Abstract
Recently a framework was presented to assess whether pediatric covariate models for clearance can be extrapolated between drugs sharing elimination pathways, based on extraction ratio, protein binding, and other drug properties. Here we evaluate when a pediatric covariate function for midazolam clearance can be used to scale clearance of other CYP3A substrates. A population PK model including a covariate function for clearance was developed for midazolam in children aged 1–17 years. Commonly used CYP3A substrates were selected and using the framework, it was assessed whether the midazolam covariate function accurately scales their clearance. For eight substrates, reported pediatric clearance values were compared numerically and graphically with clearance values scaled using the midazolam covariate function. For sildenafil, clearance values obtained with population PK modeling based on pediatric concentration-time data were compared with those scaled with the midazolam covariate function. According to the framework, a midazolam covariate function will lead to systemically accurate clearance scaling (absolute prediction error (PE) < 30%) for CYP3A substrates binding to albumin with an extraction ratio between 0.35 and 0.65 when binding < 10% in adults, between 0.05 and 0.55 when binding > 90%, and with an extraction ratio ranging between these values when binding between 10 and 90%. Scaled clearance values for eight commonly used CYP3A substrates were reasonably accurate (PE < 50%). Scaling of sildenafil clearance was accurate (PE < 30%). We defined for which CYP3A substrates a pediatric covariate function for midazolam clearance can accurately scale plasma clearance in children. This scaling approach may be useful for CYP3A substrates with scarce or no available pediatric PK information.
Highlights
METHODSTo define the optimal first-in-child dose during drug development and to develop pediatric dose recommendations for clinical practice, accurate scaling of the plasma clearance of drugs is essential [1,2,3]
We only included midazolam PK data from children > 1 year of age, and the pediatric covariate function for midazolam clearance we developed in this analysis cannot be used to scale clearance values of CYP3A substrates in neonates and infants < 1 year of age
To be able to apply this covariate function to scale CYP3Amediated clearance in neonates and young infants up to 1 year of age, the model should be extended with a covariate relationship for clearance based on data from children < 1 year of age. This analysis showed that a pediatric covariate relationship describing how midazolam clearance changes throughout the pediatric age range can be used to scale adult clearance values for many other CYP3A substrates to pediatric clearance values
Summary
To define the optimal first-in-child dose during drug development and to develop pediatric dose recommendations for clinical practice, accurate scaling of the plasma clearance of drugs is essential [1,2,3] This is of particular relevance as performing dedicated pharmacokinetic (PK) studies for all drugs in all pediatric (sub)populations may not be feasible because it would take too many resources. This has already been successfully applied for scaling pediatric clearance for drugs glucuronidated by UGT2B7 enzymes and for drugs eliminated by glomerular filtration [4,5,6] Within this context, recently, a framework was presented by Calvier et al for hepatically metabolized drugs identifying the conditions for which between-drug extrapolation is systematically accurate [7]. One of the key findings of this framework was that the accuracy of this scaling method depends on the fraction metabolized by the isoenzyme pathway for which plasma clearance is scaled, on the hepatic extraction ratio of both the probe drug and the evaluated drugs in adults, on the type of binding plasma protein, and on the unbound drug fraction (fu) in adults [7]
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