使用异速缩放，降架法和PK / PD建模方法，对选择性SGLT2抑制剂janagliflozin的首次人体药代动力学和药效学进行翻译预测。,European Journal of Pharmaceutical Sciences

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使用异速缩放，降架法和PK / PD建模方法，对选择性SGLT2抑制剂janagliflozin的首次人体药代动力学和药效学进行翻译预测。
European Journal of Pharmaceutical Sciences ( IF 4.3 ) Pub Date : 2020-02-29 , DOI: 10.1016/j.ejps.2020.105281
Ling Song ₁ , Xueting Yao ₂ , Yang Liu ₂ , Wen Zhong ₂ , Ji Jiang ₂ , Hongzhong Liu ₂ , Huimin Zhou ₃ , Chongtie Shi ₃ , Kaiqi Zong ₃ , Chong Wang ₃ , Chuanxiang Ma ₃ , Dongyang Liu ₄ , Pei Hu ₂

Affiliation

AIM Janagliflozin是一种口服选择性SGLT2抑制剂。预测janagliflozin的人体药代动力学/药效学（PK / PD）特征。为janagliflozin首次人体（FIH）研究设计最佳起始剂量和有效剂量。方法从临床前体内和体外研究中获得了雅格列净的动物PK / PD特性。通过dapagliflozin，empagliflozin和canagliflozin的临床前和临床疗效数据评估了同类型SGLT2抑制剂的药理有效水平。人类PK参数和janagliflozin的轮廓通过各种方法进行了预测，例如异速生长定标（AS），井架和PK / PD建模分析。建立了机制性PK / PD模型来描述janagliflozin介导的对尿葡萄糖排泄（UGE）的影响。通过校正大鼠和人类体外IC50的种间差异以及血浆fu，从大鼠模型估计的IC50缩放人类IC50。通过观察健康受试者的PK / PD档案评估了janagliflozin的定量PK / PD预测。贾格列净的预测PK / PD特性应用于FIH剂量设计。通过考虑临床前PD和janagliflozin的毒性数据来建议最佳起始剂量。通过考虑同类药物的药理有效水平来建议有效剂量。结果总结了临床前物种中雅格列净的PK / PD特征。根据三种同类药物的疗效数据，SGLT2抑制剂的药理有效水平定义为25％至30％ΔUGE（24小时内ΔUGE=-（PG * GFR））。人类预测的CL，Vss和F为1.04 L / h，77.5 L和0.80。雅格列净的10和50 mg的预测AUC和Cmax在观察值的0.47〜2.08倍之间。10和50 mg剂量范围的预测人UGE0-24 h和UGE0-144 h在观察值的0.66〜1.41倍内。最佳起始剂量和药理活性剂量（PAD）建议为10 mg和50 mg。FIH研究的剂量范围设计为10-450 mg。结论本研究根据临床前数据预测了人参苯那列净的PK / PD特征，并根据药理学有效水平对同类药物提供了最佳剂量设计。最佳起始剂量和药理活性剂量（PAD）建议为10 mg和50 mg。FIH研究的剂量范围设计为10-450 mg。结论本研究根据临床前数据预测了人参苯那列净的PK / PD特性，并根据药理学上有效的同类药物水平为人参联素FIH研究提供了最佳剂量设计。最佳起始剂量和药理活性剂量（PAD）建议为10 mg和50 mg。FIH研究的剂量范围设计为10-450 mg。结论本研究根据临床前数据预测了人参苯那列净的PK / PD特征，并根据药理学有效水平对同类药物提供了最佳剂量设计。

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Translational prediction of first-in-human pharmacokinetics and pharmacodynamics of janagliflozin, a selective SGLT2 inhibitor, using allometric scaling, dedrick and PK/PD modeling methods.

AIM Janagliflozin is an orally selective SGLT2 inhibitor. To predict human pharmacokinetics/pharmacodynamics (PK/PD) characteristics of janagliflozin. To design optimal starting dose and effective dose for janagliflozin first-in-human (FIH) study. METHODS Animal PK/PD properties of janagliflozin were obtained from preclinical in vivo and in vitro study. Pharmacologically effective level of same class SGLT2 inhibitors were assessed through preclinical and clinical efficacy data of dapagliflozin, empagliflozin and canagliflozin. Human PK parameters and profiles of janagliflozin were predicted by various methods such as allometric scaling (AS), dedrick and PK/PD modeling analysis. Mechanistic PK/PD model was developed to describe janagliflozin-mediated impact on urinary glucose excretion (UGE). Human IC50 was scaled from rat model-estimated IC50 by correcting interspecies difference of in vitro IC50 and plasma fu of rat and human. The quantitative PK/PD prediction of janagliflozin was evaluated via observed PK/PD profiles of healthy subjects. Predicted PK/PD characteristics of janagliflozin were applied in FIH dose design. Optimal starting dose was suggested by considering preclinical PD and toxicity data of janagliflozin. Effective dose was suggested by considering pharmacologically effective level of same class drugs. RESULTS PK/PD characteristics of janagliflozin in preclinical species were summarized. Pharmacologically effective level for SGLT2 inhibitors was defined as 25~30% ΔUGE (ΔUGE=--(PG*GFR)within24h) based on efficacy data of three same class drugs. Human predicted CL, Vss and F were 1.04 L/h, 77.5 L and 0.80. Predicted AUC and Cmax of janagliflozin of 10 and 50 mg were within 0.47~2.08 fold of observed values. Predicted human UGE0-24 h and UGE0-144 h of 10 and 50 mg dose range were within 0.66~1.41 fold of observed values. Optimal starting dose and pharmacologically active dose (PAD) were suggested as 10 mg and 50 mg. Dose range for FIH study was designed as 10-450 mg. CONCLUSIONS This study predicted human PK/PD characteristics of janagliflozin based on preclinical data and provide optimal dose design for janagliflozin FIH study based on pharmacologically effective level of same class drugs.

更新日期：2020-03-02

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