文章轉載自：中興通訊公益基金會 衛生技術評估(HTA)中心
作 者：譚延輝、冷美玲
中興通訊公益基金會依據〝同類藥品是否可相互替代的評估準則〞的十項評估要素，針對五個原廠PPI藥品的數據作整理。描述如下：
1. 各藥在中國藥監局核準的適應癥 (Therapeutic indications)
適應癥 原研PPI | 奧美拉唑 | 泮托拉唑 | 艾司奧美拉唑 | 雷貝拉唑 | 蘭索拉唑 | 艾普拉唑 |
十二指腸潰瘍 | √ | √ | √ | √ | √ | |
胃潰瘍 | √ | √ | √ | √ | ||
反流性食管炎 | √ | √ | √ | √ | √ | √ |
胃食管反流病 ? 癥狀控制 | √ | √ | ||||
H.pylori感染根除 | √ | √ | √ | √ | t | t |
卓-艾綜合征 (胃泌素瘤) | √ | √ | √ | |||
治療NSAIDs相關性潰瘍 | √ | √ | ||||
預防NSAIDs相關性潰瘍 | √ | |||||
其他： ? 吻合口潰瘍 ? 潰瘍樣癥狀 ? 酸相關性消化不良 | 潰瘍樣癥狀 √ 酸相關性消化不良 √ | 吻合口潰瘍 √
| 吻合口潰瘍 √
| |||
慢性復發性消化性潰瘍長期治療 | √ |
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，但該適應癥并未獲得藥監局批準。
結論：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
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每日標準劑量下在中國深圳的藥費
藥名 | 標準劑量 | 每日藥費a | 28天藥費 | 兩倍劑量28天藥費 |
奧美拉唑 | 20mg qd | 8.91 | 249.48 | 498.96 |
艾司奧美拉唑 | 20mg qd | 8.82 | 246.96 | 493.92 |
雷貝拉唑 | 20mg qd | 25.1 | 702.80 | 1405.60 |
蘭索拉唑 | 30mg qd | 7.82 | 218.96 | 437.92 |
泮托拉唑 | 40mg qd | 8.40 | 235.20 | 470.40 |
艾普拉唑 |
a: 深圳市某三甲醫院提供藥費訊息
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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/
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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.
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. 各藥產生類似藥效的劑量 （Therapeutically equivalent dosages）
原研PPI | 奧美拉唑 | 泮托拉唑 | 艾司奧美拉唑 | 雷貝拉唑 | 蘭索拉唑 |
Symptomatic GERD | 20mg qd | NA | 20mg qd | 20mg qd | 15mg qd |
Heartburn (OTC) | 20mg qd | NA | 20mg qd | NA | 15mg qd |
Healing of erosive esophagitis | 20mg qd | 40mg qd | 20-40mg qd | 20mg qd | 開始30mg qd 維持15mg qd |
H. pylori eradication | 二合一療法 40mg tid 三合一療法 20mg bid | NA | 三合一療法 40mg qd | 三合一療法 20mg bid | 二合一療法 30mg tid 三合一療法 30mg bid |
Hypersecretory conditions | 60mg qd | 40mg bid | 40mg bid | 60mg qd | 60mg qd |
Risk reduction for NSAID-associated gastric ulcer | NA | NA | 20-40mg qd | NA | 15mg qd |
Healing of NSAID-associated gastric ulcer | NA | NA | NA | NA | 30mg qd |
Gastric ulcer | 40mg qd | NA | NA | NA | 30mg qd |
Duodenal ulcer | 20-40mg qd | NA | NA | 20mg qd | 15mg qd |
NA代表該適應癥沒被美國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
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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)
原研PPI | 藥品禁忌 |
奧美拉唑 | 1. 對產品有過敏反應者禁用； 2. 正在服用人免疫缺陷病毒（HIV）蛋白酶抑制劑（如阿扎那韋、奈非那韋）的患者禁用。 |
艾司奧美拉唑 | |
雷貝拉唑 | |
蘭索拉唑 | |
泮托拉唑 | 1. 對產品有過敏反應者禁用； 2. 在根除幽門螺桿菌感染的聯合療法中，有中、重度肝腎功能障礙的患者禁用。 |
艾普拉唑 | 對產品有過敏反應者禁用。 |
結論：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.各藥在藥動學參數及特殊群體上使用的差異(Special patient-population considerations)
5.1 PPI的藥代動力學特征（根據藥品說明書信息整理）
藥動學參數 原研PPI | 奧美拉唑 | 泮托拉唑 | 艾司奧美拉唑 | 雷貝拉唑 | 蘭索拉唑 |
達峰時間（hr） | 3.6~5.3 | 2.2~3.5 | |||
生物利用度（%） | 60 | 77 | 89 (40mg) 68 (20mg) | 個體差異大 | |
食物影響吸收情形 | 無影響 | 降低吸收 | |||
表觀分布容積 | 0.3 L/kg | 0.15 L/kg | 0.22 L/kg | ||
半衰期t1/2（分） | 40 (30~90) | 60 | 60 | 1~1.4 hr | 1.5 ± 1 hr |
慢性肝病患者 t1/2 | 3 hr | 4 to 7.2 hr | |||
血漿蛋白結合率（%） | 95 | 98 | 97 | 97 | |
肝臟排泄量（%） | 完全代謝 | 完全代謝 | 完全代謝 | 完全代謝 | |
代謝途徑、代謝酶 | CYP2C19和CYP3A4酶 | CYP2C19為去甲基泮托拉唑硫酸酯 | 大部分CYP2C19 和少部分 CYP3A4 | 主要通過非酶還原產生硫醚結合體，其他有 2C19去甲基和3A4磺基化產物 | Hepatic via CYP2C19 and 3A4 to inactive metabolites |
代謝物抑胃酸的活性 | 無 | 無 | 有 | ||
