Allopurinol以及Benzbromarone在不同腎功能高尿酸血症患者其臨床上劑量和治療效果之評估

Evaluation of the clinical dose and effectiveness of allopurinol and benzbromarone on hyperuricemia in patients with different renal function

莊佩芬(Pei-Fen Chuang)

指導教授 ： 黃耀斌

共同指導教授 ： 黃尚志(Shang-Jyh Hwang)

高雄醫學大學/藥學院/臨床藥學研究所/碩士(2008年)

摘要

研究背景: Allopurinol可能引起嚴重皮膚不良反應，因此有文獻建議此藥物依照病人腎功能調整劑量，而後劑量的使用應依照病人所監測得到的血清尿酸值加以調整；重度腎功能不佳使用benzbromarone可能無治療效果以及此藥物可能導致的肝毒性等，於使用降尿酸藥物治療時都需加以考量。病人的藥物依順性不佳及allopurinol沒有適當調整劑量皆可能是病人治療不易的原因。
研究目的: 探討劑量使用情形，特別是腎功能和劑量調整之相關性；檢驗數值監測情形、固定藥物劑量的藥物治療效果、病人取藥順從性和相關因子之探討。
研究方法: 此為回溯性研究，使用高雄市某區域醫院2004年接受allopurinol或benzbromarone治療之病人，排除：未滿18歲、只有單一次門診研究藥物處方以及接受來自透析室所開立之研究藥物處方的病人；為確定病患於穩定狀態，因而亦排除急診及住院研究藥物處方。1.以2004年至2007年6月之門診處方，研究劑量使用概況；2.以2004年初次接受研究藥物治療病患之藥物劑量作為探討腎功能與劑量使用之間的相關性；3.檢驗數值監測之情形主要以最初六個月有持續接受藥物治療之病患為研究族群；4.並且以一年期間的取藥順從（medication possession ratio > 0.8）與否以對數迴歸分析可能的影響因子與取藥順從之相關性。
研究結果: 研究族群在追蹤年中的所有處方，不論allopurinol、benzbromarone皆以100 mg/day佔最多比例。使用allopurinol作為首次治療藥物的新病人，普遍所使用的劑量低於建議劑量準則（55.25%），尤其病患在腎功能≥ 60 ml/min/1.73m2有高達將近80%的比例；而首次接受藥物治療劑量為< 100 mg/day病人之基礎eGFR值顯著地小於其他劑量各組。腎功能< 30 ml/min/1.73m2之病人有11位接受benzbromarone作為首次藥物治療。檢驗數值的監測情形結果顯示：持續接受allopurinol治療的病人中可能有將近60%在最初六個月內沒有被考慮到以血清尿酸值作為劑量調整之參考；接受benzbromarone作為降尿酸藥物治療病人中，接受藥物治療前有肝功能檢驗值的有50%，開始接受治療後的最初六個月內持續以此藥物治療的病人中有肝功能檢驗值則佔55%。接受藥物最初六個月內持續以固定allopurinol或benzbromarone 100 mg/day治療之病人在接受治療三個月後曾有達到正常尿酸值的百分比各別為18.2%及92.3%。研究族群新接受降尿酸藥物治療病人其持續治療的平均期間少於三個月。痛風病人中ㄧ年期間的取藥順從之比例為7.6%；每增加一歲，就增加了1.04倍的機率達到取藥順從（AOR，1.04；95% CI，1.01-1.07，P-value=0.0091），接受藥物治療前ㄧ年內每增加一次痛風發作次數就增加了1.24倍的機率達到取藥順從（AOR，1.24；95% CI，1.08-1.41，P-value=0.0018）。
結論: 使用allopurinol作為首次治療藥物的新病人，普遍所使用的劑量低於建議劑量準則，顯示可能基於避免藥物不良反應使得用藥較為保守。維持固定劑量及沒有監測病人的尿酸值以作為適時調整allopurinol劑量之依據可能無法帶來良好的治療效益，因為在此研究中，以固定allopurinol 每日劑量100 mg/day治療的病人三個月後達到正常尿酸值的百分比低。Benzbromarone 100 mg/day可良好地達到治療目標。此藥可能導致肝毒性，以及重度腎功能障礙患者使用此藥可能沒有治療效果，都仍是值得注意的地方。本研究痛風病人使用降尿酸藥物治療多不是長期使用；年齡以及用藥前的痛風發作經驗是影響取藥順從的相關因子。

