IWCPAT 2017, Chicago

CYP3A Induction Can Predict P-gp Induction: An

Example of Sofosbuvir (a P-gp Substrate) with

Rifampin, Carbamazepine or Rifabutin

Justin D. Lutz, Brian J. Kirby, Benedetta Massetto, Qinghua Song, Angela Worth,

Brian P. Kearney, Anita Mathias

Gilead Sciences, Inc., Foster City, CA

Conservative Labeling Due to Lack of Transporter Induction

Data

Assumed parity between transporters and CYP3A induction

– Potentially conservative label recommendations adopted

Known or potential strong CYP3A inducers assumed to be strong

P-gp inducers

Co-regulation of many transporters and CYPs

– Can CYP induction data be leveraged to predict transporter induction?

– Rifampin

– Rifabutin

– Rifapentine

– St. John’s Wort

2

– Carbamazepine

– Phenytoin

– Phenobarbital

– Tipranavir/Ritonavir

Rifampin (RIF): a Prototypical Inducer and PXR Agonist

Multiple RIF dose levels (2, 10, 75, 600 mg) to elicit weak to strong CYP3A induction

Are transporters as inducible as CYP3A?

Can transport induction be predicted by CYP3A?

Probe Drug Cassette Dose CYP/Transporter Cassette Day

Dabigatran etexilate (DE)* 75 mg P-gp 1

Pravastatin (PRA) 20 mg OATP 3

Rosuvastatin (ROS) 10 mg OATP/BCRP 5

Co

ckta

il Midazolam (MDZ) 2 mg CYP3A

7Tolbutamide (TOL 500 mg CYP2C9

Caffeine (CAF) 200 mg CYP1A2

*DE was analyzed as total dabigatran (TDAB), the sum of conjugated and unconjugated active species.

3

1 1 0 1 0 0 1 0 0 0

0 .1

1

1 1 0 1 0 0 1 0 0 0

0 .1

1

P-gp Induction is One DDI Category Less Potent Than CYP3A

Combining Emax/ED50 curves allows for evaluation of relative induction potency

Gray areas represent induction parity between probes

This relationship holds true even after accounting for probe sensitivity (ie fm and ft)

4

Mean observed ± 90% CI

Corrected

Individual observed

Weak

(AUCR 0.8–0.5)

Moderate

(AUCR 0.5–0.2)Strong

(AUCR <0.2)

CY

P3A

MD

Z A

UC

R

RIF Dose, mg

P-g

pT

DA

B A

UC

R

CYP3AMDZ AUCR

P-g

pT

DA

B A

UC

R

ED50 = 66 mg

Emax = 13

Emax,Ri = 14

ED50 = 31 mg

Emax = 2.0

Emax,Ri = 3.4

0 .1 1

0 .1

1

S M W

W

M

S

CYP3AMDZ AUCR

OATP and CYP2C9 Induction is One DDI Category Less

Potent Than CYP3A

Similar effects on PRA and ROS suggest BCRP not

inducible by RIF

Data not shown

– Only weak induction of CYP1A2

– Parity between P-gp, OATP and CYP2C9 suggests

clinical simplicity in interpretation and prediction

Mean observed ± 90% CI

Corrected

CYP3AMDZ AUCR

5

OA

TP

PR

A A

UC

R

OA

TP

/BC

RP

RO

S A

UC

R

CY

P2

C9

TO

L A

UC

R

0 .1 1

0 .1

1

0 .1 1

0 .1

1

W

M

S

S M W

W

M

S

S M W

W

M

S

S M W

0 .1 1

0 .1

1

Do the RIF Relationships Predict Other Inducers:

Carbamazepine and Rifabutin?

Do the relationships observed with RIF (relative induction potency) apply to and/or predict:

– Other inducers: carbamazepine (CBZ) and rifabutin (RBT)?

