Pharmetheus, Uppsala, Sweden.
UCB Pharma, Slough, UK.
J Clin Pharmacol. 2023 Apr;63(4):435-444. doi: 10.1002/jcph.2188. Epub 2023 Jan 9.
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.
系统性红斑狼疮（SLE）是一种全身性自身免疫性疾病，其特征为慢性炎症和器官损伤。达普利尤单抗 Pegol 抑制 CD40 配体（CD40L），目前正在进行治疗 SLE 的 3 期临床试验。为了描述达普利尤单抗 Pegol 的药代动力学特征以及暴露量与实现英国狼疮评估组综合狼疮评估（BICLA）应答概率之间的关系，根据达普利尤单抗 Pegol 在 SLE 中进行的 2 期试验（RISE；NCT02804763）的结果，建立了群体药代动力学（popPK）模型和暴露-反应模型。达普利尤单抗 Pegol 的药代动力学呈剂量比例关系，且可用 2 室模型很好地描述，其中中央室的药物消除呈一级动力学。在 popPK 模型中，体重是唯一具有显著意义的协变量。来自 popPK 模型的达普利尤单抗 Pegol 平均浓度被纳入暴露-反应模型。总体而言，暴露-反应模型表明，达普利尤单抗 Pegol 治疗可提高从 BICLA“非应答者”向“应答者”转变的概率。未确定 BICLA 应答者状态的显著协变量。值得注意的是，从“应答者”到“非应答者”的转变（150μg/ml）的半数有效浓度大于从“非应答者”到“应答者”的转变（12μg/ml），这表明可能需要维持达普利尤单抗 Pegol 的浓度以维持 BICLA 应答。总之，达普利尤单抗 Pegol 的药代动力学符合聚乙二醇化分子的预期，且暴露-反应模型的结果表明，达普利尤单抗 Pegol 具有良好的效果，可同时提高从 BICLA“非应答者”向“应答者”和从“应答者”向“非应答者”转变的概率。
