Eliglustat is a glucosylceramide synthase inhibitor indicated as a long-term substrate reduction therapy for adults with type 1 Gaucher disease, a lysosomal rare disease. It is primarily metabolized by cytochrome P450 2D6 (CYP2D6), and variants in the gene encoding this enzyme are important determinants of eliglustat pharmacokinetics (PK) and drug–drug interactions (DDIs). The existing drug label addresses the DDIs to some extent but has omitted scenarios where both metabolizing CYPs (2D6 and 3A4) are mildly or moderately inhibited. The objectives of this study were (i) to develop and validate an eliglustat physiologically-based pharmacokinetic (PBPK) model with and without drug interactions, (ii) to simulate untested DDI scenarios, and (iii) to explore potential dosing flexibility using lower dose strength of eliglustat (commercially not available). PK data from healthy adults receiving eliglustat with or without interacting drugs were obtained from literature and used for the PBPK model development and validation. The model-predicted single-dose and steady-state maximum concentration (C_max) and area under the concentration-time curve (AUC) of eliglustat were within 50–150% of the observed values when eliglustat was administered alone or coadministered with ketoconazole or paroxetine. Then as model-based simulations, we illustrated eliglustat exposure as a victim of interaction when coadministered with fluvoxamine following the US Food and Drug Administration (FDA) dosing recommendations. Second, we showed that with lower eliglustat doses (21 mg, 42 mg once daily) the exposure in participants of intermediate and poor metabolizer phenotypes was within the outlined safety margin (C_max <250 ng/mL) when eliglustat was administered with ketoconazole, where the current recommendation is a contraindication of coadministration (84 mg). The present study demonstrated that patients with CYP2D6 deficiency may benefit from lower doses of eliglustat.

中文翻译：

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基于生理学的药代动力学模型开发、验证和应用，用于预测 Eliglustat 药物-药物相互作用

Eliglustat 是一种葡萄糖神经酰胺合成酶抑制剂，可作为 1 型戈谢病（一种溶酶体罕见病）成人的长期底物减少疗法。它主要由细胞色素 P450 2D6 (CYP2D6) 代谢，编码该酶的基因变异是 eliglustat 药代动力学 (PK) 和药物-药物相互作用 (DDI) 的重要决定因素。现有的药物标签在某种程度上解决了 DDI，但忽略了两种代谢 CYP（2D6 和 3A4）受到轻度或中度抑制的情况。本研究的目的是 (i) 开发和验证具有和不具有药物相互作用的 eliglustat 生理学药代动力学 (PBPK) 模型，(ii) 模拟未经测试的 DDI 场景，(iii) 探索使用较低剂量强度的 eliglustat（商业上不可用）的潜在剂量灵活性。接受含或不含相互作用药物的 eliglustat 的健康成人的 PK 数据来自文献，并用于 PBPK 模型开发和验证。模型预测的单剂量和稳态最大浓度（C_{当eliglustat}单独给药或与酮康唑或帕罗西汀共同给药时，eliglustat 的浓度-时间曲线 (AUC) 和浓度-时间曲线下面积在观察值的 50-150% 以内。然后，作为基于模型的模拟，我们将 eliglustat 暴露说明为按照美国食品和药物管理局 (FDA) 的剂量建议与氟伏沙明共同给药时相互作用的受害者。其次，我们表明，使用较低的 eliglustat 剂量（21 mg，42 mg，每天一次），中间和弱代谢表型参与者的暴露在概述的安全范围内（C _max<250 ng/mL) 当 eliglustat 与酮康唑一起给药时，目前的建议是共同给药 (84 mg) 的禁忌症。本研究表明，CYP2D6 缺陷患者可能受益于较低剂量的 eliglustat。