Sandra Grañana Castillo1, Samantha Ribeiro1, Diansong Zhou2, Lindsay Clegg3, Weifeng Tang3, Pradeep Sharma4
1Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, 2Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, 3Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, 4Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D
Introduction Paediatric dose optimization is essential due to the physiological differences between children and adults. Given the variability in children’s weights, dosing often relies on adjustment by body weight (BWT) or body surface area (BSA) methods. However, there is no consensus on the optimal approach, nor is it clear whether BWT and BSA dosing yield comparable drug exposure and can be used interchangeably. This study hypothesizes that BWT and BSA dosing may result in similar drug exposure in children with healthy weights but might differ in extreme weights. Methods In this study, we selected itraconazole, azithromycin, and raltegravir for analysis using Simcyp (v23.2) to refine and validate physiologically based pharmacokinetic (PBPK) models for children aged 6-12 years. These models were adapted from adult models and optimized using clinical data specific to children. Initially, we used BWT for dosing, with clinical doses of 5 mg/kg for azithromycin oral solution, 2.5 mg/kg for itraconazole oral solution, and 12 mg/kg for raltegravir chewable tablet. We simulated 5000 paediatric subjects for each drug, extracting the area under the curve (AUC) at steady state. We simulated the same clinical studies using BSA for dosing. The BSA doses were recalculated based on the average BWT of the simulated children using the formula (average BWT × dose/BWT) / average BSA; where average BWT was 28 kg and average BSA was 1.02 m2. Both values were obtained through Simcyp; in which BSA is calculated using the Du Bois equation (for children >15 kg). The resulting BSA doses were 146.46 mg/m² for azithromycin, 69.06 mg/m² for itraconazole, and 330 mg/m² for raltegravir. Subjects were categorized according to CDC BMI percentiles into <5th percentile, median (5-95th percentile, and >95th percentile groups. AUC comparability was evaluated using an AUC ratio (AUC from dose based on BSA/AUC from dose based on BWT) of 0.8-1.25 range to determine equivalence. Results This study evaluated the comparability of AUC values for itraconazole, azithromycin, and raltegravir using BWT and BSA dosing methods across different BMI categories. For itraconazole, 91.2% of median weight children showed comparable AUCs between the BWT and BSA dosing methods. Among 5th percentile children, the comparability was 57.6%, while 95th percentile children showed 69.4% comparability, with a positive correlation of R² = 0.85. In azithromycin, 99.6% of healthy-weight children achieved similar AUCs with both dosing methods. Comparability rates for 5th and 9th percentile children were 67.8% and 94.4%, respectively, with a strong correlation of R² = 0.96. Raltegravir results indicated that 99.2% of median weight children had comparable AUCs between dosing strategies. 5th percentile children showed 92.5% comparability, while 95th percentile children demonstrated an 84.7% rate, with a strong correlation of R² = 0.96. Overall, across all three drugs, all simulated children’s AUC ratio values were within a 0.5-2-fold range. This indicates that differences in drug exposure in children (6-12 age) would likely not be significant using either method. Discussion Our findings underscore that BWT and BSA dosing approaches are largely interchangeable for median weight children (age 6-12), with slightly less fit in 5th and 95th percentile subjects, although these were minimal as none of the simulated children had an AUC ratio outside the conventional 0.5-2-fold. A study by Hughes et al. (1) compared BSA and BWT strategies for dosing growth hormone in which doses could be accurately converted between formats. However, BSA-based dosing led to a diminished response as children gain weight, compared to BWT-based dosing. While the best dosing strategy for growth hormone is still debated, both approaches are generally considered comparable, with significant differences mainly occurring in extreme weight cases (2). The correlation between AUCs following dosing based on BWT and BSA was strong across all drugs, as reflected by high R² values. This suggests that both methods can be appropriate, in some cases dosing based on BSA might be superior to BWT depending on the drug (3). The choice may be influenced on age population and the drug’s ADME/PK properties and therapeutic index. Simulations used exact dosing by BWT or BSA, but clinical studies round doses to the nearest amount, adding variability. However, simulations maintained a continuous relationship with both methods. In addition, further efforts should be focused on other age ranges (e.g. neonates or infants) which might have larger physiological differences due to maturation (4) to identify if this correlation applies and also increasing the number of studied drugs.
1. Hughes et al. 2013 (10.1111/cen.12315) 2. Ranke et al. 2013 (10.1159/000347121) 3. Pan et al. 2016 (10.2147/PPA.S103156) 4. van de Anker et al. 2018 (10.1002/jcph)
Reference: PAGE 33 (2025) Abstr 11453 [www.page-meeting.org/?abstract=11453]
Poster: Drug/Disease Modelling - Absorption & PBPK