1 Introduction
Clearance (CL) is the driving parameter for dosing as it determines steady-state and trough concentrations. For children, precise scaling of CL without bias across the pediatric age range is paramount to reach both an effective and safe (starting) dose. This is of relevance for defining (first-in-child) doses in clinical studies, particularly for drugs for which differences in dose requirements between adults and children can be attributed entirely to differences in pharmacokinetics (PK) and/or for which target concentrations in children are known [
1].
CL of drugs eliminated through glomerular filtration (GF) is dependent on the GF rate (GFR) and plasma protein binding. GFR maturation across the pediatric population has been described by different functions based on data from CL of either endogenous (e.g. creatinine, cystatin C) or exogenous (e.g. inulin, iohexol, aminoglycosides) compounds, used as markers for GFR function [
2‐
7]. With respect to plasma protein binding, changes in the unbound drug fraction (
fu) with age need to be taken into account when predicting pediatric CL via GF, as only the drug fraction that is not bound to plasma proteins can be eliminated through GF. The unbound fraction across age is dependent on the protein the drug binds to (i.e. human serum albumin or α-acid glycoprotein [AGP]) and the changes in the concentrations of these proteins with age [
8]. As physiologically-based PK (PBPK) models include drug properties (i.e.
fu) and physiological differences between adults and children (i.e. maturation of plasma protein concentrations and GFR), these models are considered the ‘gold standard’ for pediatric CL predictions [
9].
However, the application of PBPK approaches is constrained by the availability of drug-specific data, skilled personnel, and resources needed to access and use different modeling platforms. Therefore, empirical bodyweight-based scaling methods such as linear scaling or allometric scaling with a fixed exponent of 0.75 are still often used to derive pediatric CL from adult CL values. However, empirical scaling methods disregard information about maturation of both GFR and protein binding. Previous work has shown that these approaches are inaccurate for certain pediatric age groups for drugs cleared by GF [
10,
11], suggesting that more mechanistic information may be needed for accurate scaling. For this, it has been proposed to adjust the allometric scaling with a maturation function for GFR, especially in the very young [
12]. In this article, we assess the accuracy of scaling based on GFR maturation, without taking into account maturational changes in
fu. We compare this approach with two relatively straightforward scaling methods based on bodyweight alone, since these methods are still often used and are perhaps even preferred because of their ease.
To this end, we first identified the GFR maturation function that yields the most accurate GFR predictions across the pediatric age range. Subsequently, we assessed the accuracy of pediatric CL and dose scaling obtained with the GFR maturation function compared with PBPK predictions for hypothetical drugs binding, to varying extents, to human serum albumin (HSA) or AGP across the pediatric age range. Additionally, the results are compared with those of the two empiric bodyweight-based methods, i.e. linear and allometric scaling with a fixed exponent of 0.75.
4 Discussion
This study aimed to identify the GFR maturation function that yields the most accurate GFR predictions across the entire pediatric age range, and to subsequently assess what the accuracy of GFR-based scaling of CL and dose is compared with the “gold standard” (i.e. PBPK-based predictions) and with two commonly used empiric bodyweight-based scaling methods. By comparing scaled CL values with PBPK CL predictions, we studied the influence of the maturation of plasma protein concentrations on CL and dose scaling, and showed at what ages this maturation is of relevance for each scaling method. The assessed scaling methods are typically used to guide pediatric dosing when little or no information is available on a drug in this population. As such, this work identifies drug properties (i.e. fu) and patient characteristics (i.e. age) for which bodyweight-based scaling methods suffice and when more mechanistic information is necessary by means of either GFR-based scaling or PBPK for accurate CL and dose scaling. Our findings provide guidance for (first-in-child) clinical studies on what scaling method to use when deriving pediatric doses from adult doses of small molecule drugs that are mainly eliminated by GF.
The published GFR maturation functions we evaluated were found to have comparable profiles, while the functions published by Salem et al. [
17] and Rhodin et al. [
14] had similar accuracy in predicting inulin [
3,
4,
6] and mannitol [
2] CL measures, with the function reported by Salem et al. [
17] being slightly more accurate overall. This function (Eq.
12) was used in PBPK-based predictions of ‘true’ pediatric CL values (Eq.
