Clinical Pharmacology Strategy for Development …regist2.virology-education.com/presentations/2019/ICPAD/...Clinical Pharmacology Strategy for Development and Labelling of new Medicine

Clinical Pharmacology Strategy for Development and Labelling of new Medicine

Alienor Berges, Stein SchalkwijkClinical Pharmacology ADME and AI, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK

ICPAD 2019, PK/PD studies and new strategies section 21 November 2019

Era of targeted therapy and accelerated approvals in oncology

Clinical Pharmacology in Drug Development

2

Clinical pharmacology:

“The study of drugs in humans”

ASCPT

Clinical pharmacology (CP) in R&D:

– Establish and leverage PKPD relationship

– Understanding impact of intrinsic or

extrinsic factors and the need for dose

adjustments

– Dose and regimen optimization

(e.g. based on exposure)

– Support the seeking of regulatory approval

(Clinical Summary 2.7.1 and 2.7.2)

– Establishing a label for safe & effective

drug use in patient populations

Drug development - it’s a team effort!

!Quantitative! Clinical Pharmacology in Drug Development

3

Why quantitative?• Integrating data from different sources

accumulating data over R&D stages

• Provide guidance and optimize experiment

design

• Allow extrapolation and prediction under

untested conditions

• Improve decision-making and R&D efficiency

• Facilitates quantitative competitive profiling and

identifying investment opportunities

ExampleDose-adjustments needed with strong or

moderate inhibitors/inducers?

Eur J Pharm Sci. 2017 Nov 15;109S:S39-S46

Nat Rev Drug Discov. 2014 Jun;13(6):419-31

Nat Rev Drug Discov. 2018 Mar;17(3):167-181

Question

R&D stage

Quantitative framework AstraZeneca

Unique Challenges for Clinical Pharmacology in Oncology

4

• CP studies often conducted in patients

with advanced disease

– More complex (e.g. multi-site & design)

– Take longer

– Bias and precision issues

(e.g. comeds, comorbidity, no placebo)

• CP package limited by time and data

– Accelerated approval can be triggered

on Phase I data

– Dose selection often based on 3+3

where MTD is taken forward

• High unmet medical need

– may justify some risks that not would

be accepted in other therapy areas

(e.g. QT margin)

ASCPT, March 2017, 1085-P

Costs in healthy volunteers & patients

Phase III(registration)

Phase IIb(dose ranging)

Phase Ib / IIa(PoC)

Phase Ia(dose escalation)Preclinical

Post approval& labelPhases

Translations

Dose Rationale Modelling and Simulation applied and refined across phases to optimise dose schedule

C-QTcTQT not recommended

Preclinical packages

to assess risk levels

Preferred optionIf additional ECG data

are needed

Food effect If FE preclinical risks

hADMEIf metabolite(s)

suspectedPreferred option

DDI If DDI preclinical risks

IVIVCBE not recommended

If manufacture

changes

Specific populations

ClinPharm package ( █ recommended timing, █ optional)

Clinical Pharmacology Package in Oncology

Our Template Road Map

CellsAnimal

HumanTargeteffect

Clinicaleffect

Surrogateendpoint

Clinicalendpoint

Trial Real world

Smallpopulation

Largepopulation

Real World Example

Olaparib Clinical Pharmacology Story

7

Executive Summary of Olaparib Tablet

• Mechanism of action– First-in-class oral PARP inhibitor

• ADME characteristics – Rapid absorption, extended distribution,

terminal half-life of 15h

– 80% CYP3A4 metabolism, 15% renal

elimination

– Dose proportional, 1.8 accumulation ratio

• Dosing recommendations

Tablet: 300 mg (2 x 150mg) bd continues

– Based on tolerability & tumour shrinkage in

phase I expansion (3 doses)

