Assessment of dosing strategies for pediatric drug products

Abstract

Pediatric drug dosing is challenged by the heterogeneity of developing physiology and ethical considerations surrounding a vulnerable population. Often, pediatric drug dosing leverages findings from the adult population; however, recent regulatory efforts have motivated drug sponsors to pursue pediatric-specific programs to meet an unmet medical need and improve pediatric drug labeling. This paradigm is further complicated by the pathophysiological implications of obesity on drug distribution and metabolism and the roles that body composition and body size play in drug dosing. Therefore, we sought to understand the landscape of pediatric drug dosing by characterizing the dosing strategies from drug products recently approved for pediatric indications identified using FDA Drug Databases, and analyze the impact of body size descriptors (age, body surface area, weight) on drug pharmacokinetics for several selected antipsychotics approved in pediatric patients. Our review of these pediatric databases revealed a dependence on body size-guided dosing, with 68% of dosing in pediatric drug labelings being dependent on knowing either the age, body surface area, or weight of the patient to guide dosing for pediatric patients. This dependence on body size-guided dosing drives the need for special consideration when dosing a drug in overweight and obese patients. Exploratory pharmacokinetic analyses in antipsychotics illustrate possible effects of drug exposure when applying different dosing strategies for this class of drugs. Future efforts should aim to further understand the pediatric drug dosing and obesity paradigm across pediatric age ranges and drug classes to optimize drug development and clinical care for this patient population.

Introduction:

Drug dosing in the pediatric population is challenging. Pediatric patients are diverse in weight, height, body composition, organ/tissue development, and ontogeny related to drug disposition, all of which can complicate dose selection (1, 2). Furthermore, these challenges are compounded by the unique pathophysiological implications of obesity, and the ongoing obesity epidemic reinforces the need to determine safe and effective dosing strategies for obese pediatric patients (3–5). Recent work has provided some insight into how pediatric dosing regimens are being selected during drug development (6–8). However, little information is available regarding the landscape of dosing strategies for drugs approved for pediatric use and how these dosing strategies may be impacted by a patient’s body size. Therefore, the objectives of this study were to 1.) characterize dosing strategies of drugs approved for use in children, from 2012-present and 2.) analyze the impact of body size descriptors (body weight, body surface area [BSA]) on drug pharmacokinetics (PK) in pediatric patients.

Methods:

Identification of Pediatric Drug Approvals:

We reviewed publicly available databases to identify drugs approved for pediatric indications between the beginning of the Food and Drug Administration Safety and Innovation Act of 2012 and March 2022. These databases include 1.) the Reviews of Pediatric Studies Conducted under BPCA and PREA, (BPCA+PREA), 2.) the Pediatric Oncology Drug Approvals (ONC), and 3.) the Orphan Drug Designation and Approvals (ODDA) (Tables S1, S2). We then obtained original and current pediatric drug labelings (the most recent version at the time of our analysis in 2022) using Drugs@FDA. Data from each publicly available database were then merged into a single database. Initial review of the database excluded duplicate drug products with the same indication that were identified in more than one database and drug products with an approval date prior to 2012. Systematic removal of these drug products was performed in BPEA+PREA then ONC then ODDA. The same drug product with approval for multiple indications was not considered a duplicate and was included for analysis.

Characterization of Assigned Dosing Strategies:

The ‘Assigned Dosing Strategy’ for each drug product was categorized as shown in Table 1 and included Age Dosing, Biomarker, BSA Dosing, Flat, or Weight Dosing categories. The ‘Assigned Dosing Strategy’ was determined based on the ‘Approach to Dosing’ found in the labelings, which included Banded Dosing by Age, Biomarker, Banded Dosing by BSA, mg/m² Dosing, Flat, Banded Dosing by Weight, and mg/kg Dosing (Table 1). Drug labelings with non-systemic administration were excluded from the analysis because they generally use a flat dosing method, resulting in exclusion of 80 drugs from the analysis (10.2% of total identified).

