간 장애 환자에서의 PPI: pantoprazole, esmoperazole

간부전 환자에서 선호되는 PPI에 대한 내용의 포스팅을 올린적이 있다. 

https://gimi-drug.tistory.com/255

간부전 환자 : pantoprazole, esomeprazole, 간장애 용량 조절

 

추가적인 내용을 위해 비슷한 내용을 덧붙여서 포스팅하고자 한다.

 

 

---

 간경변 환자(cirrhosis)와 정상 대조군에서 약동학적 변화(pharmacokinetic alteration)가 관찰됨!

 

Cmax는 큰 차이가 없었지만 AUC나 반감기는 두 그룹 간 큰 차이를 보임

모든 PPI는 CYP2C19에 대사되며 CYP3A4에서 약하게 대사됨. 또한 간기능 손상에 CYP2C19는 매우 민감함

따라서 간기능부전에 따른 CYP2C19 활성 감소는 PPI의 약동학 변화의 가장 큰 원인일 것임

 

PPI 성분 간 약동학 변화도 상당한 차이가 있음. 특히 lansoprazole과 pantoprazole이 그 변화가 큼

두 약제는 간 추출률(hepatic extraction ratio)이 낮은 반면 다른 PPI들은 중간정도의 간 추출률을 보임

간 추출률이 낮을수록 간에서의 청소율(hepatic clearance)은 내인성 대사 청소율(intrinsic metabolic clearance (i.e. activity of metabolizing enzymes))이나 단백결합 정도에 더 의존적임

따라서 간추출률이 낮은 약물(lansoprazole, pantoprazole)은 간 대사 효소의 활성 변화와 단백 결합 변화에 취약할 것으로 예상됨

간경변증 환자에서 esomeprazole의 약동학적 변화가 가장 적었고 놀라운 사실은 esomeprazole과 omeprazole의 결과가 다르다는 점임. 이는 S-enantiomer(esomeprazole)와 R-enantiomer의 대사 정도가 다르기 때문임

건강한 성인을 대상으로 한 약리 유전학적 연구에서도 esomeprazole에 대한 노출이 다른 PPI에 비해 CYP2C19 다형성(polymorphisms)에 가장 영향을 적게 받는 것으로 나옴

 

 

---

Esomeprazole

In a multiple-dose pharmacokinetic study (level 4) exposure to esomeprazole in eight cirrhotic patients with CTP A and B was comparable with healthy controls, while it more than doubled in four CTP C patients. This study was also mentioned in the product information, where a maximum dosage of 20 mg is advised in CTP C patients. Regarding safety, in one case report esomeprazole was tolerated well. In the pharmacokinetic study, 25% of 12 patients suffered an adverse event (i.e. constipation, diarrhoea and HE) when using 40 mg per day for five days. The patient with HE had severe cirrhosis.

 

Expert judgement

Based on these limited data, esomeprazole was classified as ‘no additional risks known’. In CTP C patients, the evidence is very thin (one study in four subjects). Because of a doubling in exposure in CTP C patients, the recommendations of the product information are adopted to use no more than 20 mg per day in CTP C patients.

Pantoprazole

We identified six pharmacokinetic studies (level 3 and 4) with pantoprazole in 77 cirrhotic patients. In two multiple-dose studies, the AUC was five- to sevenfold higher in patients with cirrhosis compared to healthy controls after oral and intravenous dosing. The same increase is described in the product information of pantoprazole. Another article found a similar exposure to pantoprazole for patients with CTP B and CTP C cirrhosis and controls who were slow CYP2C19 metabolizers. When comparing these data with healthy controls, the AUC was five times higher in the cirrhotic patients. A modelling study predicted the same increases in exposure. In healthy persons, pantoprazole has an elimination half-life of approximately 1 h. Five studies found an elimination half-life of 7–9 h in patients with cirrhosis.

Three articles (level 2, 3 and 4) studied the safety of pantoprazole in 101 patients with cirrhosis. Pantoprazole was mostly well tolerated. In one study, a CTP C patient developed HE and in a randomized trial two patients suffered from fever possibly related to PPI use.

 

Expert judgement

For all CTP classes, pantoprazole is classified as ‘unsafe’, based on the marked increase in exposure and prolonged half-life, which cannot be corrected by dose reduction. Since there are alternatives without these large increases in exposure, we would recommend avoiding the use of pantoprazole in cirrhotic patients.

 

 

reference:

1) Weersink, R. A., Bouma, M., Burger, D. M., Drenth, J. P., Harkes‐Idzinga, S. F., Hunfeld, N. G., ... & Borgsteede, S. D. (2018). Safe use of proton pump inhibitors in patients with cirrhosis. British journal of clinical pharmacology, 84(8), 1806-1820.