Drugs Being Eliminated via the Same Pathway Will Not Always Require Similar Pediatric Dose Adjustments

Abstract

For scaling drug plasma clearance (CLp) from adults to children, extrapolations of population pharmacokinetic (PopPK) covariate models between drugs sharing an elimination pathway have enabled accelerated development of pediatric models and dosing recommendations. This study aims at identifying conditions for which this approach consistently leads to accurate pathway specific CLp scaling from adults to children for drugs undergoing hepatic metabolism. A physiologically based pharmacokinetic (PBPK) simulation workflow utilizing mechanistic equations defining hepatic metabolism was developed. We found that drugs eliminated via the same pathway require similar pediatric dose adjustments only in specific cases, depending on drugs extraction ratio, unbound fraction, type of binding plasma protein, and the fraction metabolized by the isoenzyme pathway for which CLp is scaled. Overall, between-drug extrapolation of pediatric covariate functions for CLp is mostly applicable to low and intermediate extraction ratio drugs eliminated by one isoenzyme and binding to human serum albumin in children older than 1 month.

Figure 1

Schematic representation of the complex interplay between drug‐specific and system‐specific parameters driving hepatic CLp values. Parameters within circles are directly used in the physiologically based pharmacokinetic hepatic clearance model (e.g., dispersion model). Parameters in the purple circles represent composite parameters that are derived from the system‐specific parameters and the drug‐specific parameters indicated by the numbers in the subscripts. In children, each of the system‐specific parameters change with age, each represented by a lightning bolt. B:P, blood to plasma ratio; CLint, intrinsic metabolic clearance in the liver based on unbound drug concentrations; fu, unbound drug fraction in plasma; MPPGL, microsomal protein per gram of liver.

Figure 2

Illustration of between‐drug extrapolation of pediatric covariate functions to scale hepatic plasma clearance (CLp) from adults to pediatric patients for drugs eliminated by the same isoenzyme. The black dot in both graphs shows the adult hepatic CLp value for the model drug (“true” adult CLp_M) and the test drug (“true” adult CLp_T). The solid black line represents the change in CLp of the model drug throughout the pediatric age range, which is described by a pediatric covariate function based, in this example, on bodyweight (CLp ontogeny_M (bodyweight)). The dashed black line represents the scaled pediatric CLp predicted for the test drug by between‐drug extrapolation of the pediatric covariate function obtained for the model drug (CLp ontogeny_M (bodyweight)).

Figure 3

Physiologically based pharmacokinetic (PBPK)‐based simulation workflow used to investigate the between‐drug extrapolation potential of pediatric covariate models when scaling total plasma clearance (CLp) from adults to pediatric patients. The model drug is denoted with M and the test drug with T. AGE stands for pediatric postnatal age. All steps are performed for model drugs and test drugs binding to the same plasma proteins and eliminated by the same isoenzyme and repeated for each of the 15 isoenzymes and each of the 2 binding plasma proteins investigated.

Figure 4

The prediction error (PE) of the total (bound and unbound) drug plasma clearance (CLp) predictions for scenarios in which model and test drugs are exclusively metabolized by one isoenzyme (fmA_adult = 100%) and exclusively binding to human serum albumin (a) or to alpha‐1 acid glycoprotein (b). The boxplots represent the minimum, firth quartile, median, third quartile, and maximum PE and are categorized by low (green), intermediate (blue), and high (pink) adult extraction ratio (ER) of the model drug and low (light color), intermediate (intermediate color), and high (dark color) adult extraction ratio of the test drug. For each age, the lowest, intermediate, and highest isoenzyme ontogeny values (percentage of adult CLint,mic) reported for the 15 isoenzymes are shown. The intermediate isoenzyme ontogeny was defined as the isoenzyme ontogeny value the closest to the mean of the lowest and highest isoenzyme ontogeny values for a specific age. Low, intermediate, and high extraction ratio correspond to extraction ratio ≤30%, 30% < extraction ratio ≤70% and extraction ratio >70%, respectively. The vertical solid black line indicates a PE of 0. The dotted black and dotted red lines indicate PE intervals of +/‐ 30% and +/‐ 50%, respectively. Note that the x‐axes are different for different ages.

Figure 5

Illustration of model‐test drug scenarios that lead to accurate pathway‐specific drug plasma clearance (CLp) predictions for a test drug after between‐drug extrapolation of a pathway‐specific pediatric covariate function. Results are presented for drugs that are metabolized by CYP3A4 and that bind to human serum albumin (a) or alpha‐1 acid glycoprotein (b). Each column correspond to a range of extraction ratio (ER) values for the model drug in adults and each row to a specific range of fraction of drug (model and test drug) that is metabolized by CYP3A4 in adults. For each graph, the y‐axis represents the difference in extraction ratio between the test drug and the model drug (extraction ratio test drug – extraction ratio model drug) in adults, and the x‐axis represents the difference in unbound fraction in plasma between the test drugs and the model drug in adults (unbound fraction test drug – unbound fraction model drug). Each dot represents a model‐test drug scenario, including multiple model‐test drug combinations. A color code is used to indicate systematically accurate CLp predictions for all model‐test drug combinations within a model‐test drug scenario, for children ≥5 years (yellow), ≥2 years (pink), ≥1 year (blue), ≥6 months (orange), ≥1 month (purple), and ≥1 day term neonates (green). Red dots indicate model‐test drug scenarios leading to inaccurate predictions in children older than 5 years for at least one model‐test drug combination within the model‐test drug scenario. As an example, systematically accurate CLp scaling in children of 6 months and older is represented by the combination of the green, purple, and orange dots.