pharmacokinetic evaluation of a drug transporter … · pharmacokinetic evaluation of a drug...

Pharmacokinetic Evaluation of a Drug Transporter Cocktail Consisting of Digoxin, Furosemide, Metformin, and Rosuvastatin

Mitchell E. Taub ITCW3 Meeting – Transporters in Drug Development March 14, 2017

Project team: Thomas Ebner, Thomas Giessmann, Naoki Ishiguro, Fabian Muller, Ashish Sharma, Peter Stopfer, Mitchell Taub, Heike Zimdahl-Gelling

Outline

Background and challenges

Regulatory perspectives

Transporter cocktail design Literature survey

In vitro studies

Clinical cocktail – Study 1

Clinical cocktail – Study 2

2

Background – rationale

• In vitro and in vivo studies to evaluate the potential for transporter-based DDIs are required by regulatory authorities

• Drug transporters generally exhibit broad substrate specificity

• In vitro data generated using different experimental systems can be highly variable

• Regulatory agencies cautiously evaluate in vitro transporter data • Can result in an increase in the number of clinical DDI studies

• Probe drug cocktail approach may be applied to simultaneously assess multiple potential DDIs established for CYP450s • However, this has not yet been defined/established for transporters

Goal: Develop a readily accessible cocktail approach, using transporter substrate drugs available globally, applicable in an industrial drug development setting

3

Cooperstown cocktail: phenotyping data, CYP450 probes Streetman et al. (2000) CPT, 68:375

4

C Y P 1 A 2

Me

dia

n V

alu

e (

ran

ge

)

Ind iv id

u a l

C o c k tail

0

1

2

3

4

5

C Y P 2 C 1 9

Me

dia

n V

alu

e (

ran

ge

)

Ind iv id

u a l

C o c k tail

0 .0

0 .5

1 .0

1 .5

2 .0C Y P 3 A

Me

dia

n V

alu

e (

ran

ge

)

Ind iv id

u a l

C o c k tail

0

2 0 0

4 0 0

6 0 0

8 0 0

Caffeine (P, M)

Omeperazole (P, M)

Midazolam, IV (CL)

Also included: CYP2D6, N-acetyltransferase-2, xanthine oxidase

5

Ieiri et al. (2009) Expert Opinion in Drug Metabolism and Toxicology, 5: 703-729 Muller and Fromm (2011) Pharmacogenomics, 12: 1017-1037

Drug P-gp BCRP MRP2 OATP 1A2

OATP 1B1

OATP 1B3

OATP 2B1

OAT1 OAT3 OCT2 MATE1

Cimetidine S S / I S / I

Cyclosporine A I I I I

Estradiol-17β-D-glucuronide S S S S

Fexofenadine S S S S

Methotrexate S S S S S

Pravastatin S S S S S S S

Probenecid S S

Rifampin S / I S / I

Rosuvastatin S S S S

Drugs that are shown to interact with one transporter typically interact with multiple transporters

Thus, multiple pathways for clearance are possible for transporter substrates

Transporter interaction redundancy

Theoretical maximum statin AUC increase (pathway) Elsby et al (2012) CPT, 92(5):584-598

Simvastatin Atorvastatin Fluvastatin Pitavastatin Pravastatin Rosuvastatin CYP3A4, CYP2C9 OATP1B1, OATP1B3 NTCP, BCRP, OAT3

FDA guidance on DDIs cocktail studies

FDA – Guidance for Industry – Drug Interaction Studies (2012, draft)

• Simultaneous administration of a mixture of substrates of multiple CYP enzymes and transporters in one study (i.e., a “cocktail approach”) in human volunteers is another way to evaluate a drug’s inhibition or induction potential, provided that the study is designed properly and the following factors are present:

• (1) the substrates are specific for individual CYP enzymes or transporters;

• (2) there are no interactions among these substrates;

• (3) the study is conducted in a sufficient number of subjects.

