De Thaye Elien, Vervaeck Anouk, Marostica Eleonora, Remon Jean Paul, Van Bocxlaer Jan, Vervaet Chris, Vermeulen An
Laboratory of Medical Biochemistry and Clinical Analysis, Ghent University - Campus Heymans, Ottergemsesteenweg 460, 9000 Gent, Belgium.
Laboratory of Pharmaceutical Technology, Ghent University - Campus Heymans, Ottergemsesteenweg 460, 9000 Gent, Belgium.
Eur J Pharm Sci. 2017 Jan 15;97:135-142. doi: 10.1016/j.ejps.2016.10.039. Epub 2016 Nov 2.
In the current study, we investigated the metoprolol absorption kinetics of an in-house produced oral sustained-release formulation, matrices manufactured via prilling, and two commercially available formulations, ZOK-ZID (reservoir) and Slow-Lopresor (matrix) in both New Zealand White rabbits and Beagle dogs, using a population pharmacokinetic analysis approach. The aim of this study was to compare the in vivo pharmacokinetic (PK) profiles of different formulations based on metoprolol, a selective adrenergic β-receptor antagonist, in dogs and rabbits and to contrast the observed differences. To that end, metoprolol (50 to 200mg) was administered to 6 Beagle dogs and 6 New Zealand White rabbits as a single intravenous (IV) bolus injection and to 8 dogs and 6 rabbits as an oral modified release formulation. To derive pharmacokinetic parameters from the data, a non-linear mixed-effects model was developed using NONMEM where the contribution of observations below the limit of detection (BDL, below detection limit) to the parameter estimates was taken into account in the parameter estimation procedure. In both species and for the three modified release formulations, different absorption models were tested to describe the PK of metoprolol following oral dosing. In Beagle dogs, plasma concentration-time profiles were best described using a sequential zero- and first-order absorption model. In rabbits though, the absorption phase was best described using a first-order process only. In both species, the reservoir formulation ZOK-ZID was behaving quite similarly. In contrast, the absorption properties of both matrix formulations were rather different between species. This study indicates that the PK of the reservoir formulation is similar in both species, even after accounting for the almost completely missed absorption phase in rabbits. The insights gained further illustrate that rabbits are not very well suited to study the PK of the current matrix formulations in view of their less optimal prolonged release characteristics and the resulting fast decline in metoprolol plasma levels.
在本研究中，我们采用群体药代动力学分析方法，研究了自制口服缓释制剂、通过造粒法制备的基质以及两种市售制剂（ZOK-ZID（储库型）和缓释美托洛尔（基质型））在新西兰白兔和比格犬体内的美托洛尔吸收动力学。本研究的目的是比较基于选择性肾上腺素能β受体拮抗剂美托洛尔的不同制剂在犬和兔体内的体内药代动力学（PK）特征，并对比观察到的差异。为此，将美托洛尔（50至200mg）以单次静脉推注的方式给予6只比格犬和6只新西兰白兔，并以口服缓释制剂的形式给予8只犬和6只兔。为了从数据中推导药代动力学参数，使用NONMEM开发了一个非线性混合效应模型，在参数估计过程中考虑了低于检测限（BDL，低于检测限）的观察值对参数估计的贡献。对于这两个物种以及三种缓释制剂，测试了不同的吸收模型来描述口服给药后美托洛尔的PK。在比格犬中，血浆浓度-时间曲线最好用序贯零级和一级吸收模型来描述。然而，在兔子中，吸收阶段最好仅用一级过程来描述。在这两个物种中，储库型制剂ZOK-ZID的表现非常相似。相比之下，两种基质型制剂在不同物种之间的吸收特性差异较大。本研究表明，即使考虑到兔子几乎完全错过的吸收阶段，储库型制剂在两个物种中的PK相似。进一步获得的见解表明，鉴于兔子不太理想的长效释放特性以及由此导致的美托洛尔血浆水平快速下降，兔子不太适合研究当前基质型制剂的PK。
