Population Pharmacokinetics and Exposure-Response for Dapirolizumab Pegol From a Phase 2b Trial in Patients With Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a systemic, autoimmune disease characterized by chronic inflammation and organ damage. Dapirolizumab pegol inhibits CD40 ligand (CD40L) and is currently undergoing phase 3 trials for the treatment of SLE. To describe the pharmacokinetic characteristics of dapirolizumab pegol and the relationship between exposure and probability of achieving a British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response, a population pharmacokinetic (popPK) model and an exposure-response model were developed, based on results of the phase 2b trial (RISE; NCT02804763) of dapirolizumab pegol in SLE. Dapirolizumab pegol pharmacokinetics were found to be dose proportional and well described by a 2-compartment model with first-order elimination from the central compartment. In the popPK model, body weight was the only significant covariate. The average concentration of dapirolizumab pegol, derived from the popPK model, was incorporated into the exposure-response model. Overall, the exposure-response model showed that treatment with dapirolizumab pegol increased the probability of transitioning from BICLA "Nonresponder" to "Responder." No significant covariates on BICLA responder status were identified. Notably, the half maximal effective concentration was greater for the transition from "Responder" to "Nonresponder" (150 µg/mL) than the transition from "Nonresponder" to "Responder" (12 µg/mL), indicating that sustained dapirolizumab pegol concentrations may be required to maintain BICLA response. In conclusion, dapirolizumab pegol pharmacokinetics were as expected for a PEGylated molecule and results from the exposure-response model indicate that a favorable dapirolizumab pegol effect was identified for both BICLA "Nonresponder" to "Responder" and "Responder" to "Nonresponder" transition probabilities.