Table 1:

Characterization of Assigned Dosing Strategies

Assigned Dosing Strategy	Approach to Dosing	Definition of Approach to Dosing	Example
Age Dosing	Banded Dosing by Age	The administered dose is stratified based on the patient’s age	Patients > 10 years: 20 mg Patients < 10 years: 10 mg
Biomarker	Biomarker	The administered dose is calculated from the quantity of a biomarker	Individualized dose amounts based on glucose levels
BSA Dosing	Banded Dosing by BSA	The administered dose is stratified based on the patient’s body surface area	Patients > 1 m2: 20 mg Patients < 1 m2: 10 mg
	mg/m2 Dosing	The administered dose follows a unit of drug per squared meter	10 mg/m2
Flat	Flat	The administered dose is a flat amount for all patients	10 mg
Weight Dosing	Banded Dosing by Weight	The administered dose is stratified based on the patient’s body weight	Patients > 50 kg: 20 mg Patients < 50 kg: 10 mg
	mg/kg Dosing	The administered dose follows a unit of drug per kilogram weight	10 mg/kg

Comparisons Between Pediatric and Adult Dosing Strategies Within the Current Drug Label:

The ‘Assigned Dosing Strategies’ for pediatric and adult patients within the current drug labelings were compared. For this comparison, the banded ‘Approach to Dosing’ was recategorized as either a flat (mg), mg/m², or mg/kg ‘Approach to Dosing’ to enable a comparison of the ‘Assigned Dosing Strategy’ between pediatric and adult labels rather than reflecting the use of the banded strategy. The dosage was considered “Changed” if the ‘Assigned Dosing Strategy’ (e.g., Flat vs BSA Dosing) was different between pediatrics and adults. The dosage was considered the same if the ‘Assigned Dosing Strategy’ was similar in both patient groups.

Comparisons of Assigned Dosing Strategies Between the Initial and Current Drug Labels:

Drugs with more than one version of labeling were identified using Drugs@FDA and the ‘Assigned Dosing Strategy’ in the initial label was compared to the ‘Assigned Dosing Strategy’ in the current label. A label was defined as “Changed” if it met one of the following criteria: 1.) Either the ‘Assigned Dosing Strategy’ or the ‘Approach to Dosing’ is different in the initial vs current drug labelings, 2.) the indication was expanded to include additional pediatric populations and it resulted in change(s) to the ‘Assigned Dosing Strategy’ or ‘Approach to Dosing’, or 3.) a formulation was added/or dropped (for the same indication) resulting in change(s) to the ‘Assigned Dosing Strategy’ or ‘Approach to Dosing’.

Investigation of Body Size on the Pharmacokinetics:

We sought to assess the impact of different dosing strategies on PK in pediatric patients (ages 6–18) of varying body sizes (age, BSA, weight) by conducting an exploratory PK analysis. Antipsychotics were selected for the PK analysis because they 1.) are typically administered as a flat dose to both pediatric and adult patients (meaning current dosing practices do not consider the patient’s body size thus allowing exploration of body size impact), 2.) are associated with an increased risk for weight gain, and 3.) can be described by a 1-compartment population PK model, which improves the feasibility of PK analysis. Therefore, clinical studies on antipsychotics provide the desirable demographics to explore the impact of body size on the PK in pediatric patients.

The submitted new drug applications were identified and subject-level pediatric population PK data submitted by the applicant with the marketing application were extracted. An initial review of the pediatric PK data determined that three submissions had the appropriate PK data (AUC or clearance, and used a 1-compartment population PK model) and demographics (age, sex, height, and weight). BMI and BSA were calculated from the above demographics (9). Simulated oral doses using a derived mg/kg and mg/m² dose were generated for all patients found in the three submissions. The administered dose for each patient was divided by either the total body weight (in kg) or BSA (in m²) for that patient to generate the mg/kg or mg/m² dose, respectively, for each patient. An average mg/kg or mg/m² ratio was determined for each drug. These ratios were then multiplied by each patient’s total body weight or BSA to generate the new estimated body size dose simulated for each patient. We used the original clearance to calculate the new AUCs for each patient. The dose amounts and calculated AUCs were then compared to 1.) the flat dose of the administered drug and 2.) the other body size based dosages.

