Approval of pediatric drug indications lags behind approvals for adults and although the reasons behind the lag time are complex [i] one hurdle is the transition from adult to pediatric dosing regimens.
Model-based simulations within a pediatric population can help address this gap. In Ly et al., Amador Bioscience’s Chief Scientific Officer Lorin Roskos and his co-authors identified a dosing strategy for adolescents <40 kg when treated with cabozantinib for radioiodine‑refractory differentiated thyroid cancer, despite the lack of available data on this drug in a pediatric population.[ii]
To accomplish this, they first developed a population pharmacokinetic (popPK) model from 4746 quantifiable cabozantinib PK samples from 1745 individuals across 7 studies. This model was then applied to a simulated population of adolescent patients. This simulated population was sampled from a normal distribution of body weight ranges based on age and sex using the Centers for Disease Control and Prevention (CDC) weight-for-age pediatric data.
Using allometric scaling to account for the non-linear changes in weight with age the popPK model was applied to the simulated pediatric cohort using the 60 mg daily dosing used in adults. The authors found an elevated AUC, Cmin, and Cmax in the simulated individuals < 40 kg. Decreasing the dose to 40 mg in the < 40 kg individuals brought these measures back within the 90% predictive interval for comparative adult concentrations. Subsequent exposure-response (ER) modeling using the modified 40 mg dosing for the < 40 kg groups predicted that treatment efficacy was maintained while also limiting adverse events to a tolerable level. These simulations supported the approved cabozantinib labeling for adolescent patients with DTC.
[i] Speer EM, Lee LK, Bourgeois FT, Gitterman D, Hay WW Jr, Davis JM, Javier JR. The state and future of pediatric research-an introductory overview: The state and future of pediatric research series. Pediatr Res. 2023 Jan 24:1–5.
[ii] Ly NS, Li J, Faggioni R, Roskos LK, Brose MS. Population Pharmacokinetics and Exposure-Response
Analysis for the Phase 3 COSMIC-311 Trial of Cabozantinib for Radioiodine-Refractory Differentiated Thyroid
Cancer. Clin Pharmacokinet. 2023 Apr;62(4):587-598.