文章轉(zhuǎn)載自：中興通訊公益基金會 衛(wèi)生技術(shù)評估(HTA)中心

作               者：譚延輝、冷美玲

中興通訊公益基金會依據(jù)〝同類藥品是否可相互替代的評估準(zhǔn)則〞的十項評估要素，針對五個原廠PPI藥品的數(shù)據(jù)作整理。描述如下：

1. 各藥在中國藥監(jiān)局核準(zhǔn)的適應(yīng)癥 (Therapeutic indications)

注：A. 表中信息來源：各藥品的藥品說明書。

B. t 表示參考《第五次全國幽門螺桿菌感染處理共識報告》可用，但該適應(yīng)癥并未獲得藥監(jiān)局批準(zhǔn)。

結(jié)論：在治療反流性食管炎和根除H.pylori感染方面，6種PPI可以互換。

2. 各藥療效 (Efficacy)

Key Messages, Tips and Pearls

1. There are no clinically important differences among standard doses of PPIs in the initial treatment of most gastrointestinal conditions.

2. Double dose PPI is generally no more efficacious than standard dose as initial therapy for most GI conditions (e.g. GERD, dyspepsia, NSAID ulcer treatment & prophylaxis).

3. Assess need for ongoing therapy beyond the initial course of 4-8 weeks. Some GERD patients, especially those with erosive esophagitis (EE) will require regular PPI. Also consider lifestyle measures, e.g. stop smoking; weight loss.

4. Periodically reassess PPI therapy. Those on high / double dose PPIs may benefit from reassessing dosage; use the lowest effective dose when maintenance therapy is required.

5. Histamine 2 receptor blockers (H2RAs) are an option for some patients with mild GERD, step-down /maintenance therapy, endoscopic negative reflux disease (ENRD),

functional dyspepsia and PRN for dietary indiscretion.

6. Recent safety concerns have been raised regarding PPI use. Although PPIs are quite safe, patients should use only for the duration indicated and at the lowest effective dose.

7. For patients at high risk of NSAID induced ulcers, standard dose H2RAs are NOT effective. Use a standard dose PPI.

Are there any differences in efficacy between PPIs?

? PPIs appear more similar than different. They share a similar mechanism of action, decreasing acid secreted from the“proton pump”at the parietal cell. Systematic reviews support clinical outcome equivalency for PPIs when equivalent doses are used in the treatment of GERD, NSAID ulcer prophylaxis/healing and H. pylori eradication.

? There are minor variations in pharmacokinetic profiles and drug interactions; these are seldom of clinical significance. Variation in patient response may be seen, and is unpredictable.

? Controversy in this area surrounds esomeprazole dosing. Most literature supports that a 20mg dose is equivalent to standard doses of other PPIs; however, the 40mg dose is more commonly used. Some 40mg trials in more severe EE have shown small incremental benefit in healing. The marginal difference is insufficient to recommend its use over other PPIs. {Some would consider esomeprazole 40mg to be a cost-effective higher-dose PPI option.}

What constitutes a “standard dose” of a PPI? (可查藥費看每藥一個月花多少錢)

Omeprazole    20mg daily

Pantoprazole   40mg daily

Esomeprazole*  20mg daily

Rabeprazole    20mg daily

Lansoprazole   30mg daily

* 20mg is representative of equivalent Nexium dose and recommended dosage for most indications except H pylori eradication (20mg BID) and reflux esophagitis (initial); however, the most commonly used strength is 40mg.

文獻：Navigating acid suppression options: Considerations for Optimal PPI Therapy. Sept. 2007   www.RxFiles.ca

----------------------------------------------------------------------------------------------------------------------

每日標(biāo)準(zhǔn)劑量下在中國深圳的藥費

a: 深圳市某三甲醫(yī)院提供藥費訊息

----------------------------------------------------------------------------------------------------------------------

Randomized controlled trials (RCTs) evaluating omeprazole (20 mg/day), pantoprazole (40 mg/day), lansoprazole (30 mg/day), rabeprazole (20 mg/day), ilaprazole (10 mg/day), ranitidine (300 mg/day), famotidine(40 mg/day), or placebo for DU were included.

