Background

GNE myopathy is a rare genetic muscle disease resulting from deficiency in an enzyme critical for the biosynthesis of N-acetylneuraminic acid (Neu5Ac, sialic acid). The uncharged Neu5Ac precursor, N-acetylmannosamine (ManNAc), is under development as an orphan drug for treating GNE myopathy.

Methods

A semi-mechanistic population pharmacokinetic model was developed to simultaneously characterize plasma ManNAc and its metabolite Neu5Ac following oral administration of ManNAc to subjects with GNE myopathy. Plasma ManNAc and Neu5Ac pharmacokinetic data were obtained from two clinical studies (ClinicalTrials.gov identifiers NCT01634750, NCT02346461) and were simultaneously modeled using NONMEM.

Results

ManNAc and Neu5Ac plasma concentrations were obtained from 34 subjects with GNE myopathy (16 male, 18 female, median age 39.5 years). The model parameter estimates included oral absorption rate (k_a) = 0.256 h⁻¹, relative bioavailability relationship with dose (F-Dose) slope = −0.405 (where F = 1 for 6-g dose), apparent clearance (CL_M/F) = 631 L/h, volume of distribution (V_M/F) = 506 L, Neu5Ac elimination rate constant (k_out) = 0.283 h⁻¹, initial ManNAc to Neu5Ac conversion (SLP₀) = 0.000619 (ng/mL)⁻¹ and at steady-state (SLP_SS) = 0.00334 (ng/mL)⁻¹, with a rate-constant of increase (k_inc) = 0.0287 h⁻¹. Goodness-of-fit plots demonstrated an acceptable and unbiased fit to the plasma ManNAc and Neu5Ac concentration data. Visual predictive checks demonstrated reasonable agreement between the 5th, 50th, and 95th percentiles of the observed and simulated data.

Conclusions

This population pharmacokinetic model can be used to evaluate ManNAc dosing regimens and to calculate Neu5Ac production and exposure following oral administration of ManNAc in subjects with GNE myopathy.

中文翻译：

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GNE 肌病受试者中 N-乙酰甘露糖胺 (ManNAc) 和 N-乙酰神经氨酸 (Neu5Ac) 的群体药代动力学模型

背景

GNE 肌病是一种罕见的遗传性肌肉疾病，由对N-乙酰神经氨酸（Neu5Ac，唾液酸）的生物合成至关重要的酶缺乏引起。不带电荷的 Neu5Ac 前体N-乙酰甘露糖胺 (ManNAc) 正在开发中，作为治疗 GNE 肌病的孤儿药。

方法

开发了一种半机械的群体药代动力学模型，以在对患有 GNE 肌病的受试者口服 ManNAc 后同时表征血浆 ManNAc 及其代谢物 Neu5Ac。血浆 ManNAc 和 Neu5Ac 药代动力学数据来自两项临床研究（ClinicalTrials.gov 标识符 NCT01634750、NCT02346461），并同时使用 NONMEM 建模。

结果

ManNAc 和 Neu5Ac 血浆浓度来自 34 名患有 GNE 肌病的受试者（16 名男性，18 名女性，中位年龄 39.5 岁）。模型参数估计值包括口服吸收率 ( k _a ) = 0.256 h ^-1、与剂量 (F-Dose) 斜率的相对生物利用度关系 = -0.405（其中F  = 1 用于 6-g 剂量）、表观清除率（CL _M / F ) = 631 L/h，分布容积 ( V _M / F ) = 506 L，Neu5Ac 消除速率常数 ( k _out ) = 0.283 h ^-1，ManNAc 到 Neu5Ac 的初始转化率 (SLP ₀ ) = 0.000619 (ng/mL) ) ^-1并且在稳态 (SLP _SS ) = 0.00334 (ng/mL) ^-1，速率常数增加 ( k _inc ) = 0.0287 h ^-1。拟合优度图显示了对血浆 ManNAc 和 Neu5Ac 浓度数据的可接受且无偏的拟合。视觉预测检查证明了观察数据和模拟数据的第 5、50 和 95 个百分位数之间的合理一致性。

结论

该群体药代动力学模型可用于评估 ManNAc 给药方案并计算在患有 GNE 肌病的受试者中口服 ManNAc 后 Neu5Ac 的产生和暴露。