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痛風新藥 -- Febuxostat
敏盛藥師 徐怡真
前言
致痛風機轉
治療高尿酸血症的重要性
Febuxostat
結語
前言
痛風是因尿酸排泄減少或尿酸產生增加所造成 的疾病。
痛風好發於中年男性及停經後的女性,主要是 以男性佔90–95%居多。
痛風是現代人常見的文明病,根據台灣的流行 病學研究調查報告,推估台灣地區有高尿酸血 症民眾超過二百萬人,這點不容我們忽視,因 為依高尿酸血症患者大約十分之一會罹患痛風 的標準來估計,台灣地區可能的痛風患者超過 二十萬人,痛風患者的發作年齡也有下降的趨 勢。
2005-2008年,年齡別、性別之血清尿酸的高尿酸血症盛行比率
2005-2008年,地區別、性別之血清尿酸的高尿酸血症盛行比率
※ 痛風之定義:曾經患有痛風或最近一個月內服用痛風發作藥、 服降尿酸藥或排除尿酸藥。
2005-2008年,年齡層、性別之痛風盛行率
2005-2008年,地區別、性別之痛風盛行率
※ 痛風之定義:曾經患有痛風或最近一個月內服用痛風發作藥、 服降尿酸藥或排除尿酸藥。
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
Taiwan
USA
EU/UK
Japan
China
Maori
~2007 ~2011
The prevalence of gout in various
ethical group
%
致痛風機轉
尿酸是嘌呤﹝purine,也有人譯為普林﹞在人體代謝的最終產物,體內普林在肝臟代謝形成尿酸,最後由腎臟將尿酸隨尿液排出體外。
體內尿酸約1/3是來自飲食,另2/3是來自身體內細胞核的核酸嘌呤新陳代謝產生。
正常人每日製造的尿酸(750毫克),約有2/3(500毫克)由腎臟經尿液排出,約1/3由腸內細菌分解代謝隨大腸糞便排出,另有極少量由汗腺排泄。
血中尿酸濃度的正常值,應以生理化學的定義為準,即成年人血中尿酸值大於7.0 mg/dL為高尿酸血症。人體內的血中尿酸濃度會受種族、遺傳基因、性別、年齡的影響,如女性在停經前尿酸值較男性低,但停經後尿酸會增高;青春期前血中尿酸濃度較低,但青春期後則會逐漸增加到接近成年人水準。
Urol Clin North Am. 2007, 34, 335
尿酸 (Uric acid) 屬於一種弱酸,它的溶解度決定於尿液的酸鹼值和尿酸的濃度。當尿液pH值小於5.5時,其尿酸呈現飽和便易形成尿酸結石;但在pH大於6.5時,大部分的尿酸皆會以離子型的尿酸鹽 (Urate) 存在。
一般男性血中尿酸值大約3.5~7.0 mg/dL,女性則為2.6~6.0 mg/dL;溫度愈低則溶解度愈小,所以體溫較低及末梢血液循環較差的地方,尿酸鹽結晶則較易沉澱。
Uric acid Urate
pH > 6.5
pH < 5.5
Comparison of bone remodeling in normal and gout-affected bone. a. During a normal bone remodeling
cycle, osteoclast-mediated bone resorption is immediately followed by osteoblast-mediated bone
formation, enabling the preservation of normal bone mass. b. In a gouty joint, MSU crystals within the
tophus evoke a cellular response, associated with reduced osteoblast viability and function and increased
osteoclast formation and activity, resulting in localized erosion of bone adjacent to tophus. Abbreviations:
M-CSF, macrophage colony-stimulating factor; MSU, monosodium urate; OPG, osteoprotegerin; PGE2,
prostaglandin E2. MSU: monosodium urate.
Nat. Rev. Rheumatol. 2012, 8, 173
http://www.hss.edu/conditions_gout-risk-factors-diagnosis-treatment.asp
The first phase is elevated uric acid
without gout or kidney stone, a phase
which has no symptoms and is
generally not treated.
The second phase is the “acute
attack” – with pain and inflammation.
The third phase is the “time between
attacks” when a person feels normal
but is at risk for recurrence.