原形藥物經尿排泄(%) | <1 | <1 | 無 | <1 | |
以代謝物經尿排泄(%) 其余膽汁分泌糞便排出 | 80 | 80 | 80 | 80 | 67 |
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《質子泵抑制劑臨床應用指導原則（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。
特殊人群 | 奧美拉唑 | 泮托拉唑 | 艾司奧美拉唑 | 雷貝拉唑 | 蘭索拉唑 |
兒童 | √ | ||||
老人 | √ | √ | √ | √ | √ |
孕婦 | √ | √ | √ | √ | |
哺乳期婦女 | √ | √ | |||
肝功能異常 | √ | √ | √ | √ | √ |
腎功能異常 | √ | √ | √ | √ | √ |
6. 各藥品不良反應 （Adverse drug reactions）
從嚴重不良反應及其發生率來看：(根據藥品說明書信息整理)
原研PPI | 嚴重不良反應 | 發生頻率 |
奧美拉唑 | 全身：外周水腫 過敏反應：血管性水腫、發熱及過敏性休克 血液學：血小板減少癥、全血細胞減少癥 呼吸道：支氣管痙攣 肝膽：黃疸性或非黃疸性肝炎、肝衰竭 腎臟泌尿系統：間質性腎炎 | ≥0.01%，＜0.1% |
泮托拉唑 | 免疫系統：過敏性休克 肝膽系統：出現黃疸的嚴重肝細胞損害、伴或不伴肝衰竭 腎和泌尿系統：間質性腎炎 皮膚及皮下組織：血管神經性水腫、Stevens Johnson綜合征 | 小于0.01% |
艾司奧美拉唑 | 來源于臨床試驗： 全身體系統：外周水腫、全身性水腫 血液學：血小板減少癥 呼吸系統：哮喘加重、呼吸困難 皮膚及其附件：血管性水腫
上市后經驗： 免疫系統：速發型過敏反應/休克 肝膽系統：肝功能衰竭、黃疸性肝炎或非黃疸性肝炎 腎臟和泌尿系統：間質性腎炎 呼吸系統：支氣管痙攣 皮膚和皮下組織：Stevens Johnson綜合征、中毒性表皮壞死松解癥 | ＜1%
發生率未知
|
雷貝拉唑 | 休克以及類過敏反應； 全身血細胞減少，粒細胞缺乏癥，血小板減少（0.1%~5%）以及溶血性貧血； 暴發型肝炎，肝功能障礙（0.1%~5%）以及黃疸； 間質性肺炎（<0.1%）； 中毒性表皮溶解壞死（Lyell綜合征），Stevens Johnson綜合征及多形性紅斑； 低鈉血癥； 橫紋肌溶解 | 除括號內標出發生率外，其余發生率均不明 |
蘭索拉唑 | 休克以及過敏反應（<0.1%）； 全身血細胞減少、粒細胞缺乏、溶血性貧血（<0.1%），粒細胞減少、白細胞減少、血小板減少或貧血（0.1%~＜5%）； 嚴重肝功能障礙（<0.1%）； 間質性腎炎（發生率未知），部分病例引發腎功能衰竭； 間質性肺炎（<0.1%）； 中毒性表皮溶解壞死和Stevens Johnson綜合征（<0.1%） | 見左側 |
由上可知，各PPI的嚴重不良反應大多相同；從發生率的對比來看，泮托拉唑發生嚴重不良反應的頻率更低，其次為奧美拉唑，雷貝拉唑和蘭索拉唑的發生率大多在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)
? Fracture risk: case control studies suggest PPIs increase the risk of hip fractures. The absolute risk was small with 4/1000 personyears for PPI users compared to 1.8/1000 person-years crude rate for acid suppression non-users. The risk is associated with duration. o 1 year Adjusted: OR 1.22 (CI = 1.15-1.30) o 2 year Adjusted: OR 1.41 (CI = 1.28-1.56) o 4 year Adjusted: OR 1.59 (CI = 1.39-1.80) This risk is also associated with higher doses. ≤ 1.75 doses/day >1yr: OR 1.40 (CI = 1.26-1.54) > 1.75 doses/day >1yr: OR 2.65 (CI = 1.80-3.90) |
? Risk of C. difficile associated diarrhea (CDAD) and other enteric infection appears to be increased in patients on PPIs. (observational trials; CDAD: OR 1.96 (CI=1.28-3.00)) One Canadian study did not find an association between PPIs and hospitalization with CDAD in community elderly. |
? Community acquired pneumonia risk may be increased with PPIs. ???One case control study found an increase in risk of 1.73 (OR: CI = 1.33-2.25). This risk was greater at higher doses. o <1 dose/day: OR 1.23 (CI =0.78-1.93) o >1 dose/day: OR 2.28 (CI =1.26-4.10) ???Authors estimate NNH=226; On average, 1 of every 226 patients treated with PPI for 5 months would develop pneumonia. ???A more recent case control study also found an increase risk (OR=1.5; CI:1.3-1.7) but did not find a dose relationship. They did find that recent initiation within the last 7 days had a stronger association (OR=5.0; CI=2.1-11.7). |
? Other reported adverse reactions include low vitamin B12, iron levels and hypomagnesemic hypoparathyroidism. Health Canada is reviewing two European studies regarding increased cardiovascular events with omeprazole and esomeprazole. Preliminary analysis is inconclusive. |
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.
PPIs的藥物相互作用 | |
