ADE/PDE应依据用药途径选值

beiwei5du

Route Specific Health-based Limit Values

beiwei5du

perennials 发表于 2018-6-11 16:05
这个问题已经困扰我很久了，终于找到相关的帖子了。
如果我们计算的是注射途径的PDE，是否NOEL值必须来源 ...

个人理解：
如果是只有口服的PDE数据和口服的生物利用度，如果要求注射的PDE数据。可以直接通过下面公式：
PDE（注射）=PDE（口服）*口服生物利用度
文中提到的40%是一个举例（当然你可以选用其他值），主要是想举例介绍clear difference，其主要是说明从生物利用度高的用药途径转换为生物利用度低的用药途径的情况下（比如inhalation to oral)，PDE转换中是否引入转换因子的问题（当然为保守起见你完全可以不引入转换因子，比如使用PDE(吸入）代替PDE（口服），但是这样可能有过度要求了）。
但是一般从生物利用度低的用药途径转换为生物利用度高的用药途径（比如oral to inhalation），无论是否有明显的生物利用度差异，都建议PDE转换时引入转换因子（生物利用度（低）/生物利用度（高））。如果无法了解生物利用度（高）具体生物利用度数据，保守方法直接选用转换因子（生物利用度（低）/100%）。

下文选自：Guideline on setting health based exposure limits for usein risk identification in the manufacture of differentmedicinal products in shared facilities
4.3 Extrapolation to other routes of administration

While the PDE value derived for an active substance (contaminant) generally is based on studiesapplying the intended clinical route of administration, a different route of administration may beapplied for the active substance or medicinal product subsequently produced in the shared facility.Changing the route of administration may change the bioavailability; hence correction factors forroute-to-route extrapolation should be applied if there are clear differences (e.g. > 40%) in routespecificbioavailability. As bioavailability may vary between species, the correction factors for route-torouteextrapolation should preferably be based on human data or in the case of veterinary medicinalproducts, data in the relevant target animal.

In case human or target animal bioavailability data are not available for other routes and it is to beexpected that the change in route of administration may result in an increase in systemic exposure forthe contaminant (e.g. oral to inhalation), a conservative extrapolation can be performed by assuming100% bioavailability of the contaminant. For example, in the case of oral-to-inhalation extrapolation,the PDE derived on basis of oral data can be corrected by multiplying with the following correctionfactor:

Correction factor (oral-to-inhalation): % oral absorption/ 100% respirable absorption.

In cases where human or target animal bioavailability data are not available for other routes and it canbe expected that the systemic exposure to the contaminant will be lower via the route applied for thecontaminated active substance/medicinal product, there is no need to apply a correction factor to thePDE calculation. It is expected that the route-to-route extrapolation will be performed on a case-bycasebasis.  

syhorchid

谢谢分享

kc1711422001

Thanks for sharing

perennials

这个问题已经困扰我很久了，终于找到相关的帖子了。
如果我们计算的是注射途径的PDE，是否NOEL值必须来源于注射途径的研究数据?
但实际情况是很难找到合适的数据，一般都是口服或者吸入。
如果用口服数据，是不是说就要用生物利用度来转化？那又造成个问题，就是生物利用度也很难找到数据支持
如果用吸入途径数据，是否生物利用度就很高，如pdf中提到大于40%，是否就可以用吸入的代替注射呢？
希望讨论。

ysyd

Thanks for sharing

雪松无悔

谢谢楼主分享。真高手，入门学习中新人，向您致敬。

小金库

非常给力的资料,多谢分享

青椒炒肉

感谢分享，围观学习