The final phase is “chronic gouty
arthritis,” where there are “lumps” of
uric acid, or tophi, frequent attacks
of acute gout, and often a degree of
pain even between attacks.
Gout Stages
No symptoms
This period could
be 5 yr or longer Intercritical periods
grow shorter
First
acute
flare
Time
Inte
nsity o
f pain
Flares become longer
and more severe
Start of
advanced gout
High uric acid Recurrent acute gouty arthritis Advanced gout
Progression of gout
高尿酸血症是痛風最重要的生化基礎,但並不是痛風的同義詞。根據研究,高尿酸血症者終其一生,大約只有10%的人會發展成為痛風。
痛風最確定的診斷是從關節液中看到尿酸結晶的存在,但在痛風發作的不同時期也會影響尿酸結晶的存在。因此有時候還必須靠經驗,從過去的發作病史、臨床表現、病程及誘發因子等來做鑑別診斷。
血中的尿酸值並不能做為診斷的唯一依據,約有30%發生急性痛風關節炎之病患,關節炎發作時抽血尿酸值是小於7.0 mg/dL,但只要繼續抽血追蹤,血中尿酸值都會超過8.0 mg/dL。
治療高尿酸血症的重要性
~~from 102.9.3. 蘋果日報
J Epidemiol. 2000, 10, 403.
Uric acid as a factor for MI and stroke
(The Rotterdam Study)
Stroke. 2006, 37, 1503
Gout and metabolic syndrome
(NHANES III data)
Arthritis Rheum. 2007, 57, 109
Cleve Clin J Med. 2008, 75(Auppl. 5): S9.
Hyperuricaemia has also been implicated in the
pathophysiology of hypertension, chronic kidney
disease (CKD), congestive heart failure (CHF), the
metabolic syndrome, type 2 diabetes mellitus (T2DM),
and atherosclerosis, with or without cardiovascular
events.
BMC Nephrology 2013, 14:164
Hypertension
Animal models have shown that acute elevations of serum urate
(e.g. by inhibition of uricase) induce a prompt rise in blood
pressure and that chronic urate elevation maintains the rise in
pressure and induces irreversible vascular damage and
glomerular changes, and results in a form of saltsensitive
hypertension.
BMC Nephrology 2013, 14:164
Feig and Johnson found that about 90% of adolescent
hypertension is associated with hyperuricaemia. The threshold
for hypertension could be as low as 5.0-5.5 mg/dL (0.30-0.33
mmol/L), clearly below the supersaturation value of 6.8 mg/dL
(0.4 mmol/L). Thus, it should be independent of the formation of
monosodium crystals.
Chronic kidney disease (CKD)
A number of cross-sectional studies have found an association
of urate levels with decreased eGFR or microalbuminuria, but
the interpretation is difficult, because CKD can elevate urate
levels and hyperuricaemia might cause or aggravate CKD.
When it comes to incident CKD, most studies show an
independent association with serum urate levels. However, the
analysis of the progression of CKD 3–4 and its relationship to
urate levels show conflicting results, most studies finding no
independent association with hyperuricaemia. This could
indicate that urate is more a risk factor for the onset of CKD
than its progression.
BMC Nephrology 2013, 14:164
Congestive heart failure (CHF)
Gout is associated with CHF, subclinical measures of systolic
dysfunction and mortality according to an analysis of the
Framingham Offspring Study. However, there also seems to be
increased XO activity in the failing myocardium, perhaps due to
hypoxia and apoptosis, resulting in accumulation of uric acid
precursors (hypoxanthine and xanathine) and XO-induced
production of ROS (Reactive oxygen species), causing a vicious
cycle of damage.
Gotsman et al. in an Israeli heart failure register-based study
found that treatment with allopurinol
in CHF was associated with
improved survival.
BMC Nephrology 2013, 14:164
The metabolic syndrome, T2DM and obesity
The patient with metabolic syndrome should have at least three of
the following five clinical features: abdominal obesity, impaired
fasting glucose, hypertriglyceridaemia, low HDL-cholesterol, and
elevated blood pressure.
