Systems Pharmacology Approach to Modelling ... · Systems Pharmacology Approach to Modelling Pharmacokinetics in Pregnancy Amin Rostami-Hodjegan, PharmD, PhD, FCP Professor of Systems

Systems Pharmacology Approach to

Modelling Pharmacokinetics in

Pregnancy

Amin Rostami-Hodjegan, PharmD, PhD, FCP

Professor of Systems Pharmacology University of Manchester, Manchester, UK

& Vice President R&D

Simcyp , Sheffield, UK

[email protected]

http://www.manchester.ac.uk/index.phphttp://www.simcyp.com/

PBPK/IVIVE Linked Models

Physiologically-Based Pharmacokinetics Joined with In Vitro-In Vivo

Extrapolation of ADME: A Marriage under the Arch of Systems

Pharmacology

Amin Rostami-Hodjegan

July Issue of CPT – Online now

http://www.manchester.ac.uk/index.php

PricewaterhouseCoopers: Pharma 2020

.... proposes that new technologies will enable the adoption of virtual R&D; and by

operating in a more connected world, the industry in collaboration with researchers,

governments, healthcare payers and providers, can address the changing needs of

society more effectively.

Kate Moss June 2008

(1) Requires More

Data not Less!

(2) Requires Different

Type of Data

(3) Requires Huge

Integration Task

(4) Appropriate Tools

Are Essential


Systems Approach: e.g. Inter-Individual Variability in PK

CYP3A4

CYP3A5

Americans/Europeans

Japanese/Chinese Age / Genetics / Environment / Disease


Blo

od

Lung

Rapidly perfused

organs

Slowly perfused

organs

Kidney

Liver

Intestines

Blo

od

Elimination

Dosing

ADME, PK, PD and

MOA

Metabolism

Active transport

Passive diffusion

Protein binding

Drug-drug interactions

Receptor binding

System component

(drug-independent)

PBPK Model

Predict, Learn, Confirm

Drug-dependent

component

A. Intrinsic/extrinsic Factors B. PBPK Model components

Huang and Temple, 2008

Individual or combined effects

on human physiology

Zhao P, et al Clin Pharmacol Ther 2011

EXTRINSIC

INTRINSIC

DDI

Environment

Medical Practice

Regulatory Alcohol

Smoking

Diet

Age

Race

Disease

Gender

Genetics

Pregnancy

Lactation

Organ Dysfunction

Well Recognised by Leading Regulatory Agencies


Summary of PBPK-IVIVE M&S in Submissions

(Zhao et al., 2011)

From July 2008 to June 2010, the FDA reviewed seven investigational

new drug (IND) and six new drug applications (NDA) submissions

containing PBPK modeling and simulations conducted by the sponsors. In

addition, FDA reviewers conducted PBPK modeling and simulations to

support clinical pharmacology reviews of another four NDA submissions

for which the sponsors did not use PBPK. As a comparison, in the 3

years before 2008, FDA received only two submissions containing PBPK

modeling and simulations. Many of the PBPK modeling and simulation

evaluations addressed questions relating to drug–drug interactions;

others addressed pediatric dosing, the impact of hepatic impairment on

drug exposure, and the impact of multiple factors on drug exposure

(Table 1).

0.66 per year 8.5 per year


ASCPT 2012

YES NO


Pregnancy as Another Example

Time –varying component to account for changes

to the system (anatomical, physiological and

biological; CYPs abundance, etc.)

Clinical Pharmacokinetics 2012


Homogenisation

HOMOGENATE

S9

Nuclear / Mitochondrial pellet

Centrifugation @

9,000g

Centrifugation @

100,000g

Cytosol

Microsomes

CYP450 FMO

Aldehyde oxidase MAO

Aldehyde dehydrogenase Epoxide hydrolase

Xanthine oxidase Esterases

UGT

HLM HIM HKM rhCYP rhUGT

hepatocytes

hepatocytes

S9

S9

cytosol

Aldehyde oxidase SULT

Glutathione S transferase Alcohol dehydrogenase

Xanthine oxidase

In Vitro Drug Metabolism Tools


SIMCYP Pregnancy PBPK Model


Foetal volume (ml) = 0.01 · exp [(0.955 / 0.0702) · (1- exp (- 0.0702· GA))]

Placenta volume (ml) = - 0.716 GA + 0.9149 GA2 - 0.0122 GA 3

Amniotic Fluid (ml) = 1.9648 GA -1.2056 GA2 + 0.2064 GA3 - 0.0061 GA4+0.00005 GA5

GA= gestational age

(week)