Results: A total of 62 RCTs involving 10,339 participants (eight interventions) were included. The network meta-analysis showed that all the PPIs significantly increased the 4-UHR(4-week ulcer healing rate) compared to H2 receptor antagonists (H2RA) and placebo, while there was no significant difference for 4-UHR among PPIs. As to the incidence of AEs, no significant difference was observed among PPIs, H2RA, and placebo during 4-week follow-up. Based on the costs of both PPIs and management of AEs in China, the incremental cost-effectiveness ratio per quality-adjusted life year (in US dollars) for pantoprazole, lansoprazole, rabeprazole,and ilaprazole compared to omeprazole corresponded to $5134.67, $17801.67, $25488.31, and $44572.22, respectively.

Conclusion: Although the efficacy and tolerance of different PPIs are similar in the initial non-eradication treatment of DU, pantoprazole (40 mg/day) seems to be the most cost-effective option in China.

文獻：Jiaxing Zhang, Long Ge, Matt Hill, Yi Liang, Juan Xie, Dejun Cui, Xiaosi Li, Wenyi Zheng, Rui He. Standard-Dose Proton Pump Inhibitors in the Initial Non-eradication Treatment of Duodenal Ulcer: Systematic Review, Network Meta-Analysis, and Cost-Effectiveness Analysis. Front Pharmacol. 2018;9:1512. Published online 2019 Jan 7. doi: 10.3389/fphar.2018.01512   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330312/

-------------------------------------------------------------------------------------------------------

窗體頂端

Background: 

This study compared the effectiveness and acceptability of all Food and Drug Administration (FDA)-recommended dose proton pump inhibitors (PPIs) in erosive esophagitis (EE): Dexlansoprazole 60 mg, Esomeprazole 40 mg, Esomeprazole 20 mg, Pantoprazole 40 mg, Lansoprazole 30 mg, Rabeprazole 20 mg, Omeprazole 20 mg.

Methods: 

A systematic literature search was performed using PubMed, Embase, and Cochrane Library. Totally, 25 randomized controlled trials (RCTs) met study selection criteria and were incorporated in this network meta-analysis (NMA) study.

Results: 

For the NMA, eligible RCTs of adults with EE verified by endoscopic examination were randomly assigned to the licensed PPIs at least 4 weeks of continuous therapy. The primary efficacy outcome was the endoscopic healing rates at 4 and 8 weeks. Heartburn relief rates were a secondary efficacy outcome. The rates of withdrawal were analyzed as a safety outcome. In comparison to the common comparator omeprazole 20 mg, esomeprazole 40 mg provided significantly healing rates at 4 weeks [odds ratio (OR), 1.46 (95% confidence interval, 95% CI, 1.24–1.71)] and 8 weeks [1.58 (1.29–1.92)], and improved the heartburn relief rates [1.29 (1.07–1.56)]. In comparison to lansoprazole 30 mg, esomeprazole 40 mg provided significantly healing rates at 4 weeks [1.30 (1.10–1.53)] and 8 weeks [1.37 (1.13–1.67)], and improved the heartburn relief rates [1.29 (1.03–1.62)]. In terms of acceptability, only dexlansoprazole 60 mg had significantly more all-cause discontinuation than omeprazole 20 mg [1.54 (1.03–2.29)], pantoprazole 40 mg [1.68 (1.08–2.63)], and lansoprazole 30 mg [1.38 (1.02–1.88)].

Conclusion: 

The standard-dose esomeprazole 40 mg had more superiority in mucosal erosion healing and heartburn relief. Esomeprazole 40 mg, pantoprazole 40 mg, esomeprazole 20 mg, and lansoprazole 30 mg showed more benefits in effectiveness and acceptability than other interventions.

