Drug-drug interactions management

using DDI-predictor

Michel TOD

University Hospital from Lyon, France

Disclosure

Nothing to disclose

Introduction

• DDIs may result in severe adverse events, lack

of efficacy, treatment delay or interruption, ...

• Anticancer drugs have a narrow safety margin

• Yet DDIs on / with anticancer drugs are poorly

documented

• Need for a predictive approach for DDIs

Motivating example (1)

Tamoxifen SPC:

“PK interaction with CYP2D6 inhibitors, showing a 65-75%

reduction in plasma levels of active forms of the drug, has been

reported. Reduced efficacy of tamoxifen has been reported with

concomitant usage of e.g. paroxetine. Co-administration with

potent CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, quinidine,

cinacalcet or bupropion) should whenever possible be avoided.”

A women is treated by Tamoxifen. May Terbinafine be prescribed ?

Motivating example (2)

Terbinafine SPC:

“Terbinafine tablets inhibits the CYP2D6-mediated metabolism. This

finding may be of clinical relevance for compounds predominantly

metabolised by CYP2D6, e.g. tricyclic antidepressants, beta-

blockers, selective serotonine reuptake inhibitors, antiarrhythmics

and monoamine oxidase inhibitors.

Terbinafine tablets decreased the clearance of desipramine by 82%.”

A women is treated by Tamoxifen. May Terbinafine be prescribed ?

Motivating example

• Probably not.

A women is treated by Tamoxifen. May Terbinafine be prescribed ?

• But I am not shure: it depends on the magnitude of the

interaction.

• I need a tool to predict the magnitude of interactions.

Overview

1. Definitions and history

2. How to use DDI-predictor

3. Principle, validation and limits of the approach

4. Case studies

Definitions and history

Kinetics of a metabolic DDIProfile of the substrate average concentration

1: substrate alone

2: substrate + compet. inhibitor

3: substrate + suicide inhibitor

4: substrate + inductor

End of interactor administration

Substrate + interactor

Time (days)

Co

nce

ntr

atio

n

Magnitude of a DDI

10

The magnitude of a DDI is measured by the ratio of AUCs

at steady-state :

RAUC = AUC of the substrate administered with the interactor

AUC of the substrate alone

Interpretation of the AUC ratio

Lack of interaction: RAUC = 1

In case of inhibition: RAUC > 1

In case of induction: RAUC < 1

Dosing adaptation

Ajusted dose (mg/d) = Usual dose (mg/d) / RAUC

Brief History (1)

Since 2010, the IMSM was extended by our group :

• to other CYPs: 2D6, 2C9, 2C19, 1A2

• to CYP polymorphism

• to cirrhosis

• to DDIs in children and neonates

The In vivo Mechanistic Static Model (IMSM) for prediction

of CYP mediated DDIs was introduced in 2007 by Ohno et al.

• The substrate and the interactor are administered per os

Brief History (2)

Since 2013, the IMSM and the associated library is accessible

through a free academic website :

www.ddi-predictor.org

• Not a simple database !

• Makes predictions for undocumented DDIs (ca. 25000)

• Used for prescription analysis in hospital settings

• About 2000 connections / month worldwide

How to use the website to predict a DDI

Front page

Features

Choose a substrate

Choose e.g. an inhibitor

0 means "zero" OR "no information"

Get the results

A negative value means « inhibition ».

Here: 98% inhibition

2C19 contributes at 84% in total CL

Omeprazole AUC is increased ca. 7-fold

Principle, validation and limits

10

Metabolic CL by CYP2D6

10

45

A alone A + B

CYP inhibition = 50%

Renal CL

90

10

A + C

CYP inhibitio

n = 100%

Total CL of A

AUC ratio

100

-

55

100/55

10

100/10

A

Contribution of CYP2D6 in

CL of A

= CR2D6

B C

Fraction of 2D6 inhibited

by B or C

= IX2D6

DDI-predictor Principle Two parameters are needed to predict Rauc

DDI-predictor Principle Substrate: Fraction Metabolised by a CYP

• using the AUC ratio of a DDI study with an inhibitor whose

IR is known

• using the AUC ratio of a pharmacogenetic study in poor

metabolizers

fm

(determined in vitro)

where CR is

CLCYP / CLtotal

CR

(determined in vivo)

replaced by

CR may be estimated:

DDI-predictor Principle Inhibitor: Inhibition Potency IR

• It may be shown that: ( ),

,

/

1 /

h u

h u

I KiIR

I Ki=

+

• IR ranges from 0 to 1 (in absolute value).