Gestational Time- Dependent Parameter Description


0

1

2

3

4

5

6

7

0 5 10 15 20 25

Pla

sm

a c

on

ce

ntr

ati

on

(m

g/L

)

Time (h)

Non-pregnant women

Predictions

Brazier 1983 (n=4)

0

1

2

3

4

5

6

7

0 5 10 15 20 25

Pla

sm

a c

on

ce

ntr

ati

on

(m

g/L

)

Time (h)

Pregnant women

Predictions

Brazier 1983 (n=8)

PK Parameter

Pregnant women Non-pregnant women Fold change in Pregnancy

Observed Simulated Ratio Observed Simulated Ratio Observe

d

Simulate

d Ratio

Cmax (mg/l) 4.58 (1.2) 3.26 0.71 6.02 (1.8) 3.59 0.60 ↓0.76 ↓0.91 1.19

Tmax (h) 1.5 1.5 1.00 0.75a 0.97 1.29 ↑2.00 ↑1.55 0.77

AUC24h

(mg/l/h) 52 47 0.91 26 24 0.92 ↑2.00 ↑1.96 0.98

Simulated versus mean observed (Brazier et al 1983) PK parameters for 150 mg caffeine

Results


CYP2D6 activity was detectable and concordant with genotype by 2 weeks of

age, showed no relationship with gestational age, and did not change with post

natal age up to 1 year.

Scratching Surface

Clin Pharmacol Ther 2007

However: we know that:

Thus, the development of renal

function from birth may change in

parallel with the development of the

enzyme such that the

drug/metabolite ratio may be

relatively constant !!!!


Clin Pharmacol Ther 2008

Figure 1. Changes in CYP2D6 (a) and CYP3A4 (b) activity relative to adult values.

The data of Blake et al, corrected for the development of renal function, are

indicated by the diamonds. The simulated change in in the activity of each enzyme

(solid line) was derived from in vitro data on hepatic enzyme expression and

increase in liver weight with age.

0

0.2

0.4

0.6

0.8

1

0 4 8 12Age (Months)

CY

P2

D6

ac

tiv

ity

(D

M/D

X

rati

o r

ela

tiv

e t

o a

du

lt

0

0.2

0.4

0.6

0.8

1

0 4 8 12Age (Months)

CY

P3

A4

ac

tiv

ity

(D

X/3

HM

rati

o)

rela

tiv

e t

o a

du

lt

(A) (B)

Looking Deeper


Assessment of CYP1A2 Activity


Du

od

en

um

Je

jun

um

I

Jeju

nu

m I

I

Ileu

m I

Ileu

m I

I

Ileu

m I

II

Ile

um

IV

Co

lon

Segregated Blood Flows

Stomach

Emptying

Luminal

Transit

Systems Approach: Absorption

Enzymes (CYP3A4)

vs

Transporters (Pgp)


Qbulk QCsink

QSsink

QS

in

QS

ou

t

Qbrain Qbrain Brain blood

Brain mass

Cranial CSF

Spinal CSF

• Passive permeability at three interfaces

• Active transporters at BBB/BCSFB

CL

Bin

CL

Bo

ut

CL

Cin

CL

Co

ut

PSE

PS

B

PS

C

• CSF: circulation, pH, volume, …

• Brain: anatomy, physiology, …

Volume

pH

Volume

pH

Volume

pH

Volume

pH

CLmet

(Eyal et al., 2009)

Systems Approach: Brain


Kidney Permeability-Limited Model

Transporters are available in all

three proximal tubule cell

compartments on the apical and

basal membrane.

The model can handle:

• regional distribution/activity of

transporters

• nephrotoxicity as well as

changes in systemic exposure

• interplay between uptake, efflux

and passive permeation

• metabolism and transport

interplay

Filtration

Secretion (passive + active)

Reabsorption (passive + active) Urinal tubule Cell (renal mass) Renal blood


FDA / U Washington in Seattle /Simcyp

Midazolam, Nifedipine, Indinavir Pharmacometric & Systems Pharmacology (to appear soon)


Final Word: Model-Based Drug Development

(1) All Models Are Wrong, but Some Models Are Useful !

George EP Box 1987

WE ALL KNOW that:

WE SHOULD ALSO KNOW that:

(2) Science is built of facts as a house is built of stones; but an accumulation of facts is no more science than a pile of stones is a house.

Henri Poincare, 1902

Documents

Systems Pharmacology Approach to Modelling ... · Systems Pharmacology Approach to Modelling Pharmacokinetics in Pregnancy Amin Rostami-Hodjegan, PharmD, PhD, FCP Professor of Systems