(SLC-028) Application of Pharmacokinetic Models in Real-World Data to Estimate Therapeutic Concentration in Pediatric Pharmacoepidemiology

Background: In pediatrics weight-based dosing is common, but pharmacoepidemiology studies using real-world data often assess therapeutic effectiveness using dose without considering weight. Pharmacokinetic (PK) models have the potential to improve pharmacoepidemiology studies of therapeutic effectiveness, however, the lack of information on weight in administrative claims data has been a barrier to uptake of these methods.

Objectives: To impute weight into claims data using age-based weight estimation methods, and to calculate, using a published PK model, the therapeutic concentration of methylphenidate extended-release (ER) in youths with attention deficit-hyperactivity disorder (ADHD).

Methods: The study population was youths 5-17 years-old who were diagnosed with ADHD and received methylphenidate ER. We used the 2015-2016 and 2017-2018 National Health and Nutrition Examination Survey, a US household survey that collects information on weight, to construct test and validation datasets to assess the performance of the CDC Clinical Growth Chart age-based weight estimation. We reported performance using three measures: (1) Pearson correlation coefficient (actual versus imputed weight), (2) percent error (i.e., mean difference between actual and imputed weight divided by actual weight), and (3) accuracy (i.e., the proportion of imputed weight within a 30-50% threshold of actual weight). We imputed weight in a similar real-world cohort derived from a 25% random sample of the IQVIA PharMetrics® Plus for Academics database. Applying a PK model for methylphenidate ER from published literature, we used the imputed weight and average daily dose to estimate the therapeutic concentration as ng/mL.

Results: The age-based weight estimation had a Pearson correlation coefficient of 0.76, percent error of –8.0 (range: -24.2 -5.1), and an accuracy of 80% (30% threshold) and 96% (50% threshold). We imputed weight in real-world data for 1196 youth with ADHD who were treated with methylphenidate ER. The imputed weights ranged from 18-65kg with means by age of 26 (ages 5-9), 39 (ages 10-13), and 56 (ages 14-17). The estimated therapeutic concentrations of 2.6 to 24 ng/mL were within levels reported in previous PK studies. At the same daily dose, children aged 5-13 had a higher therapeutic concentration than adolescents aged 14-17 (median=8.1 (6.7-11.0) versus 7.4 (4.8-9.6)).

Conclusions: Therapeutic concentrations estimated using PK models can provide a nuanced measure of dose exposure, particularly for young children. Applied to pharmacoepidemiologic studies, this has the potential to enhance real-world evidence of therapeutic safety and effectiveness.