• Negative results from a well-conducted cocktail study can eliminate the need for further evaluation of particular CYP enzymes and transporters.

• The data generated from a cocktail study can supplement data from other in vitro and in vivo studies in assessing a drug’s potential to inhibit or induce CYP enzymes and transporters.

7

EMA guidance on DDIs cocktail studies

EMA – Guideline on the Investigation of Drug Interactions (2015)

• It is possible to use so called “cocktail studies” to investigate the effects of an investigational drug on several enzymes and transporters in one in vivo study.

• In vivo cocktail studies may also be used to replace studies of the in vitro inhibition and induction potential of parent drug (and metabolites) on enzymes (and transporters).

• It should have been demonstrated in vivo that the probe drugs combined in the “cocktail” do not interact with each other.

• If satisfactorily performed, the results of the cocktail studies can be extrapolated to other drugs and can be used to support treatment recommendations in the SmPC.

8

In vivo transporter cocktail project Stage 1 Stage 2

Seek advice and opinion of key experts and opinion leaders Assessment of practical application of substrate/inhibitor combinations Initial estimate of scope and extent of clinical program Propose various scenarios and recommendation for proceeding into Stage 2

Stage 1: Orientation and concept building

Stage 2: Assessment of cocktails and clinical validation

Check for mutual interactions using the (4) selected cocktail substrates Test the effect of transporter inhibitors

PK properties of proposed transporter cocktail drugs Ebner, Taub, Ishiguro (2015) J. Pharm. Sci., 104:3220-3228

Digoxin

(P-gp)

Rosuvastatin

(OATP, BCRP)

Furosemide

(OAT1, OAT3)

Metformin

(OCT2, MATEs)

Dose in cocktail (mg) 0.25 10 5 500

Half-life (h) 18 - 36 21 2 1.7 - 4.5

Bioavailability (%) 60 - 80 (tablet) 20 65 (tablet) 50 - 60

PPB (fu, %) 75 12 1.3 - 4.1 100

Route of elimination (i.v. dosing)

51% urine 15% feces

28% urine 83% urine 7.5% feces

100% urine

Metabolism minor minor, ~20% minor negligible

In vitro transporter (recommended by guidelines)

P-gp, OATP1B3, OCT2

P-gp, BCRP, OAT3, OATP1B1, OATP1B3

BCRP, OAT1, OAT3 OCT2, MATE1, MATE2-K, P-gp,

BCRP

Key criteria: Drugs and dose levels selected must be available in various countries

Inhibitory effect of cocktail drugs on transporters Ebner, Taub, Ishiguro (2015) J. Pharm. Sci., 104:3220-3228

• IC50 values primarily obtained from literature, with the exception of furosemide

• IC50 values generally high see next slide for DDI calculations

In vitro inhibitory effect, IC50 (μM)

P-gp BCRP OAT1 OAT3 OATP1B1 OATP1B3 OCT2 MATE1 MATE2-K

Digoxin 125 >30 >30 >30 7.9-47 1-42 >30 >30 >30

Furosemide >2,000 170 5.1-20 1.7-51 30-300 >300 >300 >300 >300

Rosuvastatin >400 140 >100 26 0.047-2.43 3.61 >100 >100 >100

Metformin >30,000 >30,000 >1,000 >1,000 >1,000 >1,000 289-1,700 667 6,500

Potential for mutual DDI Ebner, Taub, Ishiguro (2015) J. Pharm. Sci., 104:3220-3228

• DDI likelihood calculated based on thresholds currently listed in FDA, EMA, and PMDA guidelines

In vivo concentration at DDI site (plasma or GI tract) DDI

Likelihood Dose

(mg)

[I]1,total

(µM)

[I]1,unbound

(µM)

[I]in,max,u

(µM)

[I]2

(µM)