Available PK data were exported and managed in JMP, version 16.2. JMP was also used for graphical analyses. Linear regressions were used to compare the continuous demographic variables (age, BMI, BSA, weight) to the AUC and clearance. Relative Change in AUC was calculated for each BMI Category using Equation 1.

$$\left(\text{AUC}-{\text{AUC}}_{\text{control}}\right)÷{\text{AUC}}_{\text{control}}$$ Equation 1

Where the mean AUC for normal BMI patients was used as the control/reference.

Dosing residuals were calculated by subtracting the original study dose from the mg/kg dose. This generates a positive value when the mg/kg dose is larger than the original administered study dose. Dosing residuals were plotted by BMI Category to assess the distribution of residuals. BMI categorization for the pediatric population was determined using percentile definitions assigned by PAutilities package in R Tool.

Results:

Drug Labeling Databases:

A breakdown of the number of pediatric drug labelings assessed is shown in Figure 1. The three databases identified a total of 1033 drugs approved between January 2012 – March 2022. The dosing strategy was characterized for 370 pediatric drug labelings after excluding duplicates and non-systemically administered drug products.

Figure 1:

Overview of Studied Databases and Drug Products. The BPCA+PREA database identified 465 drugs, the Pediatric Oncology Approvals database provided 73 publicly available drugs, and the Orphan Drug Designations and Approvals database identified 495 drugs. Applying the exclusion criteria resulted in characterizing 370 pediatric dosing strategies used in current drug labelings.

Characterization of Assigned Dosing Strategies:

The ‘Assigned Dosing Strategies’ used in current drug labelings are reported for pediatrics and adults in Table 2. For current pediatric drug labelings, the ‘Assigned Dosing Strategy’ was dependent upon the patient’s body weight for 198 (53.5%) of the 370 total drug products and dependent upon the patient’s BSA for 32 (8.6%) of the 370 total drug products. Overall, 252 (68.1%) of the 370 pediatric drug products based their ‘Assigned Dosing Strategy’ on a demographic variable that describes the patient’s body-size (age, BSA, weight) and pediatric ‘Approach to Dosing’ most commonly used banded dosing by age, BSA, and weight. For adults, only 89 (24.1%) products had dosing strategies that were dependent upon the patient’s weight and 20 (5.4%) adult dosing strategies were dependent upon the patient’s BSA; indicating that the majority of the ‘Assigned Dosing Strategies’ for adult labelings were independent of a patient’s body size, with 255 (68.9%) adult drug products using a flat dosing strategy. The ‘Assigned Dosing Strategy’ for both pediatric and adult drug labeling revealed just 6 (1.6%) drug products that utilize biomarker-based dosing.

Table 2:

Assigned Dosing Strategies for Current Pediatric and Adult Drug Labels:

	# of Drug Products	Age Dosing	Biomarker	BSA Dosing	Flat	Weight Dosing
Pediatric	370	22 (5.9%)	6 (1.6%)	32 (8.6%)	117 (31.6%)	198 (53.5%)
Adult	370	-	6 (1.6%)	20 (5.4%)	255 (68.9%)	89 (24.1%)

In addition, we analyzed the ‘Assigned Dosing Strategies’ by therapeutic area and molecule type in both pediatric (Table 3) and adult (Table 4) populations. These analyses showed that antineoplastics more commonly use a BSA Dosing approach in both pediatrics and adults.