Ih,u / Ki

(determined in vitro)

Inhibitor potency IR

(determined in vivo)

replaced by

• IR is estimated using the AUC ratio of a DDI study with a substrate whose CR is known

DDI-predictor Principle

The Static Mechanistic Model of DDI-predictor

1

1 .=

−AUCR

CR IR

• Prediction of an AUC ratio knowing CR and IR (simplest

case):

• Similar approach for induction: inductive capacity IC,

ranging from 0 to infinity (actually, 10).

• Extension to multiple DDIs (= involving several CYPs)

The 3-step Approach:Learning, Confirming, Predicting

Drug 1

Drug 2

Drug

3

Drug 4

Drug 5

Inh. 1

Inh. 2

Inh. 3

Inh. 4

Learning data

Validation data

Unknown data, to be predicted

Estimating Parameters In Vivo Versus In Vitro : What Does It Change?

Alleviate the issues of in vitro-in vivo extrapolation :

• metabolites, enantiomers are not accounted for in vitro

• non metabolic pathways are not accounted for in vitro

• uncertainties on Ki, Ih,u, kinact, etc

• PBPK: scaling factors !! no longer required

BUT cannot be used at the preclinical stage of development

Substrates Inhibitors Inducers

200 100 25

Current state ofthe DDI-Predictor database

Genotypes:

5 genotypes ou groups of genotype

for each of CYP 2D6, 2C9, 2C19

External Validation on 643 Examples

The line is the y = x line. The dashed lines represent the 50–200%interval. Values above x = 1 represent DDIs by inhibition. Valuesbelow x = 1 represents DDIs by induction

Limits of DDI-predictor

• Limited to CYP3A4, 2D6, 2C9, 2C19, 1A2

• Drugs are administered per os

• Substrate PK must be linear (ex: phenytoïn)

• Predictions for a single dose level of the interactor

• Transporters are not explicitly considered : inaccurate

predictions in case of mixed mechanism

• Only two-drug interactions are handled

Temporary

Case studies

Ranking of TKIs by magnitude of interactions mediated by CYP3A4

Substrates CR3A4 Magnitude

Bosu, Dasa, Ibru, Evero > 0.80 +++

Apa, Axi, Crizo, Dabra, Erlo, Gefi, Idela, Ima, Lapa, Nilo, Ola, Palbo, Pazo, Pona, Ruxi, Suni

> 0.3 < 0.8

++

Cabosan, Regora, Vande < 0.3 +

Sorafenib 0.0 0

Undocumented interactions (1)

Back to Tamoxifene + Terbinafine

Active metabolites are decreased 3.2 fold …

Undocumented interactions (2)

Case report : ibrutinib - voricoHistory

• Man 71 years (67 kg), CLL since 2012.

• Prescription of VFEND 250 mg bid for aspergillosis

(liver function is normal).

• Several comedications, no DDI expected.

• Physicians wish to introduce ibrutinib (usual dose in

CLL : 3 capsules at 140 mg per day).

Case report : ibrutinib - vorico Management

How would you manage this treatment?

A. Ibrutinib standard dose 3 x 140 mg / day

B. Ibrutinib à 140 mg once per week

C. Ibrutinib standard dose but switch voriconazole to

itraconazole

D. Ibrutinib standard dose but switch voriconazole to

caspofungine

E. Something else

Case report : ibrutinib - vorico Ask DDI-predictor

• One capsule per week = dose reduction by a factor

3*7 = 21

• BUT ibrutinib peak concentration will still be 8 fold

(25/3) greater than the usual peak ….

• Propose to change antifungal treatment:

caspofungin, ou caspo + 5-flucytosine ?

Case report : ibrutinib - vorico Tentative answer

Conclusion

• DDI-predictor may help to manage some DDIs on

/with anticancer drugs

• Requires however some skills in pharmacokinetics

• IV interactions will also be handled in future

versions