Digoxin 0.25 0.0026 0.00195 0.018 1.28 remote

Furosemide 5 0.42, 0.64 0.017, 0.026 0.058, 0.068 60.5 remote

Rosuvastatin 10 0.0095 0.0011 0.0061-0.010 80.0 remote

Metformin 500 10 10 267 15,500 remote

Furosemide as substrate of P-gp, BCRP, and MRP2 Ebner, Taub, Ishiguro (2015) J. Pharm. Sci., 104:3220-3228

Papp and efflux ratios of furosemide (10 µM) in Caco-2 cells in the absence and presence of transporter inhibitors (n = 3 ± SD). • ZSQ (1 μM, P-gp) • FTC (1 μM, BCRP) • MK-571 (50 μM, MRP) • ZSQ, FTC, and MK571

Control+ZSQ

+FTC

+ZSQ/FTC

+ZSQ/FTC/MK571Furo

sem

ide

Papp

(x10

-6 c

m/s

ec)

0

5

10

15

20

25

AtoBBtoA

33 28 16 17 0.80

Furosemide is a substrate of OAT1 and OAT3 Ebner, Taub, Ishiguro (2015) J. Pharm. Sci., 104:3220-3228

Uptake of furosemide (20 μM) into HEK293 cells expressing OAT1, OAT3, OATP1B1, OATP1B3, and OCT2 (n = 3 ± SD) *: p <0.05.

Time (min)0 2 4 6 8 10

Upta

ke o

f Fur

osem

ide (

L/m

g)

0

10

20

30

40

50

60

70VectorOAT1OAT3OCT2OATP1B1OATP1B3

*

*

**

***

*

Time (min)0 2 4 6 8 10

Upta

ke o

f Fur

osem

ide (

L/m

g)

0

1

2

3

4

*

**

*

***

**

(A)

(A’)

Furosemide interaction with MATE1 and MATE2-K Ebner, Taub, Ishiguro (2015) J. Pharm. Sci., 104:3220-3228

Uptake of furosemide (20 μM) into HEK293 cells expressing MATE1 or MATE2-K (n=3 ± SD) *: p <0.05

Time (min)0 2 4 6 8 10

Uptak

e of F

uros

emide

( L/m

g)

0

1

2

3

4VectorMATE1MATE2-K

(B)

Conclusions from literature and in vitro studies Ebner, Taub, Ishiguro (2015) J. Pharm. Sci., 104:3220-3228

• Mutual DDI upon oral administration of the four selected drugs is unlikely to occur • Digoxin • Furosemide • Metformin • Rosuvastatin

• Based on literature and in vitro data, this 4-component probe drug cocktail is proposed for clinical validation trials

• Proposed low doses of probe drugs expected to be clinically safe • Suitable dose strengths are readily available (globally)

Trial 1: Evaluate drug probes for mutual interaction Open-label, randomized, single-dose, 6-period crossover design (n=24)

Reference Treatments A-D (single doses): • A: 0.25 mg digoxin, 1 tablet • B: 5 mg furosemide, oral solution (0.5 mL) • C: 500 mg metformin HCl, 1 film-coated tablet • D: 10 mg rosuvastatin, 1 film-coated tablet Test Treatments E-G (dosed together): Treatment E (Test 1) Reference Doses • 0.25 mg digoxin • 5 mg furosemide oral solution • 500 mg metformin HCl • 10 mg rosuvastatin, 1 tablet

Treatment F (Test 2) • 0.25 mg digoxin • 5 mg furosemide oral solution • 1000 mg metformin HCl (2 x

500 mg film-coated tablets) • 10 mg rosuvastatin

Treatment G (Test 3) • 0.25 mg digoxin • 20 mg furosemide oral

solution (2.0 mL) • 500 mg metformin HCl • 10 mg rosuvastatin

Stopfer P. et al. (2016) Pharmacokinetic Evaluation of a Drug Transporter Cocktail Consisting of Digoxin, Furosemide, Metformin, and Rosuvastatin. Clin. Pharmacol. Ther. 100(3):259-67