3) and was directly used for simplified GFR-based scaling (Eq.
7).
Drug CL by GF depends on GFR and plasma protein binding, which are taken into account by PBPK modeling approaches. However, the extent of protein binding and the proteins the drugs bind to may not always be known, especially for the pediatric population. The simplified scaling functions, which include GFR-based scaling (Eq.
7), bodyweight-based linear scaling (Eq.
8), and bodyweight-based allometric scaling with a fixed exponent of 0.75 (Eq.
9), typically do not take into account changes in plasma protein binding with age. The difference between GFR-based scaled pediatric CL values and ‘true’ pediatric CL values reflects the impact of ignoring maturation in plasma protein concentrations on CL scaling. The current analysis showed that with GFR-based scaling, this impact can be disregarded throughout the entire pediatric age range, except in neonates for a few drugs highly bound to AGP (Fig.
3). Prediction errors in scaled CL values are largest in neonates, especially for drugs that bind to AGP, possibly due to the steep maturation of AGP plasma concentrations in early life (electronic supplementary Fig. S1). GFR-based scaling leads to underprediction of CL in neonates and in drug doses, compared with ‘true’ CL and ‘true’ reference doses, which will result in not only a reduced risk of developing toxic effects but also an increased risk of treatment failure. Bodyweight-based allometric scaling with a fixed exponent of 0.75 tends to overpredict CL in children younger than 6 months, even though for drugs with a low
fu, maturational changes in the expression of drug binding plasma proteins can still partially correct this bias. Bodyweight-based linear scaling leads to reasonably accurate CL predictions in this young population. After the age of 6 months, the influence of plasma protein binding on CL scaling decreases, as shown by a smaller deviation of GFR-based scaled CL from PBPK-based CL predictions. In this age range, reasonably accurate CL predictions are obtained using bodyweight-based scaling, irrespective of whether the exponent is 1 (linear scaling), 0.75 (allometric scaling), or 0.62 (GFR function reported by Salem et al. [
17]). As scaled CL values drive the scaled dose values, the same patterns are observed for this variable.
The CL predictions of selected drugs (> 80% renal elimination) in neonates and children, using the GFR maturation function reported by Rhodin et al. [
14], has recently been described [
25]. Our results are in line with these published findings, with the added advantage that our analysis captures the entire hypothetical parameter space regarding the relevant drug-specific parameters (i.e. extent and type of plasma protein binding). As such, the presented analysis covers drugs that are currently in clinical use and other small molecule drugs that are still to be developed. Therefore, this framework can be used to make a priori assessments on the accuracy of the pediatric CL and dose-scaling methods for new drugs.
The current results are also in line with previous findings from our group comparing ‘true’ PBPK-based CL predictions with CL values scaled by both empirical methods; however, small differences in numerical results are present. These differences are caused by two different GFR maturation functions being used in the PBPK model for predictions of the ‘true’ CL values. For the current analysis, we used the function published by Salem et al. [
17], which we found to be most accurate, whereas, in the previous analyses, the function by Johnson et al. [
15] was used.
The conclusions from our analysis are based on typical individuals and do not take interindividual variability into account. For preterm and term neonates younger than 1 month, high variability in the inulin [
3,
4,
6] and mannitol [
2] CL data is observed, which poses a challenge when scaling CL and doses to this age range. This suggests that variables other than the demographics used in GFR maturation functions are predictive of GFR-based CL. For this special population, dosing recommendations that rely on empiric PK models of the same drug, even in slightly older children, or of a similar drug that is mainly eliminated through GF in the same population, may therefore offer a better alternative [
26,
27].
We emphasize that all published GFR maturation functions included in our analysis describe GFR maturation in pediatric individuals with normal renal function. These functions should therefore not be used for CL or dose scaling for pediatric patients with renal deficiencies. To account for renal impairment, functions that require a biomarker for renal function (e.g. creatinine, cystatin C, etc.) as input are more reliable and suitable to predict GFR. These functions can be implemented in the renal PBPK model in Eq. (
3) and can also be used for GFR-based scaling. The impact of ignoring plasma protein binding in these scenarios may not be the same as observed in the current analysis, as plasma protein binding may also be altered in patients with renal deficiencies.