窗體底端

文獻：Li Mei-Juan, Li Qing, Sun Min, Liu Li-Qin. Comparative effectiveness and acceptability of the FDA-licensed proton pump inhibitors for erosive esophagitis：A PRISMA-compliant network meta-analysis. Medicine. 2017; 96(39):e8120. https://journals.lww.com/md-journal/Fulltext/2017/09290/Comparative_effectiveness_and_acceptability_of_the.33.aspx

3. 各藥產(chǎn)生類似藥效的劑量 （Therapeutically equivalent dosages）

NA代表該適應(yīng)癥沒被美國FDA核可

三合一療法是 一個PPI + Clarithromycin 500mg + Amoxicillin 1000mg

二合一療法是 Lansoprazole + Amoxicillin 1000mg

Hypersecretory conditions 通常是指Z-E syndrome，個體用藥劑量差異較大

文獻：Kheloussi S. Appropriate Use and Safety Concerns of Proton Pump Inhibitors. US Pharm. 2017;42(6)(Generic Drugs suppl):38-42

-------------------------------------------------------------------------------------------------------

Although proton pump inhibitors (PPIs) are widely used, their relative potency and ideal dosing regimens remain unclear. We analyzed data from randomized clinical trials that performed pH testing in patients receiving solid-dose PPI formulations (omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole) for a minimum of 5 days. We used omeprazole equivalency and the surrogate biomarker, percentage time pH > 4 over a 24-hour period (pH4time), to compare PPI effectiveness for different PPIs given once, twice, or 3 times daily. We found that increasing strength of once-daily PPIs (9–64 mg omeprazole equivalents) increased pH4time linearly from approximately 10.0 to 15.6 hours; higher doses produced no further increase in pH4time. Increasing the frequency to twice-daily PPI increased pH4time linearly, from approximately 15.8 to 21.0 hours. Three-times daily PPIs performed similarly to twice-daily PPIs. The costs of PPIs varied greatly, but the cost variation was not directly related to potency. We conclude that PPIs can be used interchangeably based on potency. Using twice-daily PPIs is more effective in increasing efficacy increasing once-daily PPI dosage. Omeprazole and lansoprazole (30 mg) and 20 mg of esomeprazole, rabeprazole are functionally equivalent.

上文獻需購買：Graham DY, Tansel A. Interchangeable Use of Proton Pump inhibitors Based on Relative Potency. Clinical Gastroenterology and Hepatology 2018;16:800-8.

4. 各藥禁忌癥 (Contraindicatioins)

結(jié)論：除泮托拉唑和艾普拉唑外，其余4種PPI的治療禁忌沒有差異。用于根除幽門螺桿菌感染時，中、重度肝腎功能障礙患者禁用泮托拉唑。艾普拉唑不存在與HIV蛋白酶抑制劑合用的禁忌。

5.各藥在藥動學(xué)參數(shù)及特殊群體上使用的差異(Special patient-population considerations)

5.1 PPI的藥代動力學(xué)特征（根據(jù)藥品說明書信息整理）

艾司奧美拉唑鈉在治療胃食管反流病時，缺乏有活性CYP2C19酶的個體（慢代謝者）比具有活性CYP2C19的個體（快代謝者）平均總暴露量（AUC）高很多，平均血漿峰濃度也增加。對于輕中度肝功能損害患者，艾司奧美拉唑代謝可能會減弱；嚴(yán)重肝功能損害的患者代謝率降低，可使艾司奧美拉唑的暴露量增加1倍。說明該藥的這一特性差異（與其他同類藥相比，其他藥沒有這個特點）是有臨床意義的，因此，此藥有這項缺點。

文獻：《Effects of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of proton pump inhibitors》

文獻：www.drugs.com

5.2 特殊人群使用

參考《質(zhì)子泵抑制劑臨床應(yīng)用指導(dǎo)原則（2020）》和各待遴選PPI藥品說明書，各個藥品適用的特殊人群范圍如下表打勾情形。

6. 各藥品不良反應(yīng) （Adverse drug reactions）

從嚴(yán)重不良反應(yīng)及其發(fā)生率來看：(根據(jù)藥品說明書信息整理)

由上可知，各PPI的嚴(yán)重不良反應(yīng)大多相同；從發(fā)生率的對比來看，泮托拉唑發(fā)生嚴(yán)重不良反應(yīng)的頻率更低，其次為奧美拉唑，雷貝拉唑和蘭索拉唑的發(fā)生率大多在0.1%左右。

What about recent safety concerns with PPIs?

