Lercanidipine到底爛腎可否使用?

Zanidip的仿單這樣寫：

l   對輕至中度肝、腎功能不良者剛開始使用需特別謹慎，雖此類病人可耐受一般推薦劑量，但如增加至20mg仍需注意。 l   Zanidip禁用於重度肝、腎功能不全病人(GFR < 30 ml/min)，包含正在進行透析的病人

 

但我明明就看到一堆爛腎人在用Lercanidipine也沒事??

PK在lexicomp與仿單上寫到：

吸收: 快速且幾乎100%吸收

分布: Vd: 2~2.5 L/kg

Protein binding: >98%

代謝: 幾乎都由肝臟CYP3A4代謝成無活性物

Bioavailability: ~10% (高首渡代謝)，若配高油脂食物~40%

排除半衰期: 8~10 hr但因為會結合於小動脈細胞膜上，所以Duration達24 hr

Time to peak: 1.5~3 hours

排除: 50%從尿排出(無活性代謝物)、50%糞便排出(無活代)

l   重度爛肝者首渡代謝、CYP代謝減少，BA增加

l   重度爛腎者(CCr<12)血中蛋白質減少，free drug增加，血中濃度增加70%
仿單主要是因為這句話而禁用於爛腎/洗腎者…所以減劑量不就好了??zanidip濃度太高頂多低血壓、週邊水腫，都是處理得來的問題。也許是怕他的會黏在細胞膜上，效果持續太久，總之我覺得即早減劑量，監測血壓即可，我實在找不到他絕對不能用的理由。

於是我直接寫信去問Zanidip的藥廠Recordati，她是這樣回我的
-------------------------------------------------------------------------------------------------
Dear Dr Lip Lin,

 

Thank you for contacting Recordati regarding the question on Zanidip and renal impairment.

 

Lercanidipine is metabolized in the liver by cytochrome CYP3A4 and converted into inactive metabolites which are eliminated in urine and feces.

 

A specific clinical study was carried out at the time of the pre-registration development of the drug, with the intent of understanding the pharmacokinetics in patients with renal impairment and mild to moderate essential hypertension. It was a single-blind two-period study performed in 14 patients (7 males and 7 females, median age 57 years) and each of these patients received placebo once daily on days 1 to 7.

 

Thirteen patients completed the study. They were divided into 3 categories:

-creatinine clearance of 30-59 mL/min (i.e. patients with mild to moderate renal impairment)

-creatinine clearance 10-29 mL/min, not in dialysis (patients with severe renal impairment)

 

The pharmacokinetic data suggested that accumulation may not be a problem in patients with mild to moderate renal impairment, but that it can certainly occur in patients with severe renal impairment (Barchielli et al. – paper attached). Therefore, the SmPC on lercanidipine reflects the findings derived from this study.

 

Please note that this contraindication has been there since the registration and still remains.

 

Hope it helps and please feel free to contact me if you need any further information

 

結論是
CCr30-59 (trial真的是做30-59)不用腎調，血中濃度跟好腎人差不多。但CCr 10-29者建議減低起始劑量，並小心慢慢增加劑量這樣。但仿單(SmPC)還是寫了禁忌，在我看來就是見仁見智了。對，她會濃度暴增2倍，但真的就還是這麼多人用沒事，那麼我會說，如果她都用很久沒事就算了，但如果是爛腎人初次使用，我會建議換Norvasc或其他CCB，但病人說就是會週邊水腫才換Zanidip的，OK那妳從低劑量開始吧，不然就要小心藥物過量的負作用：
週變動脈血管過度放鬆低血壓，心跳反彈加快。但過高劑量周邊動脈選擇性喪失，也會抑制心跳(negative inotropic effect)，造成bradycardia，一來一往結果會怎樣不知道。
但常見的副作用是：低血壓、頭暈、頭痛與心悸

<同場加映：Zanidip用在CKD者效果好~>

https://pubmed.ncbi.nlm.nih.gov/15717638/

在2005年的ZAFRA study中，發現Scr>1.2~1.4,CCr<70的203個CKD病人，本身使用ACEI或ARB但血壓未能達標(130/85)，使用lercanidipine六個月後89%病人顯著降血壓，58%血壓達標，沒有水腫事件發生。Scr沒有顯著改變，但CCr卻增加了(原本41.8→45.8, p=0.019)，降血壓效果好，且似乎有保護腎臟效果?