Clinical trial design optimization in paediatrics using prior knowledge combined with modelling and simulations Eric Snoeck, Exprimo NV EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
Overview Introduction • PK and PK/PD in children versus adults • How M&S can help in the design of paediatric studies • Use of prior knowledge for developing paediatric PK/PD • simulation models Data analysis methods of paediatric studies • Three of our M&S examples in paediatrics • Proposing a dose adaptation rule for iv levetiracetam in • children Paediatric study with a renally cleared antiviral drug aiming to • characterize the PK and safety Ongoing M&S of a pharmacodynamic endpoint to optimize • the design of a paediatric study 2 EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
Infants and children are no little adults !! Absorption: • Increased gastric pH, different motility Distribution: Decreased protein binding, Increased total body water, • variable fat content Elimination: • Immature and changing hepatic clearance mechanisms, glomerular filtration and tubular excretion Target tissues/organs/systems are in development • Immune system in young children is different from adults • Dose-response can be different • Diseases specific to children or different from adults • Also adverse events may differ • 3 EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
These differences necessitate specific paediatric studies, but there are some constraints: Practical constraints: • Invasive sampling (pain, anxiety) • Number of blood samples • Sampling volume • Recruitment (age categories) • Ethical constraints: • Direct benefit often absent in PK studies • Consent from parents sometimes difficult to obtain • � We need to be most efficient with the information/subjects we do have in paediatric studies � Optimization of clinical trial design using M&S 4 EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
How M&S can help in the design of paediatric studies? Development of a population PK-PD-disease model using prior knowledge Simulation of ‘realistic virtual patients’ Simulation of virtual clinical trials Optimization of study design and data analysis method prior to the study 5 EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
Use of prior knowledge for developing paediatric PK/PD simulation models: Drug information Drug information in adults in children Semi-mechanistic Population PK-PD model Literature information on Literature information physiological systems involved on similar compounds 6 EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
The design of a paediatric trial highly depends on the data analysis method: Traditional approach: Non-compartmental analysis Many samples in many children Many samples Data analysis Population analysis (and sparse samples) in many children Sparse samples in Bayesian analysis a limited number of children 7 EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
Example I Proposing a dose adaptation rule for iv levetiracetam in children EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
Goals and available data: To advise about a dose adaptation rule for iv • levetiracetam in children iv dose and duration of infusion • AUC τ and Cmax in children and adults after iv levetiracetam • should be in the same range Available data and prior knowledge: • Population pharmacokinetics after oral levetiracetam in • children Population pharmacokinetics after iv levetiracetam in adults • Covariate influences on CL and V • 9 EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
Two population PK models were combined to obtain a simulation model for iv levetiracetam in children: 2-compartment 1-compartment model 1 st order absorption iv model (n = 30 adults) (n = 228 children) K 21 V 1 = ⋅ Vd ss K 12 K 21 + 2-compartment K 12 V 2 = ⋅ Vd ss iv simulation model K 12 + K 21 for children 10 EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
