DEVELOPMENTAL PK/PD: WHAT HAVE WE LEARNT? Geoff Tucker - - PowerPoint PPT Presentation

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DEVELOPMENTAL PK/PD: WHAT HAVE WE LEARNT?

Geoff Tucker

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UNDERSTANDING AND PREDICTING PK/PD IN JUVENILES

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Can we scale from juvenile animals? Can we scale from allometry? Can we scale from in vitro? PHARMACOKINETICS

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ORAL BIOAVAILABILITY

From Grass & Sinko (Adv Drug Deliv Rev,2002) from Sietsema (Int J Clin Pharmacol Ther Toxicol,1989)

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20 40 60 80 100 neonate infant child adolescent adult

% Adult

♂RAT CYP3A1 (Johnson et al, 2000) ♀RAT CYP3A1 (Johnson et al, 2000) DOG CYP3A12 (Taneka, 1998) HUMAN CYP3A4 (Johnson et al,2006)

SLIDE 6

ONTOGENY OF TRANSPORTERS (ANIMALS)

weaning

Liver Intestine Kidney PgP – MOUSE (Mahmood et al, 2001) PgP – RAT BRAIN (Matsouka et al, 1999) OATs – RAT KIDNEY (Buist et al, 2002) Bile salt/OATs – RAT LIVER (Gao et al, 2004)

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Can we scale from juvenile animals? Can we scale from allometry? Can we scale from in vitro? PHARMACOKINETICS

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“THE 3/4 (Klieber’s) LAW”

From allometric principles: Metabolic Rate ∝ BW0.75 Clearance ∝ BW0.75

Holford – “A size standard for pharmacokinetics” Clin Pharmacokin 30: 392-32, 1996

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“THE 3/4 (Klieber’s) LAW”

Liver Volume = 0.722 x BSA1.176 Liver Volume ∝ BW0.78

Johnson et al – “Changes in liver volume from birth to adulthood: a meta-analysis” Liver Transpl 11: 1481-93, 2005

From measurements in 5036 N.Europeans, N.Americans and Japanese:

BSA ∝ BW0.67 Clearance ∝ BW0.78

SLIDE 10

:

0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 20 40 60 80 Body weight (kg) Liver Size (L)

Johnson et al: LV=0.722 x BSA1.176 Allometric: LVchild =LVadult x (BW/70kg)0.75

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0.4 0.8 1.2 1.6 10 20 30 40 50 60 70

Liver Volume (L) Body Weight (kg)

LV = 0.722 x BSA1.176 LV = 1.46 x (BW/70kg)0.75 (n = 162 patients) Fanta et al – “Developmental pharmacokinetics of ciclosporin: A population pharmacokinetic study in paediatric transplant patients Br J Clin Pharmacol 64:772, 2007

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The ‘3/4 Rule’ holds for predicting the clearance of several drugs (e.g.CYP3A substrates– ciclosporine, midazolam, alfentanil etc) But it does not account for the ontogeny

• f drug metabolising enzymes in neonates

and infants. Use ‘3/4 Rule’ to normalise clearance

• nly > 2 years.

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Can we scale from juvenile animals? Can we scale from allometry? Can we scale from in vitro? PHARMACOKINETICS

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AGE-RELATED CHANGES IN CYP EXPRESSION/ACTIVITY Johnson et al (2006)

1A2 2B6 2C8 2C9 2C19 2D6 2E1 3A

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EFFECT OF DIET ON CAFFEINE ELIMINATION RATE CONSTANT (CYP1A2)

Blake et al (2006)

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GLUCURONIDATION

Time to maturity?

