(F
old
-ch
ange
)
Ritonavir affects multiple pathways (enzymes and transporters)
Huang, S-M, ACPS presentation, , http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4079s1.htm
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How do we label transporter-based
interactions?
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“Class” labeling of drugs that are substrates of
CYP3A[proposed in the 2006 draft
guidance on “drug interactions”]
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Eletriptan AUC Cmax
Labeling example - CYP3A substrate
Should not be used within at least 72 hours with strong CYP3A inhibitors…. Ketoconazole, itraconazole, ritonavir, nelfinavir, nefazodone, clarithromycin.
Ketoconazole 8x 4x
Not studied
<(Relpax (eletriptan) PDR labeling May 2005>
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“Class” labeling of drugs that are inhibitors of
CYP3A[proposed in the 2006 draft
guidance on “drug interactions”]
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• Telithromycin is a strong inhibitor of the cytochrome P450 3A4 system
Labeling example- CYP3A inhibitor
Telithromycin AUCMidazolam 6x
<Physicians’ Desk Reference at http://pdrel.thomsonhc.com/pdrel/librarian >
• Use of simvastatin, lovastatin, or atorvastatin concomitantly with KETEK should be avoided
• The use of KETEK is contraindicated with cisapride, pimozide
Not studied
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Do we have sufficient data or understanding for a
similar “class” labeling of drugs that are inhibitors or substrates of transporters?
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Labeling examples
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Eplerenone is not a substrate or an inhibitor of P-glycoprotein at clinically relevant doses
Eplerenone
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
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PramipexoleCimetidine: 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).
http://pdrel.thomsonhc.com/pdrel/librarian/PFDefaultActionId/pdrcommon.IndexSearchTranslator#PDRPRE01el/2004/21704lbl.pdf
Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence pramipexole pharmacokinetics (N=12).
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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. Co-administration 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).
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• Metformin: varenicline .. did not alter the steady-state pharmacokinetics of metformin .. which is a substrate of OCT2. Metformin had no effect on varenicline steady-state pharmacokinetics.
Varenicline (2)- in vivo
• 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>
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Multiple - inhibitor interactions
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Combination of CYP and transporter interactions
024
68
1012
14161820
Rep
agli
nid
e A
UC
(fol
d-c
han
ge)
itraconazol
eGemfib
rozil
+itraconazolegemfib
rozi
l
< Data from Neuvonen: Niemi M et al, Diabetologia. 2003 Mar;46(3):347-51>
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RepaglinideCaution 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
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Summary
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P-gp- based interactions
• 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
• Most well developed
• Other issues
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Other transporter- based interactions
• In vitro methodologies being developed
• Need standardized procedures; need probe substrates/inhibitors
• Short-term recommendations may be drug- or “therapeutic class-” specific
• Some information has been included in labeling
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Questions for the Committee
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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?
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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 Poor or non-inhibitor
[I]/IC50 (or Ki) > 0.1 [I]/IC50 (or Ki) < 0.1
An in vivo interaction studyWith a P-gp substrate (e.g., digoxin) is recommended
An in vivo interaction studyWith a P-gp substrate is not needed
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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?
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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
Bi-directional transport assay
Net flux Ratio > 2 Net flux ratio < 2
Is efflux significantly inhibited by 1 or more P-gp inhibitors
Poor or non-substrate
Likely a P-gp substrate
An in vivo interaction studyWith a P-gp inhibitor may bewarranted
Further in vivo to determine which efflux transporters are involved may be warranted
YES NOOther efflux transporters are responsible
Alternatively, use a % value (relative to a probe substrate)
Note exceptions
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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)
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4. Does the current knowledge base support the recommendation of drug interaction studies for other transporters such as OATP1B1, MRP2, BCRP, OCTs and OATs?