DEVELOPMENTAL PK/PD: WHAT HAVE WE LEARNT? Geoff Tucker

Transcription

1 DEVELOPMENTAL PK/PD: WHAT HAVE WE LEARNT? Geoff Tucker

2 UNDERSTANDING AND PREDICTING PK/PD IN JUVENILES

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

4 ORAL BIOAVAILABILITY From Grass & Sinko (Adv Drug Deliv Rev,22) from Sietsema (Int J Clin Pharmacol Ther Toxicol,1989)

5 % Adult 1 8 HUMAN CYP3A4 (Johnson et al,26) RAT CYP3A1 (Johnson et al, 2) DOG CYP3A12 (Taneka, 1998) RAT CYP3A1 (Johnson et al, 2) neonate infant child adolescent adult

6 ONTOGENY OF TRANSPORTERS (ANIMALS) weaning Kidney Intestine Liver PgP MOUSE (Mahmood et al, 21) Bile salt/oats RAT LIVER PgP RAT BRAIN (Gao et al, 24) (Matsouka et al, 1999) OATs RAT KIDNEY (Buist et al, 22)

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

8 THE 3/4 (Klieber s) LAW From allometric principles: Metabolic Rate BW.75 Clearance BW.75 Holford A size standard for pharmacokinetics Clin Pharmacokin 3: , 1996

9 THE 3/4 (Klieber s) LAW From measurements in 536 N.Europeans, N.Americans and Japanese: Liver Volume =.722 x BSA BSA BW.67 Liver Volume BW.78 Clearance BW.78 Johnson et al Changes in liver volume from birth to adulthood: a meta-analysis Liver Transpl 11: , 25

10 : Liver Size (L) Johnson et al: LV=.722 x BSA Allometric: LV child =LV adult x (BW/7kg) Body weight (kg)

11 Liver Volume (L) 1.6 LV =.722 x BSA (n = 162 patients) 1.2 LV = 1.46 x (BW/7kg) Fanta et al Developmental pharmacokinetics of ciclosporin: A population pharmacokinetic study in paediatric transplant patients Br J Clin Pharmacol 64:772, Body Weight (kg)

12 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 of drug metabolising enzymes in neonates and infants. Use 3/4 Rule to normalise clearance only > 2 years.

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

14 AGE-RELATED CHANGES IN CYP EXPRESSION/ACTIVITY 1A2 2B6 2C8 2C9 2C19 2D6 Johnson et al (26) 2E1 3A

15 EFFECT OF DIET ON CAFFEINE ELIMINATION RATE CONSTANT (CYP1A2) Blake et al (26)

16 GLUCURONIDATION Time to maturity? UGT1A1 UGT1A4 UGT1A9 UGT2B4 UGT2B7 (e.g. ethinylestradiol (e.g. imipramine) (e.g. propofol) (e.g. morphine) < 6 months < 2 years > 2 years > 2 years < 6 months Strassburg et al, 22; Miyagi & Collier, 27

17 Midazolam (IV) Midazolam (Oral) Predicting Paediatric Clearance Caffeine (Oral) Diclofenac (IV) CL (L.kg.h) Omeprazole (Oral) Carbamazepine (Oral) Phenytoin (Oral) Weight (kg) Cisapride (Oral) Theophylline (Oral) S-Warfarin (Oral) Johnson et al. Clin Pharmacokin 26

18 Below ~ 2years prediction of clearance is drug specific due to differential development of its determinants.

19 Full Paediatric PBPK Model Lung Adipose Bone Brain Venous Blood Heart Kidney Muscle Skin Arterial Blood Liver Portal Vein Spleen Gut IV PO Incorporating information on organ size, tissue composition and blood flow Allows for prediction of full PK profile (V, MRT, C max, C min )

20 % fat % Water Brain RBF Weight (L.h) (g) Renal ORGAN SIZE BBF (L.h) Brain Ogiu et al ICRP TISSUE COMPOSITION WATER Age 6 Age (y) 8 7 Age (y) Muscle Adipose % Adult Skin Age (y) Muscle TISSUE COMPOSITION 6 - FAT Skin Adipose Muscle Adipose Kidney Liver Heart Age (y) 7 5 Liver 8 4 Kidney Age (y) 6 Age (y) Heart Brain 4 Lung Bone Brain Lung Spleen Bone 6 6 Plasma Age (days) GI 5 tract Muscle BF (L.h) Spleen ORGAN BLOOD FLOWS Skin BF (L.h) Age Plasma (y) 5 Qh (L.h) Adipose BF (L.h) Age (y) Albumin (g/l) GFR (ml/min/1.73m Liver 2 ) Skin fixed 3.95% Age (year) GI tract RENAL FUNCTION Female PLASMA PROTEINS Male AgeD Alb = Ln(t) AAGg/L = GASTROINTESTINAL FUNCTION AgeD AAG (g/l) 1.4 HCl production 1.2 Bile 1 acid secretion Intestinal length Age (days) Birth1wk 2wk 3wk 1mo 3mo 1-3y 4-6y 5-1yAdult

21 PK MODELLING TOP DOWN Plasma Data POPPK Confirming Demography, Physiology, Genetics, In Vitro Data PBPK/IVIVE BOTTOM UP Learning

22 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 Takahashi et al (2) effect (INR/dose) in 1-11y group Midazolam Preterm 29w 31 Decreased CR (sedation) De Wildt et al (21)

23 MIDAZOLAM (1mg/kg S/C Rats) Latency to right (secs) 25 Koch et al (28) 2 15 Baseline After midazolam Postnatal Age (days) Dynamic mapping of human cortical development during childhood through early adulthood Gogtay et al PNAS 11: 8174, 24

24 PK-PD MODELLING Contribution of midazolam and its 1-hydroxy metabolite to preoperative sedation in children: a pharmacokineticpharmacodynamic analysis Johnson et al: Br J Anaesth 89:428, 22 A 5% increase in dose would increase odds ratio from 4 to 275 in favour of sedation score 2 (drowsy/asleep) at start of surgery

25 Br J Clin Pharmacol 54:14,22 - Homocysteinuria (3 in 1 million) - Betaine (orphan drug) - Limited population of patients to study - No Pharma funding for large studies Solution: Clinical Trial Simulation dh dt Methionine N,N.Dimethyl glycine S- Adenosyl Betaine homocysteine = S(t) = Homocysteine Cystationine beta-synthase k in k out S(t) H(t) 1+ E Max C Betaine ( t) EC5 + CBetaine ( t)

26 Increase in the usual daily dosage (15 mg/kg) or in dosage frequency greater than twice daily is predicted to give negligible added clinical benefit for an additional cost of 21 per patient year and potential decrease in compliance.two divided daily doses may be optimal. Overall reduction in

27 Concentrate on < 2 year olds - More variable - High risk - Developing systems More creative PD evaluation