Pharmacokinetics of Exenatide in nonhuman primates following its administration in the form of sustained-release PT320 and Bydureon
Pharmacokinetics of Exenatide in nonhuman primates following its administration in the form of sustained-release PT320 and Bydureon
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DOI：
10.1038/s41598-019-53356-2
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发表时间：
2019-11-20
影响因子：
4.6
通讯作者：
Greig, Nigel H.
中科院分区：
文献类型：
--
作者：
Li, Yazhou;Vaughan, Kelli L.;Greig, Nigel H.
在非人灵长类动物中评价了PT 320（一种正在临床开发的用于治疗神经退行性疾病的缓释（SR）-艾塞那肽制剂）单次皮下给药后的时间依赖性（30分钟-第84天）血浆曲线，并与Bydureon进行了比较。艾塞那肽从PT 320的释放表现出三相药代动力学特征。初始峰值出现在给药后3小时，第二峰值出现在第5天，第10-28天达到艾塞那肽稳态血浆水平。在PT 320剂量范围内，全身暴露量增加，艾塞那肽水平在达到稳态前维持在治疗阈值以上。相比之下，Bydureon的艾塞那肽释放表现出双相特征，在3小时时出现初始血浆峰，随后快速下降至亚治疗浓度，并从第35-49天逐渐升高以提供稳态。根据时间依赖性艾塞那肽浓度曲线下面积评价的艾塞那肽总暴露量与等效剂量的PT 320和Bydureon相似。然而，前者更快地达到并维持稳态血浆艾塞那肽水平，而不会下降至亚治疗浓度。两种SR-艾塞那肽制剂均被证明耐受性良好，并且在良好调节的初始释放爆发后，产生艾塞那肽的稳态血浆水平，但是PT 320产生连续的治疗性艾塞那肽水平并且更快地达到稳态。
The time-dependent (30 min - day 84) plasma profile of PT320, a sustained-release (SR)-Exenatide formulation under clinical development for treatment of neurodegenerative disorders, was evaluated in nonhuman primates after a single subcutaneous dose and was compared to Bydureon. Exenatide release from PT320 exhibited a triphasic pharmacokinetic profile. An initial peak occurred at 3 hr post-administration, a secondary peak at 5 days, and achievement of Exenatide steady-state plasma levels from day 10-28. Systemic exposure increased across PT320 doses, and Exenatide levels were maintained above the therapeutic threshold prior to achieving a steady-state. In contrast, Exenatide release from Bydureon exhibited a biphasic profile, with an initial plasma peak at 3 hr, followed by a rapid decline to a sub-therapeutic concentration, and a gradual elevation to provide a steady-state from day 35-49. Exenatide total exposure, evaluated from the area under the time-dependent Exenatide concentration curve, was similar for equivalent doses of PT320 and Bydureon. The former, however, reached and maintained steady-state plasma Exenatide levels more rapidly, without dipping to a sub-therapeutic concentration. Both SR-Exenatide formulations proved well-tolerated and, following a well-regulated initial release burst, generated steady-state plasma levels of Exenatide, but with PT320 producing continuous therapeutic Exenatide levels and more rapidly reaching a steady-state.