Prediction of Drug–Drug Interactions After Esketamine Intranasal Administration Using a Physiologically Based Pharmacokinetic Model,Clinical Pharmacokinetics

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Prediction of Drug–Drug Interactions After Esketamine Intranasal Administration Using a Physiologically Based Pharmacokinetic Model
Clinical Pharmacokinetics ( IF 4.6 ) Pub Date : 2022-05-17 , DOI: 10.1007/s40262-022-01123-4
Marie-Emilie Willemin ₁ , Peter Zannikos ₂ , Geert Mannens ₁ , Loeckie de Zwart ₁ , Jan Snoeys ₁

Affiliation

Background and Objective

A physiologically based pharmacokinetic (PBPK) modeling approach for esketamine and its metabolite noresketamine after esketamine intranasal administration was developed to aid the prediction of drug–drug interactions (DDIs) during the clinical development of esketamine nasal spray (SPRAVATO^®). This article describes the development of the PBPK model to predict esketamine and noresketamine kinetics after intranasal administration of esketamine and its verification and application in the prediction of prospective DDIs with esketamine using models of index perpetrator and victim drugs.

Methods

The intranasal PBPK (IN-PBPK) models for esketamine/noresketamine were constructed in Simcyp^® v14.1 by combining the oral and intravenous esketamine PBPK models, with the dose divided in the ratio 57.7/42.3. Verification of the model was based on comparing the pharmacokinetics and DDI simulations with observed data in healthy volunteers.

Results

The simulated and observed (171 healthy volunteers) plasma pharmacokinetic profiles of intranasal esketamine/noresketamine showed a good match. The relative contributions of different cytochromes P450 (CYPs), mainly CYP3A4 and CYP2B6, involved in esketamine/noresketamine clearance was captured correctly in the IN-PBPK model using the DDI clinical studies of intranasal esketamine with clarithromycin and rifampicin and a published DDI study of oral esketamine with ticlopidine. The induction potential of esketamine toward CYP3A4 was also well captured. Inhibition of intranasal esketamine in the presence of ticlopidine was predicted to be not clinically relevant. Different scenarios tested with esketamine as a CYP3A4 perpetrator of midazolam also predicted the absence of clinically relevant CYP3A4 interactions.

Conclusion

This PBPK model of the intranasal route adequately described the pharmacokinetics and DDI of intranasal esketamine/noresketamine with potential perpetrator and victim drugs. This work was used to support regulatory submissions of SPRAVATO^®.

中文翻译：

使用基于生理的药代动力学模型预测艾氯胺酮鼻内给药后的药物相互作用

背景与目的

艾氯胺酮鼻内给药后艾氯胺酮及其代谢物去甲氯胺酮的生理药代动力学 (PBPK) 建模方法旨在帮助预测艾氯胺酮鼻喷雾剂 (SPRAVATO®) 临床开发过程中的药物相互作用 (DDI ⁾。本文介绍了 PBPK 模型的发展，用于预测艾氯胺酮鼻内给药后的艾氯胺酮和去甲氯胺酮动力学，以及它在使用指数犯罪者和受害者药物模型预测艾氯胺酮的前瞻性 DDI 中的验证和应用。

方法

艾氯胺酮/去甲氯胺酮的鼻内 PBPK (IN-PBPK) 模型是在 Simcyp ^® v14.1 中通过结合口服和静脉内艾氯胺酮 PBPK 模型构建的，剂量比例为 57.7/42.3。该模型的验证基于将药代动力学和 DDI 模拟与健康志愿者的观察数据进行比较。

结果

鼻内艾氯胺酮/去甲氯胺酮的模拟和观察（171 名健康志愿者）血浆药代动力学曲线显示出良好的匹配。使用克拉霉素和利福平鼻内艾氯胺酮的 DDI 临床研究和已发表的口服 DDI 研究，在 IN-PBPK 模型中正确捕获了参与艾氯胺酮/去甲氯胺酮清除的不同细胞色素 P450 (CYP)（主要是 CYP3A4 和 CYP2B6）的相对贡献艾氯胺酮与噻氯匹定。艾氯胺酮对 CYP3A4 的诱导潜力也被很好地捕获。预计在噻氯匹定存在的情况下抑制鼻内艾氯胺酮与临床无关。用艾氯胺酮作为咪达唑仑的 CYP3A4 施暴者进行测试的不同场景也预测了临床相关 CYP3A4 相互作用的缺失。