– Other object drugs: Sofosbuvir, a P-gp substrate

Study Design

6

Days 1–9 10–20 21–29

SOF + Cassette SOF + Cassette

Cohort 2, n=20 RBT 300 mg qd

Days 1–9 10–26 27–35

SOF + Cassette SOF + Cassette

Cohort 1, n=24 Escalated to CBZ 300 mg bid

P-gp Induction by CBZ and RBT is Predicted by the RIF

CYP3A – P-gp Relationship

7

Blue line /shaded area

– RIF CYP3A – P-gp relationship

C Y P 3 A

M D Z A U C R

P-g

p

TD

AB

AU

CR

0 .1 1

0 .1

1

S

M

W

S M W

CBZ and RBT P-gp induction is

well predicted by the RIF CYP3A

– P-gp relationship

C Y P 3 A

M D Z A U C R

P-g

p

TD

AB

AU

CR

0 .1 1

0 .1

1

C B Z

R B T

S

M

W

S M WMean observed ± 90% CI

Predicted

CBZ-Mediated OATP Induction is Under-Predicted by RIF

CYP3A – OATP Relationship

CBZ: CYP3A – OATP parity

– Both moderate

– Is CBZ inducing via a non-PXR pathway?

• OATP is regulated by several non-PXR pathways

RBT: Follows RIF relationships

Faucette et al. J Pharmacol Exper Ther 2007; Svoboda et al. Curr Drug Metab 2011.8

Mean observed ± 90% CI

Predicted

C Y P 3 A

M D Z A U C R

OA

TP

PR

A A

UC

R

0 .1 1

0 .1

1

C B Z

R B T

S

M

W

S M W

C Y P 3 A

M D Z A U C R

OA

TP

/BC

RP

RO

S A

UC

R

0 .1 1

0 .1

1

C B Z

R B T

S

M

W

S M W

C Y P 3 A

M D Z A U C R

CY

P2

C9

TO

L A

UC

R

0 .1 1

0 .1

1

C B Z R B T

S

M

W

S M W

Effect of CBZ and RBT on SOF is Predicted by RIF CYP3A –

P-gp Relationship

Blue line / shaded area = predicted relationship between induction of CYP3A and SOF based on

RIF CYP3A – P-gp relationship adjusted for SOF ft

GMR, geometric least-squares mean ratio.

Kirby et al. Clin Pharmacokinet 2015

MDZ AUC GMR SOF AUC GMR

RIF 0.09 0.28

CBZ 0.21 0.52

RBT 0.31 0.76

CBZ and RBT considered moderate CYP3A

inducers

– elicit weak induction of SOF clearance (AUC GMR ≥0.50)

– are not expected to significantly reduce therapeutic effect

of SOF based on the known PK/PD relationship for SOF

9

Mean observed ± 90% CI

Predicted

C Y P 3 A

M D Z A U C R

SO

F A

UC

R

0 .1 1

0 .1

1

S

M

W

S M W

C Y P 3 A

M D Z A U C R

SO

F A

UC

R

0 .1 1

0 .1

1

R IF

R B T

C B Z

S

M

W

S M W

What are the Clinical Implications?

Carbamazepine and rifabutin induction categorization:

Nuclear receptor involvement is important for predictability

– Primarily PXR involvement:

• CYP3A predicts P-gp, OATP, CYP2C9 as one DDI class less potent

– strong CYP3A = moderate P-gp, OATP, CYP2C9

– Additional non-PXR agonism:

• CYP3A may under-predict OATP induction magnitude

Application of these results could provide for

– More informed label recommendations for drug transport substrates with inducers

– Decreased # of DDI studies via better leveraging available data

CYP3A P-gp OATP CYP2C9 CYP1A2 SOF

Carbamazepine Moderate Weak Moderate Weak Weak Weak

Rifabutin Moderate Weak None Weak None Weak

10

Acknowledgments

We extend our thanks to the study participants and study team. This study was funded by

Gilead Sciences, Inc.

11

IWCPAT 2017, Chicago

Thank You