An elevated serum urate concentration is commonly associated
with the metabolic syndrome; while the increase in serum urate has
often been considered to be secondary, recent studies suggest that
it may have an important contributory role:
1. elevated serum urate levels commonly precede insulin
resistance, T2DM, and obesity, which is consistent with
hyperuricaemia as a tentative causal factor.
2. studies in cell culture and animal models
have suggested a causative role for urate
in models of the metabolic syndrome.
BMC Nephrology 2013, 14:164
Two mechanisms are suggested:
1) hyperuricaemia-induced endothelial dysfunction, leading to
reduced insulin-stimulated nitric oxide-induced vasodilatation
in skeletal muscle, and as a consequence reduced glucose
uptake in skeletal muscle.
2) inflammatory and oxidative changes induced by intracellular
urate levels in adipocytes. For example, mice lacking XO
(producing uric acid from xanthine) only have half the
adipocyte mass of their wild-type littermates.
The metabolic syndrome, T2DM and obesity – 續
BMC Nephrology 2013, 14:164
Atherosclerosis and cardiovascular events
A systematic review and meta-analysis determined the risk of
coronary heart disease (CHD) associated with hyperuricaemia in
26 studies with 402,997 adults. It was found that hyperuricaemia
may modestly increase the risk of CHD events independently of
traditional CHD risk factors. Women were found to have a more
pronounced increase in risk for CHD mortality than for men.
A similar meta-analysis was performed for hyperuricaemia
and stroke (16 studies, 238,449 adults), showing that
hyperuricaemia modestly increased the risk of stroke incidence
and mortality, independent of known risk factors, but without
gender difference.
BMC Nephrology 2013, 14:164
The potential relationship between hyperuricaemia and
cardiovascular events could be through hypertension, but it
may also involve a direct relationship due to disturbed
endothelial function as a consequence of reduced nitric oxide
production. Endothelial dysfunction is believed to play a key
role in the early development of atherosclerosis and precedes
plaque formation.
Atherosclerosis and cardiovascular events – 續
BMC Nephrology 2013, 14:164
Discovery timeline showing cumulative number of genes discovered from 2008–2011.
Abbreviation: SUA, serum uric acid.
Genetic variants implicated in the pathogenesis of
hyperuricaemia or gout
Nat Rev Rheumatol. 2012, 8, 610.
與高血壓相關的基因
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
Taiwan
USA
EU/UK
Japan
China
Maori
~2007 ~2011
The prevalence of gout in various
ethical group
%
Hyperuricemia
(Asymptomatic) Gout
onset
Sererity of gout
(Recurrence, Tophs)
Japan
USA, Europe
Hisashi Yamanaka. Tokyo Women’s Medical University
Febuxostat
History
• 帝人製藥 (TAP) 於1991年研發出世界首見的xanthine oxidase inhibitor : febuxostat。與用來治療高尿酸血症長達40年的allopurinol截然不同,具有創新化學結構。
• 2004. 12. TAP Submits New Drug Application for
Febuxostat for the management of hyperuricemia in
chronic gout.
• 2008. 11. Arthritis Advisory Committee recommends
FDA approval of Febuxostat for the treatment of
hyperuricemia in patients with gout.
• 2009. 2. FDA Approves Uloric (febuxostat) for the
chronic management of hyperuricemia in patients
with gout.
History -續
商品名 國家
FEBURIC 台灣、日本
ULORIC 美國、加拿大
ADENURIC 法國、英國、德國、愛爾蘭、義大利、希臘、奧地利等
MENA 中國、韓國、香港、墨西哥、加勒比海、中東與北非
• 2009. 4. Febuxostat received marketing approval by the
European Medicines Agency.
• 2011.5. 台灣衛署核准Febuxostat為「Antigout agents」。
• 2012.4. 正式納入台灣健保給付 (Feburic 80 mg/tab/25.9元)。
Febuxostat approval
Mechanism of Febuxostat
XO +
XO
還原型態
氧化型態
Xanthine
Uric acid
XO = Xanthine Oxidase
Febuxostat
Allopurinol
Life Sci. 2005. 76, 1835.