Table 3:

Assigned Dosing Strategies for Pediatric Drug Labels by Therapeutic Area and Molecule Type

Category	# of Drug Products	Age Dosing	Biomarker	BSA Dosing	Flat	Weight Dosing
Therapeutic Area
Anti-Infectives	82	4		3	31	44
Antineoplastics	62		1	24	10	27
Blood, Cardiac, Metabolic Agents	30	1			11	18
Central Nervous System Agents	37	4			21	12
Immunosuppressives	26			2	3	21
Other	133	13	5	3	41	71
Total:	370 (100%)	22 (5.9%)	6 (1.6%)	32 (8.7%)	117 (31.6%)	193 (52.2%)
Molecule Type
Small Molecule	241	17	1	23	88	112
Biologics	101	1	4	9	21	66
Oligonucleotide	2				1	1
Contrast Agent	21	4			6	11
Other	5		1		1	3
Total:	370 (100%)	22 (5.9%)	6 (1.6%)	32 (8.7%)	117 (31.6%)	193 (52.2%)

Table 4:

Assigned Dosing Strategies for Adult Drug Labels by Therapeutic Area and Molecule Type

Category	# of Drug Products	Age Dosing	Biomarker	BSA Dosing	Flat	Weight Dosing
Therapeutic Area
Anti-Infectives	82				73	9
Antineoplastics	62		1	17	32	12
Blood, Cardiac, Metabolic Agents	30				19	11
Central Nervous System Agents	37				33	4
Immunosuppressives	26			1	14	11
Other	133		5	2	84	42
Total:	370 (100%)	0	6 (1.6%)	20 (5.4%)	255 (68.9%)	89 (24.1%)
Molecule Type
Small Molecule	241		1	13	192	35
Biologics	101		4	7	47	43
Oligonucleotide	2				1	1
Contrast Agent	21				14	7
Other	5		1		1	3
Total:	370 (100%)	0	6 (1.6%)	20 (5.4%)	255 (68.9%)	89 (24.1%)

Changes to Dosing Strategies

A comparison of the ‘Assigned Dosing Strategy’ in children versus adults found that 66 (17.8%) of the 370 drug products dosed drugs differently for pediatric patients compared to adult patients.

The ‘Assigned Dosing Strategy’ used at the initial time of approval was compared to the ‘Assigned Dosing Strategy’ in the current drug labeling. If only one version of the drug labeling was available at the time of our analysis we considered the ‘Assigned Dosing Strategy’ to be unchanged. This assessment showed that 33 (8.9%) of the 370 drug products made changes to their ‘Assigned Dosing Strategy’ between the time of approval and the time of our analysis. The most frequent cause of this change (N=26, 78%) resulted from a new formulation being available for the drug product, resulting in a change to the ‘Approach to Dosing.’ Three drug products received changes to their ‘Assigned Dosing Strategy’ after dropping previous formulations or indications. Only four (12%) ‘Assigned Dosing Strategy’ had changes improve dosing in pediatric patients that were not related to the formulation.

Investigation of Body Size on the Pharmacokinetics:

PK data were obtained from pediatric and adolescent clinical studies involving the use of either aripiprazole, asenapine, and quetiapine. The coefficient of determination (R²) is reported for the relationship between body size (age, BSA, weight) and AUC for each drug product (Table 5). The AUC for each drug product decreases with increasing body size. The strongest effect of body size on AUC was reported for aripiprazole, with a R² of at least 0.21. The impact of BMI on AUC was evaluated for each drug product. The relative difference in AUC for underweight, overweight, and obese pediatric patients were compared to a normal BMI (Figure 2). Overall, AUC was similar across weight categories and only minor numerical differences were observed with the exception of underweight patients treated with aripiprazole; however, this group only included two patients.