Digoxin: gMean plasma concentration time profiles

Metformin: gMean plasma concentration time profiles

Furosemide: gMean plasma concentration time profiles

Furosemide alone

Furosemide: ANOVA (primary endpoints Cmax and AUC0-tz)

N

Adjusted gMean ratio of Cmax [%]

90% CI [%] N

Adjusted gMean ratio of

AUC0-tz [%]

90% CI [%]

Test Cocktail 1 / Furosemide (Reference)

22/22 80.87 71.51 – 91.47 22/22 96.24 88.61 –

104.53

Test Cocktail 2 / Furosemide (Reference)

11/22 79.64 67.68 – 93.72 11/22 101.22 87.85 –

116.62

Test cocktail 1: Standard cocktail (E) Test cocktail 2: Cocktail with 1000 mg metformin (F)

Rosuvastatin: gMean plasma concentration time profiles

Rosuvastatin alone

Rosuvastatin in test cocktails

Rosuvastatin: ANOVA (primary endpoints Cmax and AUC0-tz)

N Adjusted

gMean ratio of Cmax [%]

90% CI [%] N

Adjusted gMean ratio of AUC0-tz [%]

90% CI [%]

Test Cocktail 1 / Rosuvastatin (Reference)

23/22 138.56 122.47 – 156.75 23/22 143.37 128.09 –

160.47


11/22 133.68 103.79 – 172.156 11/22 148.68 113.23 –

195.25


12/22 140.05 124.11 – 161.57 12/22 146.72 124.96 –

172.28

Test cocktail 1: Standard cocktail (E) Test cocktail 2: Cocktail with 1000 mg metformin (F) Test cocktail 3: Cocktail with 20 mg furosemide (G)

Trial 2: Adjust doses to optimize cocktail design Open-label, randomized, single-dose, 6-period crossover design (n=18)

Goal: Identify source of interaction with RSV in initial cocktail study due to coadministration of metformin or furosemide? Treatments (single doses): • All: 10 mg RSV reference treatment, film-coated tablet • T1: 10 mg RSV + 10 mg metformin (0.1 mL metformin HCl) • T2: 10 mg RSV + 50 mg metformin (0.5 mL metformin HCl) • T3: 10 mg RSV + 500 mg metformin (5 mL metformin HCl) • T4: 10 mg RSV + 1 mg furosemide (0.1 mL) • T5: 10 mg RSV + 5 mg furosemide (0.5 mL)

Subjects fasted overnight (10+ hr), doses administered with 240 mL water; continued fasting/standing 4 hr post-dosing

Rosuvastatin + metformin or furosemide ANOVA data (primary endpoints Cmax and AUC0-tz)

N Adjusted

gMean ratio of Cmax [%]

90% CI [%] N

Adjusted gMean ratio of AUC0-tz [%]

90% CI [%]

T1: RSV + 10 mg metformin 15-16 102.47 87.19 –

120.42 15-16 101.95 89.49 – 116.15

T2: RSV + 50 mg metformin 16 106.98 92.54 –

123.69 16 106.09 96.12 – 117.11

T3: RSV + 500 mg metformin 15-16 154.07 131.70 –

180.24 15-16 152.18 135.12 – 171.41

T4: RSV + 1 mg furosemide 15-16 106.81 91.78 –

124.30 15-16 106.97 94.34 – 121.30

T5: RSV + 5 mg furosemide 16 117.98 98.27 –

141.65 16 115.92 101.93 – 131.82

RSV + metformin: gMean plasma conc. time profiles

T ime [hours]

0 12 24 36 48

Rosu

vast

atin

pla

sma

conc

entra

tion

[nm

ol/L

]

0.1

1

10

100 Rosuvastatin (N=16)Rosuvastatin + 10 mg Metformin (T1) (N=15)Rosuvastatin + 50 mg Metformin (T2) (N=16)Rosuvastatin + 500 mg Metformin (T3) (N=15)

b

Rosuvastatin + Metformin (500 mg)

RSV + furosemide: gMean plasma conc. time profiles

b

T ime [hours]

