Li Qian, Qiao Ju, Jin Hongzhong, Chen Benchao, He Zhimei, Wang Guoqin, Ni Xiang, Wang Max, Xia Michelle, Li Baiyong, Chen Rui, Hu Pei
Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Dermatology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, National Clinical Research Center for Dermatologic and Immunologic Diseases, Beijing, China.
Front Pharmacol. 2022 Aug 16;13:966176. doi: 10.3389/fphar.2022.966176. eCollection 2022.
AK111 is an innovative IL-17A antibody, presenting high affinity to IL-17A and showing similar pharmacokinetic (PK) characteristics to those of typical immunoglobulin (Ig) G1 antibodies. To optimize the dosage regimen for phase 2/3 clinical trials, PK and pharmacodynamics (PD) of AK111 were first characterized in Chinese moderate-to-severe plaque psoriasis patients in a phase 1b study. AK111 PK serum sample and Psoriasis Area and Severity Index (PASI) score data were collected from 48 moderate-to-severe psoriasis patients in this study. Non-linear mixed-effects modeling was used for the population PK/PD analysis. A one-compartment model with a first-order absorption and a first-order elimination best described the PK behavior of AK111. The apparent systemic clearance was 0.182 L/day, and the central volume was 6.65 L. The exposure-response relationship was characterized using an indirect response model. The pharmacological effect of AK111 was described in the form of inhibiting the formation of psoriatic plaque, whereas placebo was quantified in the form of promoting the degradation of psoriatic skin lesions. The maximum effect of drug effect (I) and placebo effect (PLB) was 1 and 0.429, respectively. The rate constant for psoriatic plaque production (K) was 0.474 PASI/day and psoriatic plaque loss (K) was 0.024 day. The body surface area (BSA) affected by psoriasis was identified as a significant covariate on . The simulation results confirmed that all of the predicted PASI90 response rates at week 12 were higher than 60% at 150 and 300 mg dose levels with different regimens and could reach higher than 80% at week 24. We hope this first PK/PD study of AK111 in Chinese moderate-to-severe plaque psoriasis patients will be of help in the further clinical development of AK111 and provide a reference to the dosage optimization for similar antibodies with a long half-life.
AK111是一种创新型白细胞介素-17A（IL-17A）抗体，对IL-17A具有高亲和力，且其药代动力学（PK）特征与典型免疫球蛋白（Ig）G1抗体相似。为优化2/3期临床试验的给药方案，在一项1b期研究中，首先对中国中重度斑块状银屑病患者的AK111的PK和药效学（PD）进行了表征。本研究从48例中重度银屑病患者中收集了AK111的PK血清样本和银屑病面积及严重程度指数（PASI）评分数据。采用非线性混合效应模型进行群体PK/PD分析。具有一级吸收和一级消除的单室模型最能描述AK111的PK行为。表观全身清除率为0.182升/天，中央室容积为6.65升。采用间接反应模型表征暴露-反应关系。AK111的药理作用以抑制银屑病斑块形成为形式进行描述，而安慰剂则以促进银屑病皮损降解为形式进行量化。药物效应（I）和安慰剂效应（PLB）的最大效应分别为1和0.429。银屑病斑块产生的速率常数（K）为0.474 PASI/天，银屑病斑块消失的速率常数（K）为0.024/天。受银屑病影响的体表面积（BSA）被确定为关于……的显著协变量。模拟结果证实，在不同给药方案下，150毫克和300毫克剂量水平在第12周时所有预测的PASI90缓解率均高于60%，在第24周时可高于80%。我们希望这项关于AK111在中国中重度斑块状银屑病患者中的首次PK/PD研究将有助于AK111的进一步临床开发，并为具有长半衰期的类似抗体的剂量优化提供参考。