Table 5:

Effects of Body Size and Drug AUC

	Aripiprazole	Asenapine	Quetiapine
↑ Age (R2)	↓ AUC (0.21)	↓ AUC (0.01)	↓ AUC (0.04)
↑ Body Mass Index (R2)	↓ AUC (0.17)	↓ AUC (0.02)	↑ AUC (0.20)
↑ Body Surface Area (R2)	↓ AUC (0.24)	↓ AUC (0.02)	↓ AUC (0.06)
↑ Body Weight (R2)	↓ AUC (0.25)	↓ AUC (0.02)	↓ AUC (0.06)

Figure 2:

Effects of body mass index and relative change in AUC compared to normal BMI patients. The AUC was calculated using the equation: AUC=Dose/CL. Next, the mean AUC for Normal BMI patients was used as the control/reference to determine the relative change in AUC for each of the BMI Categories. The black circles are the mean relative change in AUC for each group. The whiskers are one standard deviation above and below the mean. The black vertical line represents the zero-line, or no relative change in AUC compared to normal BMI patients. BMI was calculated using the equation: TBW/(Height²). The BMI categories used the pediatric CDC percentile definitions.

Application of Body-Size Based Dosing:

Simulated doses using a derived mg/kg and mg/m² dose were performed for all patients (ages 6–18) receiving either aripiprazole, asenapine, and quetiapine. The results of this exercise show that mg/kg dosing generates a larger simulated dose compared to mg/m² dosing for both aripiprazole and asenapine (Figure S1A, SB). Both mg/kg and mg/m² dosing provided similar dose amounts for quetiapine (Figure S1C). The estimated AUC derived from both the mg/kg and mg/m² dosing are compared in Figure S2. The linear regressions for aripiprazole show a near-zero slope when applying the mg/m² dose across the ages, weights, and BSAs whereas the mg/kg dose generates increasing AUCs with increasing ages, weights, and BSAs (Figure S2A). Similar observations are made when evaluating the mg/kg and mg/m² AUCs for quetiapine (Figure S2B). However, both mg/kg and mg/m² AUCs increase with increasing ages, weights, and BSAs for asenapine (Figure S2C).

The principle of mg/kg and mg/m² dosing is to provide a constant ratio of drug across body sizes. We observed that a simulated mg/kg dose led to a greater number of dosing residuals greater than +/− 20% from the administered study dose compared to a mg/m² dose for overweight and obese patients (Figure S3). For mg/kg dosing of aripiprazole, 36 (66.7%) of the 54 total patients had a dosing residual greater than +/− 20% from the administered study dose. Of these 36 patients, 15 (41. 7%) patients were categorized as either overweight or obese. However, only 27 (50%) of the 54 patients had a dosing residual greater than +/− 20% from the administered dose when using a mg/m² dose. Of these 27 patients, 10 (37%) patients were categorized as either overweight or obese.

The mg/kg dosing of asenapine resulted in 102 (53.1%) of the 192 total patients with dosing residuals greater than +/− 20% from the administered study dose. Of these 102 patients, 52 (50.1%) patients were categorized as either overweight or obese. This compares to just 49 of the 192 (25.5%) total patients with dosing residuals greater than +/− 20% from the administered study dose when applying a mg/m² dose. Of these 49 patients, 30 (61.2%) patients were categorized as either overweight or obese.

Finally, the mg/kg dosing of quetiapine resulted in 7 of the 24 total patients with dosing residuals greater than +/− 20% from the administered study dose. Of these 7 patients, 5 (71.4%) patients were categorized as either overweight or obese. The mg/m² dosing of quetiapine resulted in only 4 of the 24 (16.7%) patients with dosing residuals greater than +/− 20% from the administered study dose. All 4 patients were categorized as either overweight or obese.

Discussion:

The purpose of this project was to 1.) characterize the pediatric dosing strategies from drug products available in the BPCA+PREA, ONC, and ODDA databases over the last ten years and 2.) analyze the impact of body size descriptors (age, body weight, BSA) on drug PK in pediatric patients.