Mechanism of Febuxostat –續
Pharmacokinetic parameters of febuxostat
and allopurinol
Parameter Febuxostat Allopurinol
Absorption (%) 85 67-81
Time to max.
conc. (hr) 1 1
Protein binding
(%) 99 (primarily albumin) Negligible
Volume of
distribution (L/kg) 0.7 1.5
Metabolism Hepatic (glucuronidation
22-44%; oxidation 2-8%)
Hepatic (70% converted to the
active metabolite oxypurinol)
Elimination half-
life (hr) 8 Allopurinol 1-3; oxypurinol up to 20
Excretion Renal (< 5%, unchanged) Oxypurinol eliminated unchanged in
urine
max. = maximum; conc. = concentration
Febuxostat
肝代謝 肝代謝
代謝物
44.9%*
糞便排泄 49.1%*
尿液排泄
Allopurinol
代謝物
90%
尿液排泄
Febuxostat的代謝排泄
*健康成年男性6位,空腹單次投與[14C]Febuxostat 80 mg,經9 天收及含代謝物之總放射量與投予量之比值
Febuxostat Compared with Allopurinol
in Patients with Hyperuricemia and Gout
N. Engl. J. Med. 2005, 353, 23.
Febuxostat is superior to allopurinol for achieving
target serum UA level
45‡
67*#
42
72*
39
74*
36
0
10
20
30
40
50
60
70
80
Febuxostat
40 mg/day Febuxostat
80 mg/day
Febuxostat
80 mg/day
Allopurinol
200/300 mg/day
Allopurinol
100/300 mg/day Febuxostat
80 mg/day
Allopurinol
300 mg/day
Febuxostat 40 mg
Febuxostat 80 mg
Allopurinol
Pe
rcen
tage o
f p
atie
nts
ach
ievin
g s
eru
m u
ric
acid
le
ve
l <
6.0
mg/d
l(%
)
CONFIRMS APEX FACT
* p
0
20
40
60
80
100
120
baseline 1 2 3 4 5 final visit
Percentage of persistent tophus after use of Febuxostat
% o
f p’t w
ith p
ers
iste
nt
baselin
e tophus
100
79
50
33
21 21 31
Treatment duration (years)
Methods: Weeks 0-4: Febuxostat 80 mg/d. Weeks 4-24: dose adjustments to 40 or 120 mg/d possible.
N: The number of subjects with index tophi at baseline and remaining in the study as specified visits
n: The number of subjects with index tophi present at specified visits.
Among the 26 subjects with a palpable tophus at baseline, resolution of the index tophi occurred in 18 (69%) subjects by final
visits.
n 26 15 8 5 3 3 8
N 26 19 16 15 14 14 26
Rheumatology, 2009, 48, 188.
0
10
20
30
40
50
60
70
80
Febuxostat 40 mg
(n = 238/479)
Febuxostat 80 mg
(n = 360/503) Allopurinol 200/300 mg
(n = 212/501)
% o
f subje
cts
with s
UA
level <
6.0
mg/d
L a
t final vis
it
50%
72%
42%
*
*
* p
Clin J Am Soc Nephrol. 2013, 8, 1.
Conclusions: Febuxostat (80 mg) lowered 24-hour
urinary uric acid significantly more than allopurinol (300
mg) in stone formers with higher urinary uric acid
excretion after 6 months of treatment. There was no
change in stone size or number over the 6-month period.