UGT1A1 UGT1A9 UGT2B4 UGT2B7 UGT1A4 < 6 months > 2 years > 2 years < 6 months < 2 years

Strassburg et al, 2002; Miyagi & Collier, 2007

(e.g. ethinylestradiol (e.g. imipramine) (e.g. propofol) (e.g. morphine)

SLIDE 17 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 0.5 1 1.5 20 40 60 80 100 0.5 1 1.5 20 40 60 80 100 1 2 3 4 5 6 7 20 40 60 80 100 1 2 3 4 5 6 7 20 40 60 80 100 0.2 0.4 0.6 0.8 1 1.2 1.4 20 40 60 80 100 0.2 0.4 0.6 0.8 1 1.2 1.4 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

0.05 0.1 0.15 0.2 0.25 20 40 60 80 100 0.05 0.1 0.15 0.2 0.25 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

CL (L.kg.h) Weight (kg)

Omeprazole (Oral)

0.05 0.1 0.15 0.2 0.25 0.3 0.35 20 40 60 80 100

Carbamazepine (Oral) Phenytoin (Oral) Midazolam (Oral) Diclofenac (IV) Cisapride (Oral) Theophylline (Oral) S-Warfarin (Oral)

0.5 1 1.5 2 2.5 20 40 60 80 100

Midazolam (IV)

0.5 1 1.5 2 2.5 20 40 60 80 100

Midazolam (IV)

0.00 0.10 0.20 0.30 0.40 0.50 0.60 20 40 60 80 100

Caffeine (Oral)

0.00 0.10 0.20 0.30 0.40 0.50 0.60 20 40 60 80 100

Caffeine (Oral)

Johnson et al. Clin Pharmacokin 2006

Predicting Paediatric Clearance

SLIDE 18

Below ~ 2years – prediction of clearance is drug specific due to differential development

• f its determinants.

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Full Paediatric PBPK Model

• Incorporating information on organ size, tissue

composition and blood flow

• Allows for prediction of full PK profile (V, MRT, Cmax

, Cmin )

Venous Blood Arterial Blood

Lung Lung Adipose Adipose Bone Bone Brain Brain Heart Heart Kidney Kidney Muscle Muscle Skin Skin Liver Liver Spleen Spleen Gut Gut Portal Portal Vein Vein

PO IV

Venous Blood Arterial Blood

Lung Lung Adipose Adipose Bone Bone Brain Brain Heart Heart Kidney Kidney Muscle Muscle Skin Skin Liver Liver Spleen Spleen Gut Gut Portal Portal Vein Vein

PO IV

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200 400 600 800 1000 1200 1400 1600 1800 5 10 15

Age (y) Brain Weight (g)

Ogiu et al ICRP

ORGAN SIZE

10 20 30 40 50 60 70 80 2 4 6 8 10 12 14

BBF (L.h)

10 20 30 40 50 60 2 4 6 8 10 12 14

Age RBF (L.h)

Renal

Age (y)

Brain

20 40 60 80 100 120 5 10 15 20

Age (y) Qh (L.h)

Liver

10 20 30 40 50 60 4 8 12 16

Age (y) Muscle BF (L.h)

Muscle

4 8 12 16 20 4 8 12 16

Age (y) Skin BF (L.h)

Skin

5 10 15 20 25 4 8 12 16

Age (y) Adipose BF (L.h)

Adipose ORGAN BLOOD FLOWS

Lung

10 20 30 40 50 60 70 80 90 5 10 15 20

Muscle

10 20 30 40 50 60 70 80 90 5 10 15 20

Adipose

10 20 30 40 50 60 70 5 10 15 20

Skin

10 20 30 40 50 60 70 80 90 5 10 15 20

Liver

10 20 30 40 50 60 70 80 90 5 10 15 20

% Water

Kidney

10 20 30 40 50 60 70 80 90 5 10 15 20

Heart

10 20 30 40 50 60 70 80 90 100 5 10 15 20

Brain

10 20 30 40 50 60 70 80 90 100 5 10 15 20

Bone

10 20 30 40 50 60 70 5 10 15 20

Spleen

10 20 30 40 50 60 70 80 90 5 10 15 20

Plasma

10 20 30 40 50 60 70 80 90 100 5 10 15 20

Age (y)

