Using the Knowledge of Biology in the Prediction Using the Knowledge - - PowerPoint PPT Presentation

&

tuoslogo_cmy...

Amin Rostami Professor of Systems Pharmacology, University of Sheffield, UK a.rostami@sheffield.ac.uk)

Day 2: Part 3 PBPK- Mechanistic Models-Allometry Tuesday 15 April 2008

Using the Knowledge of Biology in the Prediction

• f Clearance as the Main Determinant of Drug

Exposure in Paediatric Populations

Day 2: Part 3 PBPK- Mechanistic Models-Allometry Tuesday 15 April 2008

Using the Knowledge of Biology in the Prediction

• f Clearance as the Main Determinant of Drug

Exposure in Paediatric Populations

WORKSHOP ON MODELLING IN PAEDIATRIC MEDICINES 14-15 APRIL 2008; EMEA, London

&

tuoslogo_cmy...

Preface Preface 1984 1984

At any point in history of health care, our knowledge was considered to be quite extensive; however, in perspective, the knowledge of yesterday seems to have been very limited, just as today’s knowledge can be expected to seem one day as such. Fundamental in applying basic scientific and mathematical concepts to patient care is an appreciation of the physiologic constraints placed on these concepts and appreciation of how disease and/or physiologic changes can further affect these constraints. What Has Changed?

&

tuoslogo_cmy...

A Key Factor: Clarity & Validity of Assumptions

&

tuoslogo_cmy...

QH.fuB.CLuint QH + fuB.CLuint

CLH =

QH QH + fuB.CLuint

FH =

fuB.CLuint QH + fuB.CLuint

EH =

Well-Stirred Liver Model

Culiver/Ctotal (blood) Culiver/Ctotal (blood)>fuB if drug is substrate for influx transporters Culiver/Ctotal (blood)<fuB if drug is substrate for efflux transporters

&

tuoslogo_cmy...

Parallel Tube Liver Model fuB.CLuint QH

FH = e

fuB.CLuint QH

EH = 1 - e

fuB.CLuint QH

CLH = QH . (1 – e )

( )

( )

( )

( )

⎥ ⎥ ⎥ ⎦ ⎤ ⎢ ⎢ ⎢ ⎣ ⎡ − − + − =

⎥ ⎦ ⎤ ⎢ ⎣ ⎡ + − ⎥ ⎦ ⎤ ⎢ ⎣ ⎡ − Dn a Dn a H H

e a e a a Q CL

2 1 2 2 1 2

1 1 4 1

) 17 . Dn . g . e ( ; RnDn 4 1 a = + =

H B int

Q fu CLu Rn × = Dispersion Model

&

tuoslogo_cmy...

In vitro system rCYP HLM HHEP In vitro CLuint

µL.min-1 pmol P450 isoform µL.min-1 mg mic protein

CLuint per g Liver

µL.min-1 106 cells Scaling Factors in Human IVIVE Scaling Factors in Human IVIVE

CLuint per Liver Scaling Factor 1 Scaling Factor 2

X Liver Weight X X X

HPGL

pmol P450 isoform mg mic protein X MPPGL

MPPGL

&

tuoslogo_cmy...

Non-CYP Related Variation: MPPGL and Donor Age 20 40 60 80 50 100 150 Age (years) MPPGL (mg.g-1)

20 40 60 1 25 45 65 Age (years) MPPGL (mg.g-1)

43 mg.g-1 32 mg.g-1

Barter et al. 2007 Curr Drug Met Barter et al. 2008 Submitted

&

tuoslogo_cmy...

Development of CYP: Abundance

% EXPRESSION of ADULT

20 40 60 80 100 Fetal 1-12 Month

CYP1A2 CYP2A6 CYP2B6 CYP2C9 CYP2D6 CYP2E1 CYP3A4/5 Some enzymes negligible at Birth but some are not; thus any modelling should consider baseline activity at birth. Age (y) Fraction of adult value Age (y)

0.2 0.4 0.6 0.8 1 1.2 2 4 6 8 10 12

CYP1A2

0.2 0.4 0.6 0.8 1 1.2 2 4 6 8 10 12

CYP1A2

0.2 0.4 0.6 0.8 1 1.2 1.4 0.5 1

CYP2C9

0.2 0.4 0.6 0.8 1 1.2 1.4 0.5 1

CYP2C9

&

tuoslogo_cmy...

