Bonner J (1), Walsh C (1), Johnson T (2), Neuhoff S (2), Greystoke A (1), Veal G (1)
(1)Northern Institute for Cancer Research, Newcastle University, Newcastle, UK (2) Simcyp Limited (Certara), Sheffield, UK
Objectives: Determination of appropriate dosing of many anticancer agents in neonates and infants is a difficult task. Doses are routinely reduced but little pharmacokinetic data exists to act as guidance as to the magnitude of the reduction[1]. Physiologically-based pharmacokinetic (PBPK) modelling and simulation may assist in dose selection but requires a virtual paediatric population containing information on parameters that may affect PK that are known to change with age[2]. However, physiological changes affecting PK may also occur in cancer and these alterations may change typical ontogeny functions. The aim of this work is to build a virtual paediatric cancer population for use in PBPK modelling and simulation.
Methods: Anonymised patient data/plasma samples from 153 paediatric cancer patients were used (age range 1 month to 19.8 years). Plasma alpha-1 acid glycoprotein (AAG) concentrations were measured in 120 samples by ELISA. Relationships between height and age, weight and height, and AAG and corrected GFR (cGFR) and age were assessed by nonlinear regression. The slope and intercept values from the height and weight curves were used to simulate height and weight values for 2,000 virtual paediatric subjects within Simcyp version 14.1. Comparison of patient ages, BSA, AAG, and cGFR by cancer type were performed by the Kruskal-Wallis test with Dunn’s multiple comparisons test.
Results: The relationship between height and weight was described by a second order polynomial and weight vs. height by an exponential function. Heights and weights in simulated individuals created using the fitted equations did not differ significantly from those produced by use of a virtual healthy volunteer population. Plasma AAG concentrations in the paediatric cancer patients were significantly higher than the normal range (Mean AAG concentration in males was 2.24 mg/mL (64%CV) and in females 2.35 mg/mL (67%CV)) and no significant correlation with age was seen as exists in healthy subjects. There was no significant correlation between cGFR and age. No differences were observed in AAG concentrations or cGFR between cancer types.
Conclusions: These results show that while functions for height and weight do not differ greatly from those observed for healthy children, typical ontogeny functions for AAG and cGFR do not apply to this paediatric cancer population, underscoring the need for a special virtual population for modelling and simulation in children with cancer.
References:
[1] Veal GJ and Boddy AV. Chemotherapy in newborns and premature babies. Semin Fetal Neonatal Med 2012; 17:243-248.
[2] 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):931-956.
Reference: PAGE 24 (2015) Abstr 3620 [www.page-meeting.org/?abstract=3620]
Poster: Drug/Disease modeling - Paediatrics