Abstract
Linked ArticlesThis article is commented on in the editorial by Holford NHG and Anderson BJ. Why standards are useful for predicting doses. Br J Clin Pharmacol 2017; 83: 685–7. doi: 10.1111/bcp.13230 AimWhen different models for weight and age are used in paediatric pharmacokinetic studies it is difficult to compare parameters between studies or perform model‐based meta‐analyses. This study aimed to compare published models with the proposed standard model (allometric weight0.75 and sigmoidal maturation function).MethodsA systematic literature search was undertaken to identify published clearance (CL) reports for gentamicin and midazolam and all published models for scaling clearance in children. Each model was fitted to the CL values for gentamicin and midazolam, and the results compared with the standard model (allometric weight exponent of 0.75, along with a sigmoidal maturation function estimating the time in weeks of postmenstrual age to reach half the mature value and a shape parameter). For comparison, we also looked at allometric size models with no age effect, the influence of estimating the allometric exponent in the standard model and, for gentamicin, using a fixed allometric exponent of 0.632 as per a study on glomerular filtration rate maturation. Akaike information criteria (AIC) and visual predictive checks were used for evaluation.ResultsNo model gave an improved AIC in all age groups, but one model for gentamicin and three models for midazolam gave slightly improved global AIC fits albeit using more parameters: AIC drop (number of parameters), –4.1 (5), –9.2 (4), –10.8 (5) and –10.1 (5), respectively. The 95% confidence interval of estimated CL for all top performing models overlapped.ConclusionNo evidence to reject the standard model was found; given the benefits of standardised parameterisation, its use should therefore be recommended.
Highlights
IntroductionSince the 1950s paediatricians have recognised that drug clearance (CL), and usually dose requirements (which depend on drug exposure, i.e. area under the curve [AUC]), scales with body surface area rather than body weight [2]
Each model was fitted to the CL values for gentamicin and midazolam, and the results compared with the standard model
No model gave an improved Akaike information criteria (AIC) in all age groups, but one model for gentamicin and three models for midazolam gave slightly improved global AIC fits albeit using more parameters: AIC drop, –4.1 (5), –9.2 (4), –10.8 (5) and –10.1 (5), respectively
Summary
Since the 1950s paediatricians have recognised that drug clearance (CL), and usually dose requirements (which depend on drug exposure, i.e. area under the curve [AUC]), scales with body surface area rather than body weight [2]. The fact that CL scales in this way means that children will have higher dose requirements on a (linear) mg kg–1 basis compared to adults (see Figure 1). Illustration of the fractional change in clearance compared with using an allometric weight exponent of 0.63–0.78 778 Br J Clin Pharmacol (2017) 83 777–790. Basal metabolic rate and how it scales with weight has been studied for over a century and various “correct” values have been derived for the exponent with 0.75 [4] and 0.67 [5] being the two commonly argued “true” values. A comprehensive review summarising various mathematical descriptions of these observations, along with discussion on whether “basal”, “field”, or any other variety of metabolic rate should be used to infer drug CL scaling was recently provided by Mahmood [6]
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