Rate per pmol of “Each Enzyme” Weight Liver MPPGL ) (rCYP K abundance CYP ) (rCYP Vmax ] / [

n 1 j n 1 i i j m j i j

× × ⎥ ⎥ ⎦ ⎤ ⎢ ⎢ ⎣ ⎡ ⎟ ⎟ ⎠ ⎞ ⎜ ⎜ ⎝ ⎛ × = ∑ ∑

= =

h L CL

h

Proctor et al. Xenobiotica 2004

• The abundance of each CYP isoform per mg of microsomal protein
• The relative activity of the isoform(s) responsible for metabolism

5.8% 2.6% 4.8% 12.5% 2.4% 34.4% 14.6% 17.3% 1.9% 3.4%0.3%

Adults Paediatrics Liver Volume = 0.722.BSA 1.176 (L/m2)

• The microsomal protein per gram of liver
• The size of liver

&

tuoslogo_cmy...

Liver Blood Flow & fuB

See Commentary by: Yang et al. (2007) Drug Metabolism Disposition, 35(3): 501-502

fuB= fu CB/Cp

Min (CB/Cp) = 1- Hematocrit Max (CB/Cp) = ∞ CB/Cp = (CRBC:CP)*HC + (1- HC)

HC & Age: - Children

Proportion of cardiac output

22% and 7% for portal vein and arterial liver blood supply, respectively)

Cardiac output based on BSA and age

(2.5, 4, 3 and 2.4 L/min/m2 for 1, 10, 20 and 80 years of age, respectively)

2 2.5 3 3.5 4 4.5 20 40 60 80 100 Age (years)

Cardiac Index (L/min/m2)

&

tuoslogo_cmy...

Relative Gut surface area (Duodenum/ Jejunum)

0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 5 10 15 20 25 30 35 Age Surface area of small intestine relative to adult

+ Intestinal Drug Metabolism (CYP3A)

5 10 15 20 25 Fetus Neonate >3mn-2yr >2yr-5yr >5yr-12yr >12yr Age CYP3A4 (pm ol/m g p ro t

(11) (6) (6) (17) (25) (20)

0.02 0.04 0.06 0.08 0.1 0.12 Fetus Neonate >3mn-2yr >2yr-5yr >5yr-12yr >12yr Age 6OHT (n m o l/m g pr o te in /

ND (6) (6) (17 (25) (20)

5 10 15 20 25 Fetus Neonate >3mn-2yr >2yr-5yr >5yr-12yr >12yr Age CYP3A4 (pm ol/m g p ro t

(11) (6) (6) (17) (25) (20)

5 10 15 20 25 Fetus Neonate >3mn-2yr >2yr-5yr >5yr-12yr >12yr Age CYP3A4 (pm ol/m g p ro t

(11) (6) (6) (17) (25) (20)

0.02 0.04 0.06 0.08 0.1 0.12 Fetus Neonate >3mn-2yr >2yr-5yr >5yr-12yr >12yr Age 6OHT (n m o l/m g pr o te in /

ND (6) (6) (17 (25) (20)

0.02 0.04 0.06 0.08 0.1 0.12 Fetus Neonate >3mn-2yr >2yr-5yr >5yr-12yr >12yr Age 6OHT (n m o l/m g pr o te in /

ND (6) (6) (17 (25) (20)

Expression and activity of Intestinal CYP3A with age Adult CYP3A = 70,000 pmol/intestine Gut Metabolism / Permeability Model

Km V CLu

max int =

+

gut gut gut gut gut g

CLu fu Q CLu fu E

− −

× + × =

int int

Drug specific parameter related to permeability

&

tuoslogo_cmy...

Age Related Protein Binding

( )

⎥ ⎦ ⎤ ⎢ ⎣ ⎡ − × + =

adult adult adult neonate neonate

fu fu P P fu 1 1 1 ] [ ] [

In the absence of changes in dynamics

• f binding:

Serum Albumin & Age

Alb = 1.1287Ln(t) + 33.746

Serum AAG & Age

0.38 D 0.38 0.38 D g/L

Age 8.89 Age 0.887 AAG + × =

10 20 30 40 50 60 0.1 1 10 100 1000 10000 100000

Age (days) Albumin (g/L)

0.2 0.4 0.6 0.8 1 1.2 1.4 0.1 1 10 100 1000 10000 100000

Age (days) AAG (g/L)

&

tuoslogo_cmy...

CRBC:CP

Drug Dependent Influence of Plasma Proteins on CL

% of Adult Value

75.0% 87.5% 100.0% 112.5% 125.0% 0.1 10 HC 1 2 50

Age (month)

&

tuoslogo_cmy...

fu in Adults

“Drug Dependent” Influence of Haematocrit on CL

0% 50% 100% 150% 200% 250% 300% 350% 400% 450% 500% 0.1 1 10 100 AAG 0.99 0.5 0.1 0.01 % of Adult Value

&

tuoslogo_cmy...

