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Drug Transporters: Report from the International Transporter Consortium; Decisions, Impact and Future Directions
Delaware Valley Drug Metabolism Discussion GroupMay 12th, 2010Donald TweedieDirector, Drug Metabolism
NEDMDG, March 2010 2
Drug Transporter White Paper
Nature Reviews Drug Discovery 9, 215 - 236 , (2010)
‘Membrane Transporters in Drug Development’
The International Transporter Consortium.
Corresponding Authors:
NEDMDG, March 2010 3
Outline
International Transporter Consortium (ITC)
• Genesis
• Goals
• White paper– How we got there– What it is– What it is not– Examples, MDR1, OATP, decisions tree(s)
• Current Issues, Challenges, and Actions
• Future Activities
Conclusions
Acknowledgements
NEDMDG, March 2010 4
Genesis – ITC
PhRMAPharmaceutical and Research Manufacturers of America
• Advocacy forum for the industry to influence the FDA (PhRMA – America)
• Drug Metabolism Technical Group (DMTG)– Subgroup responsible for DMPK issues – (MIST, DDI, pharmacogenomics, time-dependent inhibition)1
– Nov 2007, transporters identified as a key topic
• Academic group headed by Kathy Giacomini and Toshi Ishikawa were considering initiating a global committee to generate a white paper providing preferred approaches to conduct transporter studies
1Baillie et al. (2002) Drug metabolites in safety testing Toxicol. Appl. Pharmacol. 182, 188-96
Bjornsson et al. (2004) The Conduct of In Vitro and In Vivo Drug-Drug Interaction Studies: A Pharmaceutical Research and Manufacturers of America (PhRMA) Perspective. Drug Metabolism and Disposition 31, 815-832 and Journal of Clinical Pharmacology 43, 443-469.
Williams et al. (2008) PhRMA white paper on pharmacogenomics J Clin Pharmacol. 48(7), 849-89
Grimm SW et al. (2009) The conduct of in vitro studies to address time-dependent inhibition of drug-metabolizing enzymes: a perspective
of the pharmaceutical research and manufacturers of America. Drug Metabolism and Disposition 37(7):1355-1370
NEDMDG, March 2010 5
Transporters
Key goals for the ITC
• Provide an update on current thinking on transporters.
• For in vitro studies, provide a focus on studies that can have a viable clinical interpretation (avoid raising red flags with in vitro studies that cannot be addressed in vivo in the clinic).
• Explore gaps and suggest ways forward.
• Provide a coordinated approach (Academia, Industry and Regulatory).
• Help to move the science forward.– Decision trees to assist drug development and
regulatory– Consensus on current scientific status
NEDMDG, March 2010 6
International Transporter Consortium
WorkshopBethesda North MarriottOctober 2nd and 3rd, 2008
• Sponsored by FDA Critical Path
• Workshop organized by Drug Information Association (DIA)
• Co-sponsorship by AAPS, ISSX, PhRMA
• Provide a focus to initiate a White Paper for completion in 2009
NEDMDG, March 2010 7
ITC Original Members
Academia:Kim Brouwer UNCKathy Giacomini UCSFToshi Ishikawa OSC, TokyoDietrich KepplerHeidelberg Richard Kim W. OntarioPeter Swann Maryland
Regulatory:Shiew Mei Huang FDALei Zhang FDA
Industry:Raymond Evers MerckVolker Fischer AbbottKate Hillgren LillyJoe Polli GSKDonald Tweedie BIJoe WareGenentech
NEDMDG, March 2010 8
ITC author list
Academia:Les Benet UCSFKim Brouwer UNCAmber Dahlin UCSFKathy Giacomini UCSFToshi Ishikawa OSC, TokyoDietrich KepplerHeidelberg Richard Kim W. OntarioMikko Niemi HelsinkiYuichi Sugiyama TokyoPeter Swann MarylandSteve Wright Arizona Sook Wah Yee UCSFRegulatory:Shiew Mei Huang FDALei Zhang FDA