奧美拉唑 | Omeprazole 對CYP2C19有更強的親和力，會兢爭性的被CYP2C19代謝，而讓其他也被CYP2C19代謝的藥品代謝量降低，而增加那些藥品的血中濃度與療效。而clopidogrel需要被CYP2C19代謝才能產生藥效，當被omeprazole抑制而減少CYP2C19代謝酶時，其療效也下降。 Omeprazole induced competitive inhibition of CYP2C19 has the potential to alter the metabolism of diazepam, proguanil, antidepressant moclobemide (in extensive metabolisers), phenytoin, warfarin, citalopram, etravirine. Clopidogrel must be activated by CYP2C19, an enzyme inhibited by omeprazole and esomeprazole but lansoprazole and pantoprazole-Na had less effect on the antiplatelet activity of clopidogrel (inhibition of platelet function diminished). Compounds with a high affinity for CYP3A4 (e.g.ketoconazole or fluconazole, clarithromycin and moclobemide) may affect the bioavailability of omeprazole by increasing its serum concentrations, but this is only likely to be clinically relevant in those with CYP2C19 deficiency who metabolise omeprazole via the CYP3A4 metabolic pathway. Omeprazole kinetics are also affected via the CYP2C19 pathway. Decreased plasma concentrations of omeprazole and omeprazole sulphone occurred after administration of ginkgo biloba or St. John’s wort. Metabolism of omeprazole was reduced following administration of fluvoxamine (extensive metabolisers only), and the omeprazole AUC was increased following use of a combined oral contraceptive containing ethinyloestradiol. A total of 199 drugs are known to interact with omeprazole: 18 major drug interactions (46 brand and generic names); 135 moderate drug interactions (1225 brand and generic names); 46 minor drug interactions (263 brand and generic names) |
泮托拉唑 | Pantoprazole interaction with clopidogrel is significant less than that of omeprazole mediated by CYP2C19. Extensive studies in healthy volunteers and patients have shown that pantoprazole-Na has a low potential to interact with other medications A total of 147 drugs are known to interact with pantoprazole: 14 major drug interactions (35 brand and generic names); 114 moderate drug interactions (1147 brand and generic names); 19 minor drug interactions (139 brand and generic names) |
艾司奧美拉唑 | The interaction potentials of esomeprazole and racemic omeprazole seem not to differ significantly. Multiple doses of esomeprazole increased diazepam concentrations and reduced diazepam elimination, but no similar changes were reported with pantoprazole-Na. A total of 172 drugs are known to interact with Nexium: 17 major drug interactions (44 brand and generic names); 122 moderate drug interactions (1184 brand and generic names); 33 minor drug interactions (181 brand and generic names) |
雷貝拉唑 | Most studies report interactions attributed to the group effect of all PPIs on gastric pH (e.g. interactions with digoxin or ketoconazole). Significant CYP-mediated drug interactions with rabeprazole are generally not likely because rabeprazole has a low affinity for a range of CYP isoenzymes. The CYP2C19 inhibitor fluvoxamine had a significant effect on rabeprazole metabolism in extensive metabolisers of CYP2C19, there were no differences in any pharmacokinetic parameters in poor metabolisers. rabeprazole was not found to be involved in metabolic drug interactions with theophylline, warfarin, phenytoin, tacrolimus or antacids.
