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J Pharmacokinet Pharmacodyn. 2017 Aug;44(4):375-388. doi: 10.1007/s10928-017-9525-1. Epub 2017 May 2.
Association of Vitamin D (D3 & D2) and its 25OHD metabolite (25OHD3 & 25OHD2) exposures with various diseases is an active research area. D3 and D2 dose-equivalency and each form's ability to raise 25OHD concentrations are not well-defined. The current work describes a population pharmacokinetic (PK) model for D2 and 25OHD2 and the use of a previously developed D3-25OHD3 PK model [1] for comparing D3 and D2-related exposures. Public-source D2 and 25OHD2 PK data in healthy or osteoporotic populations, including 17 studies representing 278 individuals (15 individual-level and 18 arm-level units), were selected using search criteria in PUBMED. Data included oral, single and multiple D2 doses (400-100,000 IU/d). Nonlinear mixed effects models were developed simultaneously for D2 and 25OHD2 PK (NONMEM v7.2) by considering 1- and 2-compartment models with linear or nonlinear clearance. Unit-level random effects and residual errors were weighted by arm sample size. Model simulations compared 25OHD exposures, following repeated D2 and D3 oral administration across typical dosing and baseline ranges. D2 parent and metabolite were each described by 2-compartment models with numerous parameter estimates shared with the D3-25OHD3 model [1]. Notably, parent D2 was eliminated (converted to 25OHD) through a first-order clearance whereas the previously published D3 model [1] included a saturable non-linear clearance. Similar to 25OHD3 PK model results [1], 25OHD2 was eliminated by a first-order clearance, which was almost twice as fast as the former. Simulations at lower baselines, following lower equivalent doses, indicated that D3 was more effective than D2 at raising 25OHD concentrations. Due to saturation of D3 clearance, however, at higher doses or baselines, the probability of D2 surpassing D3's ability to raise 25OHD concentrations increased substantially. Since 25OHD concentrations generally surpassed 75 nmol/L at these higher baselines by 3 months, there would be no expected clinical difference in the two forms.
维生素 D（D3 和 D2）及其 25OHD 代谢物（25OHD3 和 25OHD2）暴露与各种疾病的关联是一个活跃的研究领域。D3 和 D2 的剂量等效性以及每种形式提高 25OHD 浓度的能力尚未得到明确界定。目前的工作描述了 D2 和 25OHD2 的群体药代动力学（PK）模型，并使用先前开发的 D3-25OHD3 PK 模型[1]来比较 D3 和 D2 相关的暴露。使用 PUBMED 中的搜索标准选择了来自健康或骨质疏松人群的公开来源 D2 和 25OHD2 PK 数据，包括 17 项研究，代表 278 人（15 个个体水平和 18 个手臂水平单位）。数据包括口服、单次和多次 D2 剂量（400-100,000 IU/d）。通过考虑具有线性或非线性清除的 1 室和 2 室模型，同时为 D2 和 25OHD2 PK 开发了非线性混合效应模型（NONMEM v7.2）。单位水平的随机效应和残差通过手臂样本量加权。模型模拟比较了重复口服 D2 和 D3 后，在典型的给药和基线范围内 25OHD 的暴露情况。D2 母体和代谢物均由 2 室模型描述，其中许多参数与 D3-25OHD3 模型[1]共享。值得注意的是，母体 D2 通过一级清除（转化为 25OHD）消除，而之前发表的 D3 模型[1]包括饱和的非线性清除。与 25OHD3 PK 模型结果[1]相似，25OHD2 通过一级清除消除，其速度几乎是前者的两倍。在较低基线（较低等效剂量）下的模拟表明，D3 比 D2 更有效地提高 25OHD 浓度。然而，由于 D3 清除的饱和，在较高剂量或基线时，D2 超过 D3 提高 25OHD 浓度的能力的可能性大大增加。由于在这些较高的基线水平下，25OHD 浓度通常在 3 个月内超过 75 nmol/L，因此两种形式之间不会有预期的临床差异。