– Confirmed by pooled exposure response

analysis

Dose adjustment

In patients with moderate renal impairment

With CYP3A strong & moderate inhibitor

With CYP3A strong & moderate inducer

Caution

With CYP3A, CYP2B6, CYP1A2 substrates

With transporters substrates

2015 2020

8

The Long Unexpected Journey of Olaparib

B

BRCAm population

Beyond BRCAm population

B SOLO1

SOLO2

SOLO3 OlympiAD

GOLD

PROpel

POLOPROfound

Capsule formulation since 2005


Phased outB

Study 19

indication

approved

submission

ongoing

Tablet formulation since 2008

Olaparib clinical pharmacology - hurdles and opportunities

Phase III(registration)

Phase IIb(dose ranging)

Phase Ib / IIa(PoC)

Phase Ia(dose escalation)

PreclinicalPost approval

& label

Capsules & tablets data from late phase trials1

1

Dose rationale not fully established2

2

Risk of drug-drug interactions3

3

2015 2020

10

B

BRCAm population



Phased out

B

B

Study 19

SOLO2

Regulatory approval beyond BRCAm

Conditional approval from Phase II

Tablet formulation since 2008

Capsule formulation since 2005

1

Bridging Capsules & Tablets

1


11

11


PK Modelling Capsule / Tablet Exposure

• Data- 11 studies

(5 capsules, 5 tablets, 1 capsule & tablet)

- 659 patients

(ovarian, breast, & other solid tumours)

• Model and covariates

- No PK impact of tumour type, line of treatment, gender

race, sex, age, weight

Impact

• FDA approved 300mg tablet for a broader ovarian population

• Pivotal to the capsule to tablet switch

Clin Pharmacokinet. 2019;58(5):615-625


12

11





- 659 patients



- No PK impact of tumour type, line of treatment,

gender race, sex, age, weight

Impact



zero order

absorption

Formulation

Tablet strength

& formulation

F1

Depot

1st order

absorption

1

2

distribution

elimination

Auto-inhibition &

ECOGFormulation



13

11




- 659 patients





Impact



zero order

absorption

Formulation

Tablet strength

& formulation

F1

Depot

1st order

absorption

1

2

distribution

elimination

Auto-inhibition &

ECOGFormulation


Relative exposure of 300 mg tablet

is 13% higher than the 400 mg capsule.

100mg capsule

N=46

200mg tablet

N=30

200mg capsule

N=30

250mg tablet

N=19

400mg capsule

N=48

300mg tablet

N=227

AU

Css µ

g*h

/mL

11

Bridging Capsules & TabletsBridging Capsules & Tablets




- 659 patients





Impact



14

zero order

absorption

Formulation

Tablet strength

& formulation

F1

Depot

1st order

absorption

1

2

distribution

elimination

Auto-inhibition &

ECOGFormulation


11

Relative exposure of 300 mg tablet

is 13% higher than the 400 mg capsule.

100mg capsule

N=46

200mg tablet

N=30

200mg capsule

N=30

250mg tablet

N=19

400mg capsule

N=48

300mg tablet

N=227

AU

Css µ

g*h

/mL

11

Bridging Capsules & TabletsBridging Capsules & Tablets

15 Clin Pharmacol Ther. 2018 doi: 10.1002/cpt.1338

Dose rationale

1


1 2

Dose rationale

Data & Model Risk/benefit profile across doses

PK – PFS

• 410 ovarian

patients

(with placebo)

PK – Safety

• 757 patients

(with placebo)

• Hemoglobin

data

• CTC grades of

most common

adverse events

Impact

• Justify olaparib 300 mg bd tablet

• Accepted by Regulatory authorities

(e.g. EMA and Canada)

16 Clin Pharmacol Ther. 2018 doi: 10.1002/cpt.1338

Dose rationale

1


1 2

Dose rationale


PK – PFS

• 410 ovarian

patients

(with placebo)

PK – Safety

• 757 patients

(with placebo)

• Hemoglobin

data

• CTC grades of

most common

adverse events

Impact




17

favors 300 mg favors 200 mg

Hazard ratio (95% CI)