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蘭索拉唑 | The interaction profiles of lansoprazole and dexlansoprazole have not been as thoroughly investigated as those of omeprazole or pantoprazole-Na. Nonetheless, neither compound appears to be associated with major clinically relevant drug interactions. Lansoprazole decreased oral tacrolimus clearance, significantly increasing blood tacrolimus concentration, particularly in those with CYP2C19 mutant alleles. Finally, the CYP2C19 inhibitor fluvoxamine had a significant effect on lansoprazole metabolism (increased plasma concentrations) in extensive metabolisers for CYP2C19 but not in poor metabolisers. A total of 163 drugs are known to interact with lansoprazole categorized as 17 major, 123 moderate, and 23 minor interactions. |
結 論 | Pantoprazole-Na, lansoprazole and rabeprazole appear to be associated with lower incidences of drug interactions than omeprazole and esomeprazole, resulting either from their lower affinity for specific CYP isoenzymes or the involvement of additional elimination processes. However, only the interaction profile of pantoprazole-Na has been well characterised. 文獻1 There are significant genetic polymorphisms for one of the cytochrome P450 isoenzymes involved in PPI metabolism (CYP2C19), and this polymorphism has been shown to substantially increase plasma levels of omeprazole, lansoprazole and pantoprazole, but not those of rabeprazole. Hepatic metabolism is also a key determinant of the potential for a given drug to be involved in clinically significant pharmacokinetic drug interactions. Omeprazole has the highest risk for such interactions among PPIs, and rabeprazole and pantoprazole appear to have the lowest risk. 文獻2 With little difference among the PPIs in terms of clinical efficacy at equivalent doses, differences in drug interaction propensities become important factors in prescribing decisions, particularly in patients who are taking multiple concomitant medications (such as the elderly) or those receiving drugs with a narrow therapeutic window. A PPI with a well proven low risk of drug interactions would be the favourable choice in these patients. 從此結論可看出，五個藥品療效類似，若需要選兩個藥留在醫院使用，可從omeprazole and esomeprazole中選一個藥，另從Pantoprazole-Na, lansoprazole and rabeprazole中選一個藥，共兩藥留在目錄中。一般患者都用第一類的藥，若多重用藥而擔心有相互作用，則可選擇第二類的藥品使用。 |
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)
原研PPI | 奧美拉唑 | 泮托拉唑 | 艾司奧美拉唑 | 雷貝拉唑 | 蘭索拉唑 |
劑型 | 片劑 | 片劑 | 片劑 | 片劑 | 膠囊 |
服用頻率 | 每日1-2次 | 每日1-2次 | 每日1次 | 每日1次 | 每日1次 |
小結：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)
原研PPI | 奧美拉唑 | 泮托拉唑 | 艾司奧美拉唑 | 雷貝拉唑 | 蘭索拉唑 |
Symptomatic GERD | 4周 | NA | 4周, 可再延長4周 | 4周, 可再延長4周 | 8周 |
Heartburn (OTC) | 14天, 可4個月后重復治療 | NA | 14天, 可4個月后重復治療 | NA | 14天, 可4個月后重復治療 |
Healing of erosive esophagitis | 4-8周, 可再延長4-8周, 復發可再4-8周 | 8周, 可再延長8周 | 4-8周, 可再延長4-8周, 不超過6個月 | 4-8周, 可再延長8周, | 8周, 可再延長8周, 不超過12個月 |
H. pylori eradication | 二合一 14天 三合一10-14天 | NA | 10天 | 7天 | 二合一 14天 三合一10-14天 |
Hypersecretory conditions | 長期治療 | 長期治療 | 長期治療 | 長期治療 | 長期治療 |
Risk reduction for NSAID-associated gastric ulcer | NA | NA | 6個月 | NA | 12周 |
Healing of NSAID-associated gastric ulcer | NA | NA | NA | NA | 8周 |
Gastric ulcer | 4-8周 | NA | NA | NA | 8周 |
Duodenal ulcer | 4周, 可再 4周 | NA | NA | 4周, 可再延長使用 | 4周 維持治療是開放 |
NA代表該適應癥沒被美國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：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. 各藥品達到療效的時間 (Time to therapeutic effect)
小結：根據藥品說明書，所有PPI藥品達到最小有效濃度的時間小于60min，屬于快速起效藥品，因此達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
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