The current landscape of pediatric dosing strategies seems to favor the use of body size descriptors, with roughly 68% of pediatric drug products being dependent upon knowing either the age, weight, or BSA to guide pediatric drug dosing (Table 2). This is nearly double the number of drug products that use a body size descriptor to guide dosing for the same drugs in adults (30%). The use of a flat dose in adults stands to reason given that the variability in body sizes in adults is less than that for pediatric patients (10). The ‘Assigned Dosing Strategy’ for both pediatric and adult drug labeling revealed only a small minority of drug products utilize biomarker-based dosing; these drug products are all cardiometabolic agents that adjust dosing based on metabolic needs and glycemic control, indicating this dosing strategy is rarely used except in cases where there are clinically relevant biomarkers and a need for precise dosing.

Despite the differences in body size variability between pediatric and adult patients and the understanding that pediatrics are not small adults (11, 12), it is interesting to note that 66 (17.8%) drug labelings differ in the dosing strategy between pediatrics and adults. The difference in the dosing strategy is less than the expected 38% because the pediatric ‘Approach to Dosing’ most frequently uses banded dosing by age, BSA, or weight. After further characterizing the banded dose to either a flat [mg], mg/m², or mg/kg dose, we identified 66 drug labels that differ in the ‘Assigned Dosing Strategy’ between pediatrics and adults. These data show that pediatric dosing strategies generally follow those used in adults and highlights the need for more data on dosing strategies in pediatrics to ensure that the dosage regimens used are adequate for this unique population.

Another aspect of the data collection for the dosing strategies was comparing the ‘Assigned Dosing Strategy’ used at the time of the initial pediatric approval to the ‘Assigned Dosing Strategy’ used for the current pediatric drug label. The rationale behind collecting these data was to determine the percentage of drug products that have received an updated dosing strategy since the initial approval. Our data reveals that 33 (11%) pediatric dosing strategies received an updated dosing strategy since the initial pediatric approval. This means that 89% of the initial pediatric dosing strategies at the time of approval continue to be acceptable dosing strategies. It is important to note that the comparisons between the initial pediatric approval and current drug labeling are of dosing strategies only; therefore, if the actual administered dose amount changed, but the ‘Assigned Dosing Strategy’ or ‘Approach to Dosing’ did not change, then our analysis would observe no change over time.

An increasing prevalence of pediatric obesity across the United States creates a growing concern that overweight and obese pediatric patients could be receiving unoptimized care (3–5, 13, 14). Given the increasing diversity of pediatric body sizes, dosing strategies that administer a flat dose across all body sizes should be assessed to determine if the estimated AUC of the drug is consistent across body sizes and body compositions within the real-world population. We explored these relationships using available PK data from pediatric patients (ages 6–18) receiving one of three selected antipsychotics. As shown in our dosing exercises, aripiprazole, asenapine, and quetiapine displayed marginal decreasing AUCs with increasing body size (Table 5). While these are weaker associations, this could suggest that administering a flat dose to larger pediatric patients may increase their risk for subtherapeutic exposure. Similarly, we observed that flat dosing may also increase the risk of overexposure for underweight patients when comparing the BMI to AUC – this was observed in our underweight patients receiving aripiprazole (Figure 2). This relationship between body size and drug exposure also emphasizes the need for the purposeful inclusion of overweight and obese pediatric patients as a special population within the drug development process (14), which was the topic discussed during a one-day virtual public workshop entitled “Bridging Efficacy and Safety to the Obese: Considerations and Scientific Approaches” hosted by the FDA in collaboration with the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI). Despite the observed trend that quetiapine AUC decreases with increasing body size, we also observed that overweight and obese patients demonstrated an increase in the relative change in AUC compared to normal BMI patients (Figure 2). These data are consistent with the recent findings that CYP3A4 (the major metabolic enzyme for quetiapine metabolism) activity decreases with increasing body weight (15) and highlights the importance of discerning the impact of body size and body composition on drug PK, and subsequently efficacy, and safety (3, 14, 16, 17). The pathophysiological implications of obesity can affect many prominent organ systems responsible for a drug’s PK (4, 5, 13, 14). However, there are not currently clear guidelines on when drug developers would need to include such a special population.