Clin Pharmacol Ther. 2018 doi: 10.1002/cpt.1338

1

Bridging Capsules & Tablets Dose rationale

1 2

300mg statistically superior to 200mg

Dose rationale


PK – PFS

• 410 ovarian

patients

(with placebo)

PK – Safety

• 757 patients

(with placebo)

• Hemoglobin

data

• CTC grades of

most common

adverse events

Impact




18




Hem

oglo

bin

g/d

L

1


1 2

300mg statistically superior to 200mg Small safety impact between 200 & 300mg

Perc

enta

ge %

CTC grade

Anaemia Nausea

200mg

300mg

Dose rationale

200mg range

300mg range

Cmax ng/mL


PK – PFS

• 410 ovarian

patients

(with placebo)

PK – Safety

• 757 patients

(with placebo)

• Hemoglobin

data

• CTC grades of

most common

adverse events

Impact




19




Cmax ng/mL

Hem

oglo

bin

g/d

L

200mg range

1


1 2

300mg statistically superior to 200mg Small safety impact between 200 & 300mg

Perc

enta

ge %

CTC grade

Anaemia Nausea

200mg

300mg

Dose rationale

300mg range

Non-clinical DDI risk

• Olaparib as victim with CYP3A4

inhibitors/inducers

• Olaparib as perpetrator with

transporters (BCRP, OATP1B1, P-gp)

20

1


1

DDI predictions

3

DDI predictions

ClinPharm DDI package

• Two DDI studies

(with itraconazole & with rifampicine)

• PBPK predictions to support non

clinical package

Data & PBPK Model Applications Impact

PBPK model built using

physiochemical parameters,

in vitro data and clinical study

studies

- Effect of moderate and weak

inhibitors/inducers solely

from PBPK

- Supported olaparib drug

label and dose reductions

21

Clin Pharmacol Ther. 2019; 105(1):229-241

1


1 3

DDI predictionsDDI predictions





studies



from PBPK



22


1


1 3

DDI predictions

PBPK validation against observed DDI & predictions

DDI predictions





studies



from PBPK



23


1


1 3

DDI predictions


DDI predictions





studies

Supported olaparib drug label

and dose reductions



from PBPK

- Predicted to have minor

impact on BCRP, Pgp and

OATP1B1 substrates

24


1


1 3

DDI predictions


DDI predictions

25

From ClinPharm

Package to Label

Summary

DDI supported by Clin

Pharm studies & PBPK

simulations

Dosing rationale

supported by PKPD

modeling

Key parameters from the

PopPK model

PK bridge across

formulations

Dose recommendations

in sub- populations

based on Clin Pharm

studies & PBPK

simulations

Drug administration

regardless of food

Conclusions

26

• Traditional approach to clinical pharmacology strategies is not feasible in

oncology setting:

– CP trials in patients are complex, long and expensive

– Development in oncology is often fast and often on one dose level

– Trial outcomes may be associated with bias and precision issues

(e.g. extrinsic factor like comeds, comorbidity, no placebo arm )

• This challenges us to:

– Leverage the quantitative framework to guide our clinical (pharmacology) questions

– Integrate knowledge and collaborate across departments

– For each development program – allocate recourses cost-effectively for safe and

effective dosing of patients in the clinic

• Eventually, years of clinical pharmacology work is condensed in the label to

support safe and effective dosing in patients

Thanks for your attention!

27

Acknowledgements

Olaparib team

Maria Learoyd

Diansong Zhou

Khanh Bui

Venkatesk Pilla Reddy

James Li

Hongmei Xu

Clin pharm team

Helen Tomkinson

Alex MacDonald

David Carlile (Roche)

The olaparib project team, and the students, PhD and postdoc

students who contributed to this work

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Clinical Pharmacology Strategy for Development …regist2.virology-education.com/presentations/2019/ICPAD/...Clinical Pharmacology Strategy for Development and Labelling of new Medicine