Simulations based on covariate values for typical children… Based on stature-for-age and weight-for-age percentile graphs (National Center for Health Statistics) The iv paediatric model was Simulation model was implemented • • successfully qualified for simulations in TS2 Existing covariate influences on CL Simulation of 2000 steady-state • • and V in children were retained plasma concentration-time profiles Inter-individual variability on CL, Calculation of C trough , C max and AUC τ • • Vd ss and K12 Residual error of 30% CV • 11 EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
… showed that C max,ss and AUC τ after a 15-min iv infusion of 30 mg/kg in children were within the range of those after iv 1500 mg in adults: 12 EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
Added value of M&S for iv levetiracetam in children: With no iv data of levetiracetam in children, but with separate population PK models developed based on iv data in adults and oral data in children, it was possible to evaluate dose adaptation rules of iv levetiracetam in children in terms of: iv dose and infusion duration: • • to avoid high plasma concentrations and thus minimizing the risk of adverse events • to have an AUC τ similar to adults and thus to obtain a similar efficacy Predicted PK of iv levetiracetam in children • Similar inter-compartmental distribution rates between • adults and children should be confirmed in paediatric studies 13 EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
Example II Paediatric study with a renally cleared antiviral drug aiming to characterize the PK and safety EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
Goals and available data: To advise about a dose adaptation rule • Study design optimization • Dose(s)? • How many samples and at what time points? • How many children? • What might happen in neonates and infants? • Available data and prior knowledge: • General PK characteristics of the drug • Literature information on CL related to AGE and BW and • kidney maturation Limited data on PK in adults and children • 15 EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
What is the expected behaviour of the drug that we are studying in children, knowing that it is renally cleared? Dose normalised plasma concentration in children and adults Dose normalised plasma concentration in children and adults • The drug Higher peak Higher peak 50.0 50.0 50.0 50.0 • distributes in body water concentration concentration Normalised Conc (ng/mL)/mg Normalised Conc (ng/mL)/mg Normalised Conc (ng/mL)/mg Normalised Conc (ng/mL)/mg • has a low protein binding Faster elim ination Faster elim ination rate rate 5.0 5.0 5.0 5.0 • is mainly renally excreted unchanged 1.0 1.0 1.0 1.0 Sam e C 8 h Sam e C 8 h 0.5 0.5 0.5 0.5 concentrations concentrations a 0.7 CL {mL/min} ⋅ [ 140 − AGE{y}] ⋅ BW{kg} ref CL{mL/min} = 1660 0.1 0.1 0.1 0.1 0 0 0 0 2 2 2 2 4 4 4 4 6 6 6 6 8 8 8 8 Time (h) Time (h) Time (h) Time (h) Tod M, Lokiec F, Bidault R, De Bony F, Petitjean O, Aujard Y. Pharmacokinetics of oral acyclovir in neonates and in infants: a population analysis. Antimicrob Agents Chemother 2001 45:150-7 PCA 6.17 MF = 13.4 6.17 PCA 6.17 + MF = Maturation Factor PCA = Post Conceptional Age in months Rowland and Tozer: Clinical Pharmacokinetics Concepts & Applications 16 EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
For simulations using virtual realistic patients the relationship between age and weight need to be known θ 140 AGE WT ⎛ ⎞ ( ) 2 − CL θ MF exp η ⎜ ⎟ ( ) = ⋅ ⋅ ⋅ ⋅ 1 105 70 ⎝ ⎠ Model: θ WT ⎛ ⎞ 4 V θ exp η ⎜ ⎟ ( ) = ⋅ ⋅ 3 70 ⎝ ⎠ Population: 1.0 Simulated CL/F 0.8 100 penciclovir clearance, l/h/kg 0.6 50 Weight (kg) 0.4 10 0.2 5 0 20 40 60 80 0 20 40 60 80 Age, years Age (years) 17 EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
Exploration of the model shows that maturation of the renal function has a large influence on the PK profile 6.17 PCA MF = 6.17 6.17 13.4 PCA + θ 140 AGE WT ( ) ⎛ ⎞ 2 − CL θ MF exp η ⎜ ⎟ ( ) = ⋅ ⋅ ⋅ ⋅ birth 4.4 months 1 year infant 1 105 70 ⎝ ⎠ 1.0 0.8 PCA 6.17 aturation, fraction MF = 13.4 6.17 PCA 6.17 0.6 + 0.4 θ WT ⎛ ⎞ 4 M V θ exp η 0.2 ⎜ ⎟ ( ) = ⋅ ⋅ infant 3 70 ⎝ ⎠ 0.0 0 5 10 15 20 25 PCA, months 10.0 5.0 Concentration (µg/mL) 2 mo 1.0 0.5 12 mo LLOQ 0.1 0 2 4 6 8 10 Time (h) 18 EMEA Workshop on Modelling in Paediatrics, 14-15 April 2008
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