Are Children Small Adults?

Transcription

1 Are Children Small Adults? What can modeling offer to (clinical) practice? Catherijne Knibbe, PharmD, PhD Hospital Pharmacist-Clinical Pharmacologist

2 How are children dosed in (clinical) practice? In practice drugs in children are mainly dosed in mg/kg Often different mg/kg per age group Even in the absence of relevant differences in PK or PK-PD relationships

3 How should children be dosed? Individualised dosing in paediatrics: dosing recommendation should be based on potential differences in PK, PD or PK-PD relationships: developmental growth X other covariates (genetics, (critical) illness, comedication etc)

4 Correlation between age and bodyweight Bodyweight (kg) Age (months) WHO Child Growth Standards,

5 Glucuronidation of morphine in children 1.0 Clearance (l/min) Bodyweight (g) Knibbe CA, Krekels EH et al, Clin Pharmacokinet, in press 5

6 Glucuronidation of morphine in children 1.0 Clearance (l/min) fixed exponent for BW Bodyweight (g) 6

7 Glucuronidation of morphine in children 1.0 Clearance (l/min) fixed exponent for BW age maturation Bodyweight (g) 7

8 covariate analysis: correlation between age and bodyweight If a fixed function for BW is used: Additional functions based on age are needed to correct for deviations caused by fixed functions for BW (drug-specific age-functions) Complex and often unstable models particularly under the age of two years

9 Optimize one surrogate marker for maturation 1.0 Clearance (l/min) Estimate the exponent Bodyweight (g) Knibbe CA, Krekels EH et al, Clin Pharmacokinet, in press

10 Comparison of fixed and estimated functions BW 0.75 fixed BW 1.44 estimated Cl 2 V 2 (M3G) V 1 (M) Cl 1 Cl 3 V 3 (M6G) Cl 4 Cl 5 Unstable model Cl 2 V 2 (M3G) V 1 (M) Q eq Cl 3 V 3 (M6G) Cl 4 Cl 5 Stable model V 4 (M)

11 Comparison of fixed and estimated functions exp PNA PNA or 10 days V 2 (M3G) Cl 2 Cl 3 Cl 1 Cl 4 V 1 (M) V 3 (M6G) Cl 5 Six thetas needed Cl 2 V 2 (M3G) V 1 (M) Q eq Cl 3 V 3 (M6G) Cl 4 Cl 5 V 4 (M) 1-3 thetas needed

12 Internal validation of the estimated model Morphine M3G M6G Predicted vs Observed Observed concentration [ng/ml] Population predicted concentration [ng/ml] Normalized Prediction Distribution Errors Mean: Variance: 0.90 Mean: Variance: 0.86 Mean: Variance: 1.00 Knibbe CA, Krekels EH et al, Clin Pharmacokinet, in press

13 Internal validation of the estimated model Parameters Model fit Bootstrap (99 out of 100) value CV(%) mean value CV(%) Fixed effects (n=10) k = exponential scaling factor Cl 1 PNA < 10 d (ml/min/kg k ) Cl 1 PNA > 10d (ml/min/kg k ) Cl 2 PNA < 10d (ml/min/kg k ) Cl 2 PNA >10d (ml/min/kg k ) Cl 3 (ml/min/kg k ) Cl 4 (ml/min/kg k ) Q eq (ml/min) V 1 = V 4 (l/kg) V 2 = V 3 (fraction of V 1 ) Inter-individual variability (n=5) ω 2 Cl ω 2 V ω 2 Cl ω 2 Cl ω 2 Cl 3 -Cl 4 interaction Residual error (n=3) σ 2, prop (morphine) σ 2, prop (M3G) σ 2, prop (M6G)

14 External validation of the estimated model Morphine M3G M6G Predicted vs Observed Observed concentration [ng/ml] Population predicted concentration [ng/ml] Normalized Prediction Distribution Errors Mean: Variance: Mean: Variance: Mean: Variance: 1.501

15 Validation of the proposed dosing regimen in a prospective trial (NTR Number NTR1438) Traditional dosing scheme in ug/kg/h Proposed dosing scheme µg/kg 1.5 /h Concentration [ng/ml] Concentration [ng/ml] Morphine Time [min] Time [min] Knibbe CA, Krekels EH et al, Clin Pharmacokinet, in press

16 Perspectives Apply PB-PK modelling concepts Identify system specific properties in the models of developmental changes Explore its use for drugs sharing similar disposition pathways e.g. morphine, zidovudine

17 Conclusions Population PK and PD models are the basis for identification dosing algorithms for individualization of therapy that can be used in clinical practice Keep an open mind when analysing pediatric data Estimate the influence of covariates bodyweight and/or age Use only fully validated models for simulations of dosing algorithms. Evaluate developed dosing algorithms in prospective clinical trials

18 Involved researchers in paediatrics Leiden Elke Krekels, Ibrahim Ince, Maurice Wang, Massimo Cella, Roosmarijn de Cock, Oscar Della Pasqua, Meindert Danhof Rotterdam, Erasmus MC Sophia Heleen Blusse van Oud-Albas, Saskia de Wildt, John van den Anker, Dick Tibboel Utrecht Medical Centre Imke Bartelink, Toine Egberts, Lieke Sanders, Jaap Jan Boelens Nieuwegein Jeroen Diepstraten, Rifka Peeters, Mathieu Tjoeng Cincinatti Childrens Hospital Sander Vinks Leuven Karel Allegaert