Elisa Calvier1, Elke H.J. Krekels 1,2 ,Meindert Danhof1, Catherijne A.J. Knibbe1,3
1 Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands 2 Department of Pharmaceutical Biosciences, Uppsala University 3 Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands
Objectives: A semi-physiological covariate model describing the glucuronidation clearance (Clgluc) of morphine in young children was successfully applied to model zidovudine paediatric pharmacokinetic data [1]. As both drugs are mainly metabolized by UGT2B7 and have a high unbound drug fraction (fu) and extraction ratio (ER), a simulation study was undertaken showing that drug properties do not influence this covariate relationship [2]. More recently, using a bodyweight-dependent exponent model, this covariate model has been extended to adults [3] and thus could potentially be used to predict paediatric Clgluc based on body weight (BW) only. The objective of this study was to assess the predictive value of the recent semi-physiological covariate model (SPC) [3] compared to classical allometric scaling (CAS) for scaling Clgluc from adults to different paediatric ages for drugs metabolized by UGT2B7 or UGT2B15 and with different fu and ER.
Methods: Literature values for CLgluc in adults for zidovudine (high fu, high ER) [4], lorazepam (low fu, low ER) [5], both metabolized by UGT2B7, and paracetamol (high fu, low ER, glucuronidated by UGT2B15) [6] were scaled by SPC [3] and by CAS to predict CLgluc across the paediatric weight-range. The predictions were compared to values of population glucuronidation clearance in children [1][5][7][8][9][10] with the use of +/-50% prediction interval, bias (percentage mean prediction error) and precision (root mean-squared error). For the predictions, 60 to 75%, 100% and 50 to 60% glucuronidation was assumed in adults for zidovudine, lorazepam and paracetamol respectively.
Results: For neonates the predictions from SPC are significantly less biased (10 fold) than those from CAS. Observations for neonates are at least partially (zidovudine and paracetamol) or entirely (lorazepam) in the 3-fold prediction interval of the SPC and either partially (zidovudine) or completely (lorazepam and paracetamol) out of the +/-50% prediction interval of the CAS predictions. For infants, the bias of SPC predictions are either close to (lorazepam) or 100 fold less (paracetamol) than with CAS. For children and adolescents, similar trends can be observed. Apart from adolescents, SPC predictions are systematically more precise than CAS predictions.
Conclusions: Scaling drug clearance from adults to children using a semi-physiological covariate model is a rapid and accurate approach that requires less information than whole-body PBPK modelling and should be preferred over the classical allometric scaling approach.
References:
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Reference: PAGE 23 (2014) Abstr 3175 [www.page-meeting.org/?abstract=3175]
Poster: Drug/Disease modeling - Paediatrics