Industry:Xiaoyan Chu MerckRaymond Evers MerckVolker Fischer AbbottKate Hillgren LillyKeith A. Hoffmaster NovartisCaroline Lee PfizerJoe Polli GSKDonald Tweedie BIJoe WareGenentechMaciej Zamek-Gliszczynski Lilly
NEDMDG, March 2010 9
ITC author list
Academia:Les Benet UCSFKim Brouwer UNCAmber Dahlin UCSFKathy Giacomini UCSFToshi Ishikawa OSC, TokyoDietrich KepplerHeidelberg Richard Kim W. OntarioMikko Niemi HelsinkiYuichi Sugiyama TokyoPeter Swann MarylandSteve Wright Arizona Sook Wah Yee UCSFRegulatory:Shiew Mei Huang FDALei Zhang FDA
Industry:Xiaoyan Chu MerckRaymond Evers MerckVolker Fischer AbbottKate Hillgren LillyKeith A. Hoffmaster NovartisCaroline Lee PfizerJoe Polli GSKDonald Tweedie BIJoe WareGenentechMaciej Zamek-Gliszczynski Lilly
NEDMDG, March 2010 10
ITC author list
Academia:Les Benet UCSFKim Brouwer UNCAmber Dahlin UCSFKathy Giacomini UCSFToshi Ishikawa OSC, TokyoDietrich KepplerHeidelberg Richard Kim W. OntarioMikko Niemi HelsinkiYuichi Sugiyama TokyoPeter Swann MarylandSteve Wright Arizona Sook Wah Yee UCSFRegulatory:Shiew Mei Huang FDALei Zhang FDA
Industry:Xiaoyan Chu MerckRaymond Evers MerckVolker Fischer AbbottKate Hillgren LillyKeith A. Hoffmaster NovartisCaroline Lee PfizerJoe Polli GSKDonald Tweedie BIJoe WareGenentechMaciej Zamek-Gliszczynski Lilly
Kathy Giacomini UCSF
NEDMDG, March 2010 11
White paper
1. Basic Introduction and Summary of Transporters– Highlights what we know
2. Methods for Studying Transporters– Current solutions and future prospects
3. Drug Development Issues– Decision trees
Drug Transporters in Drug Development
The International Transporter Consortium, ITC
NEDMDG, March 2010 12
Section 1
Transporters covered
• Efflux: P-gp, BCRP
• Renal: OAT/OCT
• Hepatic uptake: OATP
Other transporters not discussed in detail
• MRPs
• MATEs
• Considered less critical in the overall view
• But could be important for specific drugs?
NEDMDG, March 2010 14
Tables of Substrates and Inhibitors
NEDMDG, March 2010 15
Section 2. Methods for Studying Transporters
A. Cell and Membrane Models
B. Intact Organ/In Vivo Models
C. Methods to Measure the Contribution of Transporters to Tissue Distribution and Excretion
D. Interplay of Efflux Transporters and Enzymes
E. Coordination of Influx and Efflux Transporters and Enzymes in the Clearance of Drugs
F. Computational Models
NEDMDG, March 2010 16
Section 3. Drug Development Issues
Box 2. Decision trees for P-gp or BCRP substrate interactions
Box 3. Decision trees for P-gp or BCRP inhibitor interactions
Box 4. Decision trees for OCT or OAT substrate interactions
Box 5. Decision trees for OCT or OAT inhibitor interactions
Box 6. Decision trees for OATP interactions
Box 7. OATP1B1 Decision Analysis: Case Studies
Summary and Conclusions
NEDMDG, March 2010 17
P-gp Substrate
NEDMDG, March 2010 18
Current issues?
Decision Trees Pros
• evolution of concepts
• highlight discussion points
• offers flexibility
Cons
• rigid interpretation – prescriptive and overly cautious
• insufficient knowledge to populate the decision points
• lack of selective substrates and inhibitors
‘The evolution and appropriate application of these decision trees will require constant monitoring. How can this be achieved with an assured and encompassing measure of success?’
NEDMDG, March 2010 19
Decision Trees - Current issue with P-gp?
False Positives (unnecessary clinical studies)
Alert for [I]1/IC50 ≥ 0.1 or [I]2/IC50 ≥10, – [I]1 is steady-state total Cmax at the highest
clinical dose– [I]2 is the GI concentration calculated as dose
(mg)/250 mL
[I]2/IC50 > 10 will be exceeded at a dose of ~12 mg for a drug with an inhibition potency of ~10 µM in vitro (MW ~ 500).
False Negatives (safety concerns)
NEDMDG, March 2010 20
White Paper - What it is
A consensus view on the current thinking on drug transporters
• What are the current realities
The known knowns
• What do we know about the relative importance of all transporters?
• Where do you put your effort?
The known unknowns
• What facts are known to be untrue (dispelling myths)?
• Where are our gaps in knowledge (so where should we focus short and long term to increase our knowledge)?
A guideline (not a guidance) towards what we should focus on currently
• What are we capable of addressing?
NEDMDG, March 2010 21
White Paper - What it is not
A complete literature review.
A prescriptive guidance on what to do and how to do it, with a clear description of what it will mean.
A consensus document that everyone agrees to.
A description of all of the exceptions.
• Your experience is important to you and we would certainly appreciate you sharing that with the scientific community to educate us all.
The decision trees are clearly not definitive.
• Included to help move the science forward by acting as templates for discussion
• P-gp most mature but not perfect
NEDMDG, March 2010 22
What are some of the current issues?
The issues presented by transporters are significantly more complex than for DMEs
Involved in absorption, distribution and excretion, so multiple processes of concern
Broad tissue distribution; different effects at different sites, e.g. P-gp at intestine and BBB
Redundancy; different transporters (P-gp and BCRP) and different subfamilies (OATP1B1 and 1B3)
Uptake and efflux transporters (need to consider both to assess the overall effect)
Applicability of kinetic parameters and their interpretation
NEDMDG, March 2010 23
Ieiri et al. (2009) Expert Opinion in Drug Metabolism and Toxicology, 5: 703-729.
Transporter Interaction Redundancy:
Drugs that are shown to interact with one transporter typically interact with multiple transporters.
Thus, multiple pathways for clearance are possible for transporter substrates.
Slide courtesy of Dr. Mitchell Taub
NEDMDG, March 2010 24
Lack of selective inhibitors of drug transporters
1. Dantzig et al. (1999) JPET 290, 854-862
2. Hsiang et al. (1999) J Biol Chem 274, 37161-8
3. Abe et al. (1999) J Biol Chem 274, 17159-63
4. Konig et al. (2000) Am J Physiol Gastrointest Liver Physiol 278, G156-64
5. Hagenbuch. & Meier (2003) Biochim Biophys Acta 1609, 1-18
6. Oostendorp et al. (2009) DMD 37, 917-923
1999 1999 – 2003 2009
• LY 335979 (zosuquidar) is a potent inhibitor/modulator of P-gp, but does not inhibit MRP1 or MRP2.
• Selectivity over inhibition of CYP3A4 is ~60-fold.[Reference 1]
• Discovery, cloning, and publication of OATP superfamily of uptake transporters[References 2-5]
• OATP1B1-mediated uptake of anticancer drugs gimatecan and BNP1350 were inhibited by zosuquidar.
• The effect of modulators on the plasma pharmacokinetics of OATP1B1 substrate drugs may not be solely ascribed to inhibition of P-gp[Reference 6]
Slide courtesy of Dr. Mitchell Taub
NEDMDG, March 2010 25
P-gp at the Blood-Brain Barrier: Clinical DDI?
Sadeque et al. (2000). Clin Pharmacol Ther 68(3): 231-7
NEDMDG, March 2010 26
P-gp at the Blood-Brain Barrier: Species Differences
P-gp inhibitorP-gp
inhibitor dosage
Drug (P-gp substrate)
Clinical usage of the drug
CNS exposure index
Plasma AUC and Cmax
CNS effectBrain P-gp
inhibitionReference
Quinidine 600 mg Fentanyl Synthetic opioid Pupil diameterOral AUC ↑ 171%,
Cmax ↑162%
Quinidine had no major influence on fentanyl pharmacodynamics in
humans.No (1)
Quinidine 600 mg Loperamide
A peripherally acting opioid receptor
agonist for treatment of chronic diarrhea
Respiratory response to CO2
rebreathingAUC ↑ 148%
Respiratory depression occurred when loperamide was given with quinidine.
Yes? (2)
Quinidine 800 mg Loperamide
A peripherally acting opioid receptor
agonist for treatment of chronic diarrhea
Pupil size AUC ↑ 80%Pupil size decreased with co-administration of quinidine.
Yes? (3)
Quinidine 600 mg Methadone Opioid Pupil diameteri.v. AUC and Cmax, no
changesNo effect on methadone miosis after
i.v. administrationNo (4)
Quinidine 600 mg Morphine Opioid Pupil diameterOral AUC ↑60% , Cmax
↑88%
No effect on i.v. morphine miosis, Difference in oral morphine miosis
were commensurated with changes in plasma morphine concentration.
No (5)
Quinidine 800 mg Morphine OpioidPupil diameter and
respiratory response to CO2 rebreathing
Plasma concentration, no change
Not result in an enhancement of central nervous opioid effects.
No (6)
Quinidine 800 mgMorphine 6-glucuronide
An active metabolite of morphine
Pupil size
No effect on the pharmacokinetics of
morphine 6-glucuronide
No effect. No (7)
(1) Kharasch et al. J Clin Pharmacol. 44:224-233 (2004) (2) Sadeque et al. Clin Pharmacol Ther. 68:231-237 (2000) (3) Skarke et al. Pharmacogenetics. 13:651-660 (2003) (4) Kharasch et al. Br J Clin Pharmacol. 57:600-610 (2004) (5) Kharasch et al. Clin Pharmacol Ther. 74:543-554 (2003) (6) Skarke et al. Clin Pharmacol Ther. 74:303-311 (2003) (7) Skarke et al. Anesthesiology. 101:1394-1399 (2004)
Slide courtesy of Dr. Yongmei Li
NEDMDG, March 2010 27
Can digoxin be used as a clinical P-gp probe substrate?
Narrow therapeutic window of digoxin requires close monitoring
Abundant digoxin clinical DDI study data – especially for relatively new drugs
Digoxin currently viewed as the “gold standard” probe for studying clinical P-gp–related DDIs
• recent data may indicate that digoxin interacts with other transporters; OATPs
Fenner et al. (2009) CPT 85, 173-181
NEDMDG, March 2010 28
• 11C-verapamil and CsA dosed IV • AUCbrain/AUCblood of 11C-radioactivity ↑ 88% in the presence of CsA• ↑ 770% in similar study in mouse
Human CNS P-gp localization: PET Imaging
Sasongko et al CPT (2005) 77:503-514; Hendrikse et al Br. J. Pharmacol. (1998) 124:1413-1418
MRI - CsA + CsA
NEDMDG, March 2010 29
P-gp at the Blood-Brain Barrier: Mouse KO
A. Ayrton and P. Morgan. Role of transport proteins in drug absorption, distribution and excretion, Xenobiotica. 31:469-497 (2001)
NEDMDG, March 2010 30
ITC Transporter Workshop (2008)Mikko Niemi - University of Helsinki
31
Transporter-Mediated Drug-Drug Interactions (DDIs)
Lei Zhang, Ph.D.Special Assistant to Office DirectorOffice of Clinical PharmacologyOffice of Translational Sciences CDER, [email protected]
Clinical Pharmacology Advisory Committee MeetingTopic 4: Transporter-Mediated Drug-Drug Interactions
Atlanta, GA, March 17, 2010
32
Question 1
For evaluation of NMEs as potential substrates of transporters:
a. Do you agree that P-gp, BCRP, OATP1B1/1B3, OAT1/3 and OCT2 are the major transporters that should be routinely evaluated based on the proposed flow chart during drug development? [VOTING]
b. What transporter(s) should be included in the flow chart for routine study and why?
c. What alternative criteria would you suggest to identify transporters that would have clinical significance and should be studied?
33
Question 2
For evaluation of NMEs as potential inhibitors of transporters:
a. Do you agree that P-gp, BCRP, OATP1B1/1B3, OAT1/3 and OCT2 are the major transporters that should be routinely evaluated based on the proposed flow chart during drug development? [VOTING]
b. What transporter(s) should be included in the flow chart for routine study and why?
c. What alternative criteria would you suggest to identify transporters that would have clinical significance and should be studied?
FDA advisory Board Meeting:ASCPT Conference: Atlanta, March 2010
NEDMDG, March 2010 34
FDA brought to the committee several voting questions ……..
…the panel voted 12-4 that P-glycoprotein, BCRP and OATP1B1/1B3, OAT 1/3 and OCT 2 are the major transporters that mediate DDI and all NME should routinely be evaluated …. as substrates for these transporters….
Those voting no agreed the proposed transporters are reasonable, but cited the absence of appropriate tools to conduct the studies. "Throwing this out there to the pharmaceutical industry, it's just not ready for prime time yet. We need more tools," argued Gregory Kearns, Children's Mercy Hospitals & Clinics of Kansas City, Mo.Jerry Collins of the National Cancer Institute agreed, saying it would be better to invest in developing the tools - which garnered concurrence from other committee members.Citing the burden on industry, Howard McLeod, University of North Carolina, also suggested that "in the future, every time we want to add something, we should also identify something we want to take away."Caldwell, who supported the expanded testing, said "the tools are coming, and quickly," while Thummel, another proponent of the testing, contended that the preclinical tools are available.
The vote was 11-5 on a question of routinely evaluating all NMEs as inhibitors of the same transporters
Future Interactions
NEDMDG, March 2010 35
AAPS Website
Intended to be active soon (Maciej J Zamek-Gliszczynski; Lilly)
Email link to provide comments and questions@??mail.com
• Collate common questions• Future chat rooms• Collate thoughts and concerns for future white paper(s)• Others?
NEDMDG, March 2010 36
Overall Conclusions/Impact
Transporters are a very dynamic field – the white paper is intended to be a snapshot
White paper will need to be updated (timeline?)
White paper provides framework for FDA to add to current guidance(s) – DDI
Emphasizes the need for flexibility
• which provides some realistic challenges for regulatory agencies
Has identified areas of highest immediate need
• decision trees for other transporters
• relevance of unbound drug concentrations
Never intended to be a panacea
Focus group for collating new data
NEDMDG, March 2010 37
Moving Forward
Committee of FDA and Pharma
• Lei Zhang ([email protected] ) and Donald Tweedie ([email protected] )
Main committee with sub-committees for specific topics
• Identify experts for different transporters
• Identify experts for selected topics (P-gp and digoxin, kinetics)
Outcome
• Provide feedback on discussions, action items
• Make recommendations– change current practices– monitor specific practices
• Publish mini-white papers
NEDMDG, March 2010 38
Acknowledgements
ITC members
• Shiew Mei Huang, FDA
• Kathy Giacomini, UCSF
DMTG, PhRMA
• Volker Fischer
DIA (Drug Information Assocation)
Mitch Taub, Boehringer Ingelheim
Yongmei Li, Boehringer Ingelheim
NEDMDG, March 2010 39
Acknowledgements
Academia:Les Benet UCSFKim Brouwer UNCAmber Dahlin UCSFKathy Giacomini UCSFToshi Ishikawa OSC, TokyoDietrich KepplerHeidelberg Richard Kim W. OntarioMikko Niemi HelsinkiYuichi Sugiyama TokyoPeter Swann MarylandSteve Wright Arizona Sook Wah Yee UCSFRegulatory:Shiew Mei Huang FDALei Zhang FDA
Industry:Xiaoyan Chu MerckRaymond Evers MerckVolker Fischer AbbottKate Hillgren LillyKeith A. Hoffmaster NovartisCaroline Lee PfizerJoe Polli GSKDonald Tweedie BIJoe WareGenentechMaciej Zamek-Gliszczynski Lilly