Conversely, dosing strategies that guide dosing based on a patient’s body size could increase the risk of overdosing a pediatric patient given that a larger body size will lead to larger administered doses. As observed in the aripiprazole, asenapine, and quetiapine simulated dosing exercises, mg/kg dosing increased the administered dose and estimated AUC with increasing body size compared to mg/m² dosing (Figure S1). These findings are consistent with the notion that mg/m² dosing offers a more conservative dosing strategy (18, 19). This principle is often a governing factor for mg/m² dosing for antineoplastics (16). The mg/m² dose for aripiprazole was able to generate somewhat steady AUCs across body sizes (Figure S2A). Similarly, mg/kg and mg/m² dosing for quetiapine was able to generate somewhat steady AUCs across body sizes while neither mg/kg nor mg/m² dosing was able to provide such a relationship between estimated AUC and body size for asenapine (Figure S2).

When applying these dosing strategies to overweight and obese patients, we observed that the mg/kg dosing led to a greater number of dosing residuals that were more than +/− 20% from the administered study dose compared the mg/m² dosing (Figure S3).

Limitations to consider when evaluating the results from the exploratory PK analyses are that the original PK for asenapine was characterized by a 2-compartment PK model whereas aripiprazole and quetiapine were both characterized by a 1-compartment PK model. The calculation of AUC used in our exploratory PK analysis is more appropriate for drugs that are described by 1-compartment kinetics compared to 2-compartment kinetics; however, these findings are not limited to drug’s that are described by a 1-comaprtment pharmacokinetic model. The available drug data did not include exposure-response data nor targeted AUC threshold; therefore, we can neither determine whether the relationship between body size and AUC impacted therapeutic response nor whether body size dosing would improve target attainment. Additionally, the clinical studies for these selected antipsychotics did not include pediatric patients less than 6 years old. Subsequent work is needed to explore these effects in younger pediatric patients. Furthermore, the three selected antipsychotics were chosen in part because they used an ‘Assigned Dosing Strategy’ of flat. These enabled comparisons of both mg/kg and mg/m² dosing; however, these data do not support the use of either mg/kg or mg/m² over flat dosing for antipsychotics nor support the use of one body-size dosing strategy over the other. Lastly, this investigation on PK did not utilize alternative definitions of body size (i.e., ideal body weight, fat-free mass, lean body weight, adjusted body weight, or percent ideal body weight)(9) nor pharmacometric approaches. Future works should explore the impact of various definitions of body size on dosing strategy and PK using pharmacometric approaches, like physiology-based PK modeling, to further characterize these effects (20, 21).

Overall, the landscape of pediatric drug dosing over the past 10 years illustrates the dependence on body size guided dosing, with 68% of pediatric labels being dependent on knowing either the age, BSA, or weight of the patient to guide dosing for pediatric patients. Given this dependence, additional efforts might have to be directed toward further understanding the pediatric drug dosing and obesity paradigm to optimize drug development and clinical care for this patient population.

Study Highlights:

What is the current knowledge on the topic?

• Dose selection in the pediatric population is an evolving science that is challenged by the heterogenous growth and development of this population.

What question did this study address?

• This study characterizes the current landscape of pediatric dosing strategies including how they compare to adult dosing strategies and how they change over time, and explores the impact of body size on dosing outcomes.

What does this study add to our knowledge?

• This study found that 68% of pediatric dosing strategies include age, weight, or BSA compared to just 30% of adult dosing strategies. These dosing strategies appear to agree between pediatric and adult products and display little change after their initial approval.

How might this change clinical pharmacology or translational science?

• The use of body size to inform drug dosing could pose a challenge for overweight and obese patients. This study adds to our understanding of the impact of body size on pediatric dosing and may help shape future studies of dosing strategies in pediatric patients.