0 12 24 36 48

Rosu

vast

atin

pla

sma

conc

entra

tion

[nm

ol/L

]

0.1

1

10

100Rosuvastatin (N=16)Rosuvastatin + 1 mg Furosemide (T4) (N=15)Rosuvastatin + 5 mg Furosemide (T5) (N=16)

Rosuvastatin + Furosemide (5 mg)

Conclusions

• Use of a probe drug cocktail is a promising approach to reduce the number of clinical studies required to investigate transporter-mediated DDIs

• Trial 1: Increased RSV exposure likely attributable primarily to coadministration with metformin, and to a minor degree furosemide

• Trial 2: Increased RSV exposure when coadministered with 500 mg metformin (slightly with 5 mg furosemide); DDI eliminated by reducing the dose of metformin to 10 or 50 mg, reducing the dose of furosemide to 1 mg

• Interaction mechanism: Not predictable from in vitro transporter data; possibly due to an effect on absorption? More studies needed.

• Overall assessment: A four-component drug transporter cocktail should be further evaluated using 0.25 mg digoxin, 1 mg furosemide (previously 5 mg), 10 or 50 mg metformin (previously 500 mg) and 10 mg RSV

• Future plans: Coadministration of the cocktail with known transporter inhibitors

Acknowledgments

Core team and sponsors: • Thomas Ebner

• Dietmar Gansser

• Florian Gantner

• Thomas Giessmann

• James Hilbert

• Kathrin Hohl

• Naoki Ishiguro

• Arvid Jungnik

• Fabian Muller

• Ashish Sharma

• Peter Stopfer

• Heike Zimdahl-Gelling

• Donald Tweedie

• Mark Castles

• Ulrich Roth 29

Internal contributors: • Ayano Fukuhara

• Caroline MacLean

• Christian Lechner

• Meeghan O’Connor

• Naoko Ohtsu

• Lalitha Podila

• Asami Saito

• Hidetada Shimizu

• Junichi Takano

• Masahito Takatani

• Tokuko Takatsuka

• Ikumi Washio

• Walter Weber

External contributors:

• Uwe Fuhr

• Martin Fromm

• Kathleen Giacomini

• Richard Kim

• Mikko Niemi

• Peter Swaan

Backups

In vitro mechanistic studies cause of RSV change?

• Contribution of NTCP to RSV uptake, potential inhibition by cocktail components?

• Influence of allelic variants of OATP1B1 on results?

• Other uptake transporters contributing to RSV clearance, and the effects of cocktail components?

• Potential for inhibition of intestinal BCRP by cocktail components? • Need to recheck inhibition of BCRP by furosemide

• Possibility that cocktail components inhibited intestinal and/or hepatic metabolism of RSV? • Evaluate UGTs and CYP2C9

31

Key observations from Trial 1 Stopfer P. et al. (2016) CPT, 100(3):259-67

• Digoxin, metformin, and furosemide AUC0-tz were similar when dosed individually and as a cocktail

• Digoxin and metformin Cmax were similar when dosed individually and as a cocktail

Notable changes when administered as a cocktail:

• Cmax of furosemide was reduced by 19.1%

• Cmax of rosuvastatin increased by 38.6%

• AUC0-tz of rosuvastatin increased by 43.4%

Digoxin: ANOVA (primary endpoints Cmax and AUC0-tz)

N

Adjusted gMean ratio of Cmax [%]

90% CI [%] N

Adjusted gMean ratio

of AUC0-tz [%]

90% CI [%]

Test Cocktail 1 / Digoxin (Reference)

22 /22 100.51 89.61 – 112.73 22 / 22 107.32 95.41 – 120.717


11/22 96.50 75.21 – 123.83 11/22 102.26 82.21 – 127.18


11/22 90.16 78.24 – 103.90 12/22 82.61 73.33 – 100.76


Metformin: ANOVA (primary endpoints Cmax and AUC0-tz)

N


of Cmax [%]

