Lothar Bernd Zimmerhackl

Transcription

1 What works in current paediatric practice of off-label dose adjustment of adult doses? Lothar Bernd Zimmerhackl Medical University Innsbruck Austria AGAH Workshop: Pediatric Investigation Plan. Bonn

2 Dose adjustment in paediatrics Age Body weight Body surface underlying disease

3 Age groups according to EMEA Neonate: birth to day 28 Infant: 2-12 month Child: 2-12 years Adolescent: >12-16 years Adolescent: >16 years considered as adult

4 Pharmaceutics Pharmacology: E ffect = f (d ose ) Pharmacokinetics: dc onc /dt = f (c,t,...) Pharmacodynamics: de/dt = f (D,t)

5 children are young adults Dose adjustment according to body surface area D = adult dose*bsa (m 2 ) /1.73m 2 Dose adjustment according to body weight D = adult dose*bw (kg) /75kg

6 Example Introduction of Cellcept in pediatric transplantation Basic immunosuppression: Prednison (data were known) CyA (data were thought to be known) Cellcept Adult studies: 2 x 1 g, or 2 x 1.5g total

7 dose adjustment 2g total was equalled 1200mg/m 2 3g total was equalled 1800mg/m 2

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9 Influence of age

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13 MMF and other immunosuppressants

14 Adjustment 10 years after introduction of MMF

15 still open today first year of life other indications influence of other medication long term data

16 Example 2 vaccine Influence of underlying disease

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18 Study Design A randomized, placebo-controlled, doubleblind, multicenter study investigating basiliximab in combination with MMF, ciclosporine microemulsion and prednison in the prevention of acute rejection in pediatric renal allografts recipients 2 arms: Basiliximab /Ciclosporine/MMF/prednison Placebo /Ciclosporine/MMF/prednison

19 Study Design prospective, randomized, placebo-controlled, double-blind study Basiliximab/Placebo: Day 0 and 4: 10 mg per day if < 35 kg BW 20 mg per day if > 35 kg BW MMF (mycophenolate mofetil, CellCept ) mg/m²/24h ± 15% in 2 devided doses, orally Ciclosporine (CsA, Sandimmun Optoral ) start with 150 mg/m 2 target trough levels: 150 to 250 ng/ml for the first 3 months, 100 to 200 ng/ml thereafter (TDx-Assay, Abbott) Steroids: Prednison (or equivalent methylprednisolon) Day 0: 300 mg/m² (regular dose 2 x 150 mg/m²) stepwise reduction until Week 7, thereafter 4 mg/m²

20 Study Endpoints Primary endpoint To demonstrate superiority of the treatment regime of ciclosporine microemulsion, MMF, prednisone in combination with basiliximab as compared to ciclosporine microemulsion, MMF and prednisone in the time to first biopsy proven acute rejection episode or treatment failure during the first 6 months post-transplantation

21 Study Endpoints Secondary endpoints patient and graft survival acute rejection month 6 und 12 protocol biopsy at month 6 adverse events with focus on infections, malignancies and renal function

22 Participating Centers Lille Foulard M. München Montoya C. Heidelberg Tönshoff B. Hannover Offner G. Freiburg Zimmerhackl L. Lyon Cochat P. Leipzig Wygoda S. Hamburg Altona Schwarke D. Erlangen Rascher W. Berlin Querfeld U. Zürich Neuhaus T. Hamburg Eppendorf Müller-Wiefel D. Jena Misselwitz J. Stuttgart Leichter H. Frankfurt Latta K. Marburg Klaus G. Essen Hoyer P. Köln Hoppe B. Memmingen Fehrenbach H. Münster Bulla M.

23 Time Free From BPAR I-III Basiliximab Placebo Kaplan-Meier plot of time free from BPAR I-III over 6 months post transplantation by group (population ITT)

24 acute rejection episodes CHIDE01 BAS PLA BAS PLA Placebo: 47,5% BAS PLA Basiliximab: 43% BAS PLA n.s.

25 Neoral Trough Levels trough level (ng/ml) Study Day Basiliximab Placebo

26 MMF Daily Dose dose (mg/m²/day) Study Day Basiliximab Placebo

27 Liberation Absorption Distribution Metabolismus Excretion Pharmacokinetic Dost

28 Developmental Pharmacology Kearns et al, NEJM 2003 GFR

29 Developmental Pharmacology Kearns et al, NEJM 2003

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31 Pharmacokinetic important parameters half lifes t½ Cmax tmax AUC bioavailability

32 Bioavailability

33 New applications for pediatrics to 2006

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35 In conclusion children are no small adults with regard to new drugs PK and PD have to be established in pediatrics you need experts also for measurements in small sample sizes you need therapeutic drug monitoring ongoing limited sampling strategy Bayes theorem?

36 Optimising the Design of Pediatric Trials Thank you for listening KKS.i-med.ac.at