關鍵字

allopurinol ； benzbromarone ； 腎功能 ； 取藥順從性

並列摘要

Background: There are some noticeable points for urate-lowering therapy. 1. The potential of allopurinol severe cutaneous adverse reactions led to the development of clinical guidelines that advocate dosing of allopurinol according to renal function. For achieving therapy target, appropriate dose adjustments of allopurinol should base on serum uric acid level. 2. Benzbromarone may have no effects on patients with severe renal dysfunction and treatment with this drug might lead to potential liver toxicity. 3. Poor compliance with urate-lowering therapy and a fixed dose of allopurinol may result in undertreatment and difficult management of disease.
Objective: Dose for prescription, espically the adjusted dose in different renal function and the percent of regular laboratory monitoring are all prescription patterns discussed. The effectiveness of fixed daily dose after 3 months treatment and factors associated with 1 year compliance are all evaluated and analyzed in this study.
Patients and methods: This study population is from a regional hospital in Kaohsiung who received allopurinol or benzbromarone prescriptions in 2004. Patients who were less than 18 years, with only one time prescription of urate-lowering drug and with prescriptions from dialysis department are excluded. Prescriptions from emergency department and inpatients are also exclusion criteria to enhance the doses for patients with stable situation. The prescription doses from 2004~2007/6 are analyzed. Newly treated patients with baseline serum uric acid and creatinine, with first 6 months of continued use and with gout are inclusion criteria for three different discussion parts including the daily dose in different renal function, the percent of regular laboratory monitoring and the association between factors and compliance.
Results: The most commonly used allopurinol daily dose was 100 mg/day in these prescriptions of study population within 2004 to June 2007. Most patients received allopurinol 100 mg/day as initial daily dose, although with different renal function. More than 50% patients with lower allopurinol daily dose when compared with recommended. Patients receiving daily dose less than 100 mg/day were with more severe renal dysfunction. There were 11 patients receiving benzbromarone with renal function < 30 ml/min/1.73m2. Titrating allopurinol dose might not be considered in 60.0% patients with first 6 months of continued use and the awareness of the liver toxicity of benzbromarone might be less than 50%. In this study, the percent of patient achieving normal uric acid were 18.2% and 92.3% in patients with fixed allopurinol and benzbromarone daily dose 100 mg/day after 3 months treatment. Mean duration of continuous drug treatment was less than 3 months in newly treated patients and compliance with treatment for 1 year was 7.6% in gout patients. Increasing age was associated with compliance (odds ratio, 1.04; 95% confidence interval, 1.01-1.07, P-value=0.0091) and patients with more gout attacks within 1 year before the start of drug treatment was associated with compliance (odds ratio, 1.24; 95% confidence interval, 1.08-1.41, P-value=0.0018).
Conclusions: Generally, the initial daily doses were lower than recommended, suggesting conservative therapy for fear of allopurinol severe cutaneous adverse reactions. Adjusting daily dose and monitoring uric acid adequately might bring more benefit of therapy because of few patients with fixed allopurinol 100 mg/day achieved normal uric acid after 3 months treatment. Benzbromarone 100 mg/day may well achieve target uric acid. It is noticeable that the awareness of possible liver toxicity in patients with benzbromarone might be less than 50%. Urate-lowering drugs were not being used long term in this study population. Age and the experience of gout attack before start of drug treatment were associated with compliance.

並列關鍵字

allopurinol ； benzbromarone ； renal function ； compliance

參考文獻

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