? PPIs have an excellent safety profile and few side effects. {Common SE 1-8%: headache, diarrhea, rash; Rare SE: allergy, nephritis}

? Observational data has raised concern regarding the following:

* Fracture risk (with higher doses & long-term use)

* C. difficile associated diarrhea (conflicting data)

* Pneumonia (associated with recent initiation)

* Low vitamin B12, iron and magnesium levels {routine monitoring not recommended}

? Summary: Given uncertainties and potential risks with long term PPI use, patients should use the lowest effective dose and only for the duration indicated. “Reassess periodically!”

{See Table 3–PPI Safety Concerns–Supplementary Data}

Table 3: PPI Safety Concerns – Supplementary Data

(Observational data: limited & potential confounders)

CI=confidence Interval; OR=odds ratio; NNH=number needed to harm

7. 各藥品相互作用訊息 (Drug Interaction profiles)

The interaction profiles of omeprazole and pantoprazole-Na have been extensively studied, whereas those for esomeprazole, lansoprazole and rabeprazole are less well defined.

文獻1：Wedemeyer RS, Blume H. Pharmacokinetic Drug Interaction Profiles of Proton Pump Inhibitors: An Update. Drug Saf  2014;37:201–211

文獻2：Robinson M, Horn J. Clinical Pharmacology of Proton Pump Inhibitors: What the Practising Physician Needs to Know. Drugs  2003;63:2739-2754.

8. 各藥在用藥依從性訊息 (Patient Compliance)

小結(jié)：上述PPI的劑型均為片劑或者膠囊劑，服用頻率均在每日1次或2次，對于患者的用藥配合度影響較小。

9. 各藥品治療療程 (Duration of therapy)

NA代表該適應(yīng)癥沒被美國FDA核可

Kheloussi S. Appropriate Use and Safety Concerns of Proton Pump Inhibitors. US Pharm. 2017;42(6)(Generic Drugs suppl):38-42

 小結(jié)：所有PPI的療程均小于8周，大體都在4~8周之間，因此所有藥品的療程類似。

10. 各藥品達(dá)到療效的時間 (Time to therapeutic effect)

小結(jié)：根據(jù)藥品說明書，所有PPI藥品達(dá)到最小有效濃度的時間小于60min，屬于快速起效藥品，因此達(dá)到治療效果的時間類似。

The mechanism of inhibition of omeprazole acid secretion involves the formation of the stable enzyme inhibitor complex between acid-generated sulfenamide of omeprazole and hydrogen-potassium-stimulated adenosine triphosphatase (H+,K+-ATPase) on the parietal cell.  Although the half-life of omeprazole in plasma is about 60 minutes, the duration of action of omeprazole following a single dose exceeds 24 hours because of the stable enzyme inhibitor complex.  Acid inhibition does not correlate with plasma concentration of the drug and its antisecretory effect.

文獻：Vinayek R , Amantea MA , Maton PN, et al. Pharmacokinetics of Oral and Intravenous Omeprazole in Patients With the Zollinger-Ellison Syndrome. GASTROENTEROLOGY 1991:101:138-147.

PPIs inhibit the final step of gastric acid secretion and should be taken prior to the first meal of the day for maximal effect. In patients with severe nocturnal reflux, it may be advisable to try taking the medication prior to the evening meal. Patients should be counseled that PPIs have a long onset of action, and they may not experience the full effect immediately. Once-daily dosing of PPIs results in maximum reduction of acid output at 5 days.

