Pharmacokinetic and Exposure-Response Analyses for Extrapolation of Efficacy of Adalimumab in Adolescent Patients with Hidradenitis Suppurativa
Ahmed Nader (1), Ben Kluender (2), Colleen Wegzyn (1), Nisha V Kwatra (1), Nael M Mostafa (1)
(1) AbbVie Inc, North Chicago, IL, United States, (2) AbbVie Deutschland GmbH & Co KG, Ludwigshafen, Germany
Objectives: As a clinical trial in adolescents with hidradenitis suppurativa (HS) was not feasible due to the rarity of HS in this population, pharmacokinetic (PK) and exposure-response (E-R) analyses were performed to allow extrapolation of adalimumab (ADA) efficacy and support dosing recommendation in adolescent HS patients (pts) using PK and efficacy data from adult HS pts and PK data from other pediatric populations.
Methods: A population PK model was developed based on ADA PK data (524 pts aged 2-17 years) in other pediatric indications (pediatric psoriasis, crohn’s disease, polyarticular juvenile idiopathic arthritis, and enthesitis-related arthritis). PK simulations were performed to predict a dosing regimen for adolescent HS pts that would achieve concentrations similar to those observed in adult HS pts. ADA serum concentrations and HS Clinical Response (HiSCR) rates from adult HS Phase 3 studies were used to develop an E-R model for ADA in adult HS pts. Assuming a similar E-R relationship between adult and adolescent HS pts, the model was used to predict clinical outcomes in adolescent HS pts.
Results: Disease indication was not found to be a significant factor affecting ADA PK, suggesting that ADA PK in adolescent HS pts can be extrapolated from other pediatric populations. Simulation results showed that predicted ADA steady state concentrations (mean±SD) in adolescent HS pts (8.4 ± 5.2 μg/mL) were similar to those observed in adult HS pts (8.8 ± 6.3 μg/mL) at a dosing regimen of 80 mg(Week 0), then 40 mg every other week (eow) (from Week 1). Results of the simulations based on the developed E-R model showed that the predicted HiSCR rates in adolescents were 55% and 28% after 12 weeks of ADA treatment (80 mg, then 40 mg eow) and placebo, respectively. These rates were similar to the overall response rates observed for adults in the Phase 3 HS studies (51% and 27% after 40 mg every week and placebo dosing, respectively).
Conclusions: Population PK and E-R modeling and simulation analyses enabled extrapolation of ADA efficacy from adults to adolescent HS pts in the absence of clinical trial data in the adolescent HS population. Based on the predicted ADA concentration and efficacy in adolescent HS pts, a dosing regimen of 80 mg at Week 0 and 40 mg eow is expected to provide similar ADA exposure and efficacy in adolescent HS pts to those observed in adult HS pts.