GI tract

10 20 30 40 50 60 70 80 90 5 10 15 20

TISSUE COMPOSITION - WATER

Skin fixed 3.95% Lung

0.5 1 1.5 2 2.5 3 3.5 4 5 10 15 20

Adipose

10 20 30 40 50 60 70 80 90 5 10 15 20

Muscle

0.5 1 1.5 2 2.5 3 3.5 4 4.5 5 10 15 20

Liver

1 2 3 4 5 6 7 8 5 10 15 20

Kidney

1 2 3 4 5 6 5 10 15 20

Heart

1 2 3 4 5 6 7 5 10 15 20

Brain

2 4 6 8 10 12 14 5 10 15 20

% fat Bone

1 2 3 4 5 6 7 8 5 10 15 20

Spleen

0.5 1 1.5 2 5 10 15 20

Plasma

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 5 10 15 20

Age (y) GI tract

1 2 3 4 5 6 7 5 10 15 20

TISSUE COMPOSITION - FAT

50 100 150 200 250 300 4 8 12 Age (year) GFR (ml/min/1.73m

2

) Female Male

RENAL FUNCTION

Alb = 1.1287Ln(t) + 33.746

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 100010000 100000

Age (days) Albumin (g/L)

0.2 0.4 0.6 0.8 1 1.2 1.4 0.1 1 10 100 100010000 100000

Age (days) AAG (g/L)

PLASMA PROTEINS 50 100 150 200 Birth1wk 2wk 3wk 1mo 3mo 1-3y 4-6y5-10yAdult HCl production Bile acid secretion Intestinal length % Adult GASTROINTESTINAL FUNCTION

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PK MODELLING

“TOP DOWN” “BOTTOM UP”

Demography, Physiology, Genetics, In Vitro Data

POPPK PBPK/IVIVE

Confirming Learning Plasma Data

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PHARMACODYNAMICS

Age-Related Changes in Concentration-Reponse

Drug Age Range n Observation Reference Cyclosporin 3mo – 39y 56 Increased CR effect in <1-4y group Marshall & Kearns (1999) Warfarin 1 – 76y 134 Increased CR effect (INR/dose) in 1-11y group Takahashi et al (2000) Midazolam Preterm – 29w 31 Decreased CR (sedation) De Wildt et al (2001)

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5 10 15 20 25 3 10 21 Latency to right (secs) Postnatal Age (days) Koch et al (2008)

MIDAZOLAM (10mg/kg S/C – Rats)

Baseline After midazolam “Dynamic mapping of human cortical development during childhood through early adulthood” Gogtay et al – PNAS 101: 8174, 2004

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“Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation in children: a pharmacokinetic- pharmacodynamic analysis” Johnson et al: Br J Anaesth 89:428, 2002

PK-PD MODELLING

“A 50% increase in dose would increase odds ratio from 4 to 275 in favour of sedation score 2 (drowsy/asleep) at start of surgery”

SLIDE 25

• Homocysteinuria

(3 in 1 million)

• Betaine

(orphan drug)

• Limited population of

patients to study

• No Pharma

funding for large studies

Solution:

Clinical Trial Simulation

Br J Clin Pharmacol 54:140,2002

Methionine Homocysteine S- Adenosyl homocysteine Cystationine beta-synthase Betaine N,N. Dimethyl N,N. glycine

kin – kout S(t) H(t)

= dt dH

S(t) =

) ( ) ( 1

50

t C EC t C E

Betaine Betaine Max

+ +

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Overall reduction in

Increase in the usual daily dosage (150 mg/kg) or in dosage frequency greater than twice daily is predicted to give negligible added clinical benefit for an additional cost of £2100 per patient year and potential decrease in compliance.Two divided daily doses may be optimal.

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Concentrate on < 2 year olds

• More variable
• High risk
• Developing systems

More ‘creative’ PD evaluation