Sophie Peigné1, Charlotte Gesson1, Vincent Jullien2,3 and Marylore Chenel1
1Department of Clinical Pharmacokinetics, Institut de Recherches Internationales Servier,
Objectives: The “first dose in children” could be determined mainly by two approaches:
- A physiological approach (PBPK “Physiollogically based PharmacoKineticsmodel)
- A compartmental approach using allometric scalling and maturation function
Comparison of these two methods had already been performed [1]. The aim of this work was to provide another example with a drug X metabolized only via CYP3A4 (80%) and with CLR (20 %). A study performed in paediatric population with this drug is currently underway.
Methods: Four children age classes were defined
- 20 infants in age-subset [6-12[ months received 0.02 mg/kg twice daily
- 20 infants in age subset [1-3[ years received 0.05 mg/kg twice daily
- 20 infants in age subset [3-18[ years with weight <40 kg received 0.05 mg/kg twice daily
- 20 infants in age subset [3-18[ years with weight ≥ 40 kg received 2.5 mg twice daily
A full PBPK model with Kp predicted by Poulin and Theil’s method was previously developed in adult and was used to simulate 10 times the four children age classes concentration-time profiles with SimCyp.
Simultaneously, an adult semi- physiologic joint PK model for the drug X and its active metabolite was scaled to children. The parent drug X part of the model was a three-compartment model while the metabolite was a two compartment model. These two parts were linked by two additional compartments representing liver. Weight effects were fixed to the allometric values of 0.75 and 1 on clearances and volumes of distribution, respectively [2]. In addition, a maturation function was added on clearance for the youngest age classes [3]. The concentration-time profiles of the 800 children obtained with SimCyp were compared to 1000 simulations performed with NONMEM using the same demographic data.
Results: The two approaches predicted the same magnitude of concentrations for the parent drug. On the contrary, some differences were observed between the two approaches on the metabolite PK profiles. For the absorption phase, refinement of the PBPK model was necessary (ADAM absorption model or ka).
Conclusions: Two approaches were compared and showed differences especially for the metabolite. Clinical PK data in children will be available by the end of the year and compared to the two sets of prediction.
References:
[1] Strougo A, Eissing T, Yassen A, Willmann S, Danhof M, Freijer J. First dose in children: physiological insights into pharmacokinetic scaling approaches and their implications in paediatric drug development. J Pharmacokinet Pharmacodyn. 2012 Apr;39(2):195-203. doi: 10.1007/s10928-012-9241-9. Epub 2012 Feb 5. PubMed PMID: 22311388; PubMed Central PMCID: PMC3306781.
[2] Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet. 2009;24(1):25-36. Review. PubMed PMID: 19252334.
[3] Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet. 2006;45(9):931-56. PubMed PMID: 16928154.
Reference: PAGE 22 () Abstr 2888 [www.page-meeting.org/?abstract=2888]
Poster: Paediatrics