0.5 1 1.5 20 40 60 80 100 0.5 1 1.5 20 40 60 80 100

0.5 1 1.5 2 2.5 3 3.5 4 4.5 20 40 60 80 100 0.5 1 1.5 2 2.5 3 3.5 4 4.5 20 40 60 80 100

CL (L.kg.h)

Omeprazole (Oral) Cisapride (Oral)

Non-Monotonic Drug Dependent CL/kg with Age

0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 20 40 60 80 100 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 20 40 60 80 100 0.002 0.004 0.006 0.008 0.01 0.012 0.014 0.016 20 40 60 80 100 0.002 0.004 0.006 0.008 0.01 0.012 0.014 0.016 20 40 60 80 100

Weight (kg)

Phenytoin (Oral) S-Warfarin (Oral)

&

tuoslogo_cmy...

Organ Blood Flows & Tissue Composition

e.g. Brain

10 20 30 40 50 60 70 5 10 15

Age (y) BBF as % CO

• Known changes in blood flow & tissue composition with age

80 90 100 5 10 15 20 Age (y) % Water

Questions?

• CL vs CLu
• PK in plasma vs PK in Organs
• True PD vs Apparent PD

&

tuoslogo_cmy...

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.

Knowledge of System Could Describe Observed Data

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 !!!!

&

tuoslogo_cmy...

Clin Pharmacol Ther 2008 Figure 1. Changes in CYP2D6 (a) and CYP3A4 (b) activity relative to adult values. The data

• f 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.

0.2 0.4 0.6 0.8 1 4 8 12

Age (Months) CYP2D6 activity (DM/DX ratio relative to adult

0.2 0.4 0.6 0.8 1 4 8 12

Age (Months) CYP3A4 activity (DX/3HM ratio) relative to adult

(A) (B)

Bottom-Up Approach Meets Top-Down Analysis (1):

&

tuoslogo_cmy...

Pop-PK and Covariate Effects

Sometimes obvious (what to look for and also to see the effect): Example

&

tuoslogo_cmy...

Pop-PK and Covariate Effects

Sometimes obvious (what to look for and also to see the effect): Example

CL = Typical parameter estimate x (Body weight/13) 3/4 x [1 - 0.0542 x (Cholesterol - 5.4)] x [1 - 0.00732 x (Haematocrit - 31)] x [1 + 0.000214 x (Serum creatinine - 524)] The typical values refer to a patient with a body weight of 13 kg, cholesterol of 5.4 mmol l-1, serum creatinine of 524 mmol l-1 and a haematocrit of 31%, according to the following covariate model:

&

tuoslogo_cmy...

0.3 0.6 0.9 1.2 1.5 10 20 30 40 50 60 70

Liver Volume (L) Body Weight (kg)

LV = 0.722 x BSA1.176 LV = 1.38 x (BW/70kg)0.75 Fanta et al – “Developmental PK of ciclosporin: A population pharmacokinetic study in paediatric transplant patients Br J Clin Pharmacol 64:772, 2007 (with Corrections)

Bottom-Up Approach Meets Top-Down Analysis (2):

&

tuoslogo_cmy...

[1 - 0.00732 x 100*(HC - 0.31)]

0.2 0.4 0.6 0.8 1 1.2 1.4 0.1 0.2 0.3 0.4 0.5 0.6 CL Multiplier (Top-Down) CL Multiplier (Bottom-Up) Haematocrit Relative Change in CL

fuB.CLuint

CLpo ∝

Clpo ∝ fu/[(CRBC/Cp)*HC + (1- HC)] fu = 0.037 and CRBC/Cp = 1.8 fuB = 0 0.0296 (at HC = 0.31)

[[0.037/[1.8*HC + (1- HC)] ]/ 0.0296]

Bottom-Up Approach Meets Top-Down Analysis (3):

&

tuoslogo_cmy...

POP-PK and using drug specific data is a useful tool in studying PK in paediatrics however there are many “advantages” in application of system information (human body) which are often neglected when investigating paediatric pharmacology. (1) The definition of insanity is – Doing the same thing over and over again but expecting a different result. Deepak Chopra Moving Away from Traditions: Take Hone Messages (4) 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 (2) All Models Are Wrong, but Some Models Are Useful ! George EP Box 1987 (3) Everything should be made as simple as possible, but not simpler. Albert Einstein