90% CI [%] N


of AUC0-tz [%]

90% CI [%]

Test Cocktail 1 / Metformin (Reference)

23/22 106.95 97.65 – 117.12 23/22 99.44 93.40 – 105.88

Test Cocktail 3 / Metformin (Reference)

12/22 113.48 91.98.67 – 140.00 12/22 107.76 93.28 – 124.49


RSV + metformin: gMean plasma concentration time profiles

T ime [hours]

0 12 24 36 48

Rosu

vast

atin

pla

sma

conc

entra

tion

[nm

ol/L

]

0.1

1

10

100 Rosuvastatin (N=16)Rosuvastatin + 10 mg Metformin (T1) (N=15)Rosuvastatin + 50 mg Metformin (T2) (N=16)Rosuvastatin + 500 mg Metformin (T3) (N=15)

b



RSV + furosemide: gMean plasma conc. time profiles

a

T ime [hours]

0 12 24 36 48

Rosu

vast

atin

pla

sma

conc

entra

tion

[nm

ol/L

]

0

2

4

6

8

10

12

Rosuvastatin (N=16)Rosuvastatin + 1 mg Furosemide (T4) (N=15)Rosuvastatin + 5 mg Furosemide (T5) (N=16)

b

T ime [hours]

0 12 24 36 48

Rosu

vast

atin

pla

sma

conc

entra

tion

[nm

ol/L

]

0.1

1

10

100Rosuvastatin (N=16)Rosuvastatin + 1 mg Furosemide (T4) (N=15)Rosuvastatin + 5 mg Furosemide (T5) (N=16)



Clinical DDI studies with RSV + inhibitors Source: University of Washington DDI Database

37

Incr

ea

se in

ro

suva

sta

tin A

UC

an

d C

max

(fo

ld v

s. c

on

tro

l)

c y c los p o r in

e

r ifam

p in

s ime p re

v ir

a taz a n a v ir

a n d r ito

n a v ir

c lop id

o g rel

e ltrom

b o p a g

g emfib

roz il

u rso d e o x y c h o lic

ac id

d a run a v ir

a n d r ito

n a v ir

e lv iteg ra

v ir a n d c

o b ic is tat

itra c o n a z o le

t ipra

n a v ir a n d r i

ton a v ir

lom

itap id

e0

1

2

3

4

6

8

1 0

1 2

A U C

C m ax

Clinical DDI study protocol

Design: Open-label, randomized, single-dose, 6-period crossover (n=24)

Primary endpoints: AUC0-tz and Cmax

Secondary endpoint: AUC0-∞

Additional PK parameters of interest: tmax, λz, t1/2, %AUCtz-∞, MRTpo, CL/F, Vz/F, Aet1-t2, fet1-t2, CLR,t1-t2 Statistical methods: ANOVA

Rosuvastatin fe0-36 OATP1B1 / PGx

Rosuvastatin CLr0-36 OATP1B1 / PGx

Cooperstown cocktail Streetman et al. (2000) CPT, 68:375

41

Influence of OATP1B1 variants on RSV exposure (mean +/- SD)

42

AU

Cla

st (

nm

ol*

h/L

)C

max (n

mo

l/L)

R S V : *1 A a

n d *1B

R S V : *1 B /*1

5 or *

1 B /*5

R S V : *1 5 /*1

5 (n= 1 )

C o c k tail

1 : *1 A a

n d *1B

C o c k tail

1 : *1 B /*1

5 or *

1 B /*5

C o c k tail

1 : *1 5 /*1

5 (n= 1 )

R S V : *1 A a

n d *1B

R S V : *1 B /*1

5 or *

1 B /*5

R S V : *1 5 /*1

5 (n= 1 )

C o c k tail

1 : *1 A a

n d *1B

C o c k tail

1 : *1 B /*1

5 or *

1 B /*5

C o c k tail

1 : *1 5 /*1

5 (n= 1 )

