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 13-14.1. 2009
Dose adjustment in paediatrics Age Body weight Body surface underlying disease
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
Pharmaceutics Pharmacology: E ffect = f (d ose ) Pharmacokinetics: dc onc /dt = f (c,t,...) Pharmacodynamics: de/dt = f (D,t)
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
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
dose adjustment 2g total was equalled 1200mg/m 2 3g total was equalled 1800mg/m 2
Influence of age
MMF and other immunosuppressants
Adjustment 10 years after introduction of MMF
still open today first year of life other indications influence of other medication long term data
Example 2 vaccine Influence of underlying disease
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
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 ) 1.200 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
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
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
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.
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)
acute rejection episodes CHIDE01 BAS PLA BAS PLA Placebo: 47,5% BAS PLA Basiliximab: 43% BAS PLA n.s.
Neoral Trough Levels 450 400 trough level (ng/ml) 350 300 250 200 150 100 50 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Study Day Basiliximab Placebo
MMF Daily Dose 1200 1000 dose (mg/m²/day) 800 600 400 200 0 0 4 7 28 90 140 180 270 360 Study Day Basiliximab Placebo
Liberation Absorption Distribution Metabolismus Excretion Pharmacokinetic Dost
Developmental Pharmacology Kearns et al, NEJM 2003 GFR
Developmental Pharmacology Kearns et al, NEJM 2003
Pharmacokinetic important parameters half lifes t½ Cmax tmax AUC bioavailability
Bioavailability
New applications for pediatrics to 2006
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?
Optimising the Design of Pediatric Trials Thank you for listening KKS.i-med.ac.at