文獻：Copeland KR. Considerations for Proton Pump Inhibitor Utilization. Pharmacy Times, Volume 75, Issue 6   https://www.pharmacytimes.com/view/p2pppi--0609

◆ 前瞻性聲明

本中心及與之相關(guān)的所分發(fā)的任何資料可能含有與相關(guān)企業(yè)未來業(yè)務(wù)、未來狀況和運營業(yè)績有關(guān)的前瞻性陳述、看法或意見，包括相關(guān)企業(yè)的預(yù)估、預(yù)測、目標(biāo)和計劃。前瞻性陳述常常包含但不限于下列措辭，例如"目標(biāo)"、"計劃"、"認(rèn)為"、"希望"、"繼續(xù)"、"預(yù)計"、"旨在"、"打算"、"確保"、"將"、"可能"、"應(yīng)"、"會"、"或許"、"預(yù)期"、"估計"、"預(yù)測"或類似表述或其否定形式。

本中心的前瞻性陳述僅基于本報告截至發(fā)布日期的估計和假設(shè)。此類前瞻性聲明并非是本實中心對企業(yè)和相關(guān)藥品、耗材、醫(yī)療技術(shù)未來業(yè)績所做的任何預(yù)測或者定量結(jié)論，并涉及已知和未知的風(fēng)險、不確定性和其他因素。

◆ 醫(yī)學(xué)聲明

本中心所撰寫的報告、文件等包含的藥品信息可能并非在所有國家/地區(qū)適用，或在不同的國家/地區(qū)可能適用不同的商標(biāo)、適應(yīng)癥或患者使用劑量。本中心旨在傳遞醫(yī)藥相關(guān)證據(jù)質(zhì)量信息，不構(gòu)成對任何藥物或診療方案的推薦或推廣。如您想了解更多疾病知識或藥品、診療相關(guān)信息，請咨詢醫(yī)療衛(wèi)生專業(yè)人士。

◆ 免責(zé)聲明

一、本網(wǎng)站提供報告中的部分信息是于報告標(biāo)注日期前從第三方文獻、網(wǎng)站等資料中所收集的信息，本網(wǎng)站提供報告及信息僅供參考，不作為診斷、確診和治療依據(jù)，不能成為任何享有法律效力的書面證明文件，不能代替專業(yè)醫(yī)學(xué)建議，訪問者不能憑借或依據(jù)本網(wǎng)站報告或信息進行疾病診治。若訪問者以此為診斷和治療依據(jù)，由此可能引發(fā)的任何負(fù)面影響、損失由訪問者自行負(fù)責(zé)，本網(wǎng)站不予負(fù)責(zé)。本網(wǎng)站已盡力確保網(wǎng)站所載內(nèi)容的準(zhǔn)確性、完整性、及時性和應(yīng)用性，但不對此作任何的承諾和保證。除本聲明明示的條款外，其他一切因使用本網(wǎng)站而引致之任何意外、疏忽、誹謗、版權(quán)或知識產(chǎn)權(quán)侵犯及其所造成的損失，本網(wǎng)站不承擔(dān)任何法律責(zé)任。大融（深圳）數(shù)據(jù)咨詢服務(wù)有限公司由合法權(quán)利的第三方所有，受中國有關(guān)法律、法規(guī)及規(guī)章的保護。

三、您在使用本網(wǎng)站時，請遵守有關(guān)知識產(chǎn)權(quán)保護的規(guī)定。本網(wǎng)站內(nèi)容僅供您個人使用，除非經(jīng)大融（深圳）數(shù)據(jù)咨詢服務(wù)有限公司的事先書面許可，任何人不得為了商業(yè)目的使用本網(wǎng)站內(nèi)容或擅自對本網(wǎng)站內(nèi)容進行任何修改、復(fù)制、出版、分發(fā)、放映、廣播或再傳送等。

四、本聲明以及其修改權(quán)、更新權(quán)及最終解釋權(quán)均屬大融（深圳）數(shù)據(jù)咨詢服務(wù)有限公司所有。大融（深圳）數(shù)據(jù)咨詢服務(wù)有限公司有權(quán)對擁有版權(quán)的資料隨時進行修改和更新。

五、因本網(wǎng)站及本聲明產(chǎn)生的任何爭議，由本網(wǎng)站所有者所在地的法院管轄。

六、本聲明于2023年3月1日公布并生效，訪問者須仔細(xì)閱讀并同意本聲明。