Demographics and baseline characteristics
Percent change frombaseline tomonths 3 and 6 in 24-hour urinary uric acid excretion. a p
Change from baseline in stone diameter and number
Urinary variables at baseline and month 6 and change
from baseline to month 6
Febuxostat
1. 常見副作用/不耐受性、過敏反應:肝功能異常、噁心、關節炎、皮疹
2. 禁忌症:正在使用azathioprine或mercaptopurine
3. 藥物交互作用:併用theophylline時須小心
Febuxostat健保給付規定
限慢性痛風患者之高尿酸血症使用,且符合以下條件之一:
(1)曾使用過降尿酸藥物allopurinol及benzbromarone,經治療反應不佳,尿酸值仍高於6.0 mg/dl
(2)曾使用過benzbromarone治療反應不佳,但對allopurinol有不耐受性,過敏反應,或使用禁忌者使用,
Therapeutic
agent Typical regimen Side effects/Commets
NSAIDs Lowest effective
dose
• Avoid in patients with peptic ulcer disease,
active bleeding
• May cause gastritis, liver dysfunction, fluid
retention, hypertension
• Use with caution in patients with
congestive heart failure
Colchicine 0.6-1.2 mg a day • Diarrhea, peripheral neuropathy,
rhabdomyolysis
Xanthine oxidase inhibitors
Allopurinol 50-300 mg a day • Allopurinol can be used in urate
overproduction and urate underexcretion
• Common class side effects: rash, gastric
irritation, and acute gout attacks
• Rash is less common with feuxostat that
with allopurinol
Febuxostat 40-80 mg a day
(target serum urate
< 6 mg/dl)
Agents for chronic management of gout
The first placebo-controlled dosecomparison study of
colchicine for acute gout included 184 subjects and compared
low dose colchicine (1.2 mg initially, then 0.6 mg 1 h later), a
traditional high-dose regimen (1.2 mg initially followed by 0.6
mg every hour for a total of 4.8 mg), and placebo, with a
primary outcome of >50% pain reduction at 24 h. The low-
dose and high-dose groups experienced similar efficacy,
and significant and equivalent pain reduction versus placebo:
the primary outcome was met by 37.8%, 32.7%, and 15.5% of
the low-dose, high-dose, and placebo groups, respectively.
Although diarrhea was common in the high-dose group,
adverse events in the low-dose group were equivalent to
placebo. Based on these results, the US Food and Drug
Administration (FDA) approved low-dose colchicine for acute
gout in 2009.
Colchicine
Annu. Rev. Med. 2013. 64, 325.
Agents for chronic management of gout-續
Therapeutic
agent Typical regimen Side effects/Commets
Uricosurics
Probenecid 250 mg twice a day,
titrated up to 500-2000 mg
a day (target serum urate,
6 mg/dl)
• Avoid in patients with history of
urolithiasis and impaired renal function
• Probenecid can affect the excretion of
many drugs
• Sulfinpyrazone has fewer side effects
than probenecis
• Class side effects: gout flares,
gastrioinntestinal irritation, rash
50 mg twice daily, titrated
at 100-400 mg a day
(target serum urate, 6
mg/dl)
PEGylated uric acid specific enzyme
Pegloticase 8 mg IV infusion over 2
hr once every 2 weeks
• Indicated for patients with chronic gout that
have failed conventional therapies
• Contraindicated in G6PD deficiency
• Boxed warning: anaphylaxis and infusion-
related reaction
• Side effects: gout flares, infusion-related
reaction, nausea, anaphylaxis
Drugs that affect excretion of uric acid
Drugs that enhance activity of
URAT-1 (Promoting increased
uric acid levels)
Drugs that reduce activity of
URAT-1 (Promoting decreased
uric acid levels)
Pyrazinamide Probenecid
Niacin Sulfinpyrazone
Alcohol NSAIDs
Ketoacids (often endogenous) Diuretics
Aspirin (< 3 g/day) Aspirin (> 3 g/day)
NSAIDs = nonsteroidal anti-inflammatory drugs; URAT-1 = urate transporter 1.
Harrison's Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill; 2011:chap 353.
Current Medical Diagnosis & Treatment. New York, NY: McGraw-Hill; 2011:chap 20.
結語
The present review of the available literature shows
that there is an association between serum urate
levels and hypertension, CKD, heart failure, the
metabolic syndrome, obesity and cardiovascular
events. However, as is often the case in the published
literature, support is not unanimous.
痛風是一種慢性病,只要正確的處理,幾乎都可以得到良好的治 療與控制,減少併發症的發生。唯有耐心治療及長期追蹤才是成功治療 的不二法門。痛風的預防, 首要的是生活型態的調整及 使用降尿酸藥物,維持血中 尿酸值在6 mg/dL 以下。
Limitations of urate lowering therapy
treatment in Taiwan
• High proportion of renal impairment
• High proportion of hepatitis B
• High proportion of HLA-B*5801(+)
• High proportion of tophaceous gout
• Poor adherence to long-term treatment
A committee of the British National Institute for Health
and Clinical Excellence concluded that although
febuxostat had