0

5 0

1 0 0

1 5 0

2 0 0

2 5 0

0

5

1 0

1 5

2 0

2 5A U C la s t

C m ax

Transporters discussed in the ITC White Paper: Expression and distribution

Transporters are expressed in multiple organs, contribute to the ADME of drugs, metabolites, endobiotics, vitamins, and nutrients Complex system - tissue levels of drugs facilitated or hindered by transporters

Giacomini et al. (2010) 9:215-236

43

Cooperstown and C + 1 cocktail Chainuvati et al. (2003) CPT, 74:473

44

Biomarker Ratios: Cooperstown + 1 Cocktail Study

Mea

n R

atio

(95%

con

fiden

ce in

terv

al)

CYP1A2

NAT2 XO

CYP2C9

CYP2C19

CYP2D6

CYP3A0.0

0.5

1.0

1.5

2.0

caffeine

IV midazolam

dextromethorphan omeperazole

warfarin

Furosemide interaction with OATP1B1 and OATP1B3 Ebner, Taub, Ishiguro (2015) J. Pharm. Sci., online

• Uptake of furosemide into HEK293 cells expressing OATP1B1 or OATP1B3

• Inhibition of OATPs by the inhibitor rifampicin (n = 3 ± SD)

v/S (

L/m

in/m

g pr

otein

)

0

1

2

3

4

5Vector OATP1B1 OATP1B3

20 M 2000 M 20 M +100 M Rif

(C)

Challenges choosing a substrate or inhibitor of BCRP Lee et al. (2015) DMD, 43:490-509

46

Intestine Liver

Bile

Lumen Epithelial cells Blood

Blood

Hepatocytes

passive permeability

Intestinal BCRP inhibition Lee et al. (2015) DMD, 43:490-509

Precipitant I2 (µM) BCRP Parameters

IC50 I2/IC50

lapatinib 5299.42 0.025 211976.80

sulfasalazine 40160.64 0.46 87305.74

curcumin 21716.71 1.6 13572.94

erlotinib 1525.01 0.13 11730.85

elacridar 2838.64 0.31 9156.91

nilotinib 2826.96 1.38 2048.52

gefitinib 2013.83 1.01 1993.89

sunitinib 501.91 0.64 784.23

pantoprazole 370.03 5.5 67.28

rabeprazole 445.12 8.5 52.37

47

substrate

availability/ interactions complications with absorption

cancer therapies

Hepatic BCRP inhibition Lee et al. (2015) DMD, 43:490-509

Precipitant I (µM, Cmax)

BCRP Parameters

IC50 I/IC50

sulfasalazine 79 0.46 171.74

lapatinib 4.2 0.025 168.00

erlotinib 6.06 0.13 46.62

nilotinib 4.3 1.38 3.12

pantoprazole 6.5 5.5 1.18

elacridar 0.327 0.31 1.05

gefitinib 0.8 1.01 0.79

48

Other enzyme/transporter interactions Lack of clinical BCRP inhibition data

Complications with absorption Would need to use a therapeutic dose

Regulatory discussions: Enzymes, transporters, DDIs

1997 1999 2003 2004 2006 2010 2011 2012

FDA In Vitro

DDI Guidance

FDA In Vivo

DDI Guidance

Guidance Publication

Public Workshops

Advisory Committee Meetings

Public Workshops, Comments

FDA Concept

Paper

CYPs P-gp CYP2B6 CYP2C8

Transporters

1st FDA Draft DDI

Guidance

EMA Draft DDI

Guidance

ITC Whit

e Pape

r

2nd FDA Draft DDI

Guidance

ITCW1

ITCW2

EMA Final DDI

Guidance

Cooperstown cocktail studies Streetman et al. (2000) CPT, 68:375 | Chainuvati et al. (2003) CPT, 74:473

50

Transporter studies: Tools available at BI

Initial transporter

profiling studies

Mechanistic studies: • Indication-specific • Clearance-specific • Project data

Transfected cells Caco-2

SCHH HepatoPac Inverted membrane vesicles

Isolated perfused rat liver/lung

Bidirectional transport studies: Caco-2, MDCK-MDR1

BL to AP Papp Secretory Transport

AP to BL Papp Absorptive Transport

BL-AP / AP-BL ~1 Not an Efflux Pump Substrate BL-AP / AP-BL >2 Efflux Pump Substrate

Classification of membrane transport

Membrane Transport

Passive transport 1. Simple diffusion 2. Facilitated diffusion

Active transport 3. Primary active

transport 4. Secondary active

transport –Symport / Antiport

Concentration gradient

Transported molecule

1 2 2 3 4 4

Channel Transporter Transporter Transporter Transporter

ATP AMP

Carrier-mediated

Clinical DDI studies: Few selective transporter substrates or inhibitors available

Transporter Substrates Inhibitors

ITC White Paper

Selectivity? ITC White Paper

Selectivity?

P-gp Digoxin P-gp, OATP4C1, sodium-dependent transporter (new)

Cyclosporine A P-gp, OATP, and other transporters/enzymes

BCRP Sulfasalazine Pitavastatin Ciprofloxacin Rosuvastatin

Metabolism also occurs; possibly substrates of other transporters

No inhibitor recommended

Not applicable

OATP1B1 Atorvastatin Pitavastatin Rosuvastatin

Multiple transporters

Rifampicin Cyclosporine A

P-gp, OATP, and other transporters/enzymes

OATP1B3 Telmisartan Multiple transporters

OAT1 Many drugs recommended

Not selective for OAT1 Probenecid OATs and OATPs

OAT3 Not selective for OAT3

OCT2 Metformin OCTs and MATE Cimetidine OCTs and MATE

A case-by-case approach, based on in vitro transporter and metabolism data, is essential for selecting in vivo probe

substrate/inhibitor for clinical DDI studies

abcd Clinical study: P-gp mediated DDI involving digoxin and rifampicin

Digoxin PO dose Digoxin IV dose

- RIF

+ RIF 3.5x ↑

Greiner et al., JCI (1999) 104:147

Rosuvastatin dose adjustment

0 2 4 6 8 10 12

Atazanavir / ritonavir

Lopinavir / ritonavir

Gemfibrozil

Cyclosporine A

Fold adjustment from top marketed doseFold change in AUC or Cmax

Fold Change

Source: FDA labels, presented by Joe Polli (GSK) at 2011 ISSX Meeting and 2012 ITCW2 Meeting

Dose adjustments tend to follow the fold change in AUC and/or Cmax

Theoretical maximum statin AUC increase: TPs/DMEs Elsby et al (2012) CPT, 92(5):584-598

ITC Commentary: Clinically Important Transporter Polymorphisms Giacomini et al (2013) CPT, 94(1):23-26

(1) In vitro studies (2) Clinical DDI study? (3) Consider PGx variants (4) Collect DNA samples, SNP analysis (5) Relate SNPs with data (6) Multiscale analysis – DME, TP, age, race, sex, etc.

Complex DDIs involving transporters and DMEs (CsA) Elsby et al (2012) CPT, 92(5):584-598

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• SMV: Hepatic CYP3A4 DDI unlikely (passive uptake) intestinal CYP3A4/OATP1B1 inhibition

• ATV: Inhibition of intestinal BCRP and CYP3A4, OATP1B1; passive uptake low (<1 5%)

Complex DDIs involving transporters and DMEs (CsA) Elsby et al (2012) CPT, 92(5):584-598

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• PTV: OATP1B1 and OATP1B3 • PRV: OATP1B1 and intestinal efflux transporter – possibly MRP2? • RSV: Intestinal BCRP; active hepatic uptake facilitated by OATP1B1/1B3 and

NTCP

Complex DDIs involving transporters and DMEs Elsby et al (2012) CPT, 92(5):584-598

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pharmacokinetic evaluation of a drug transporter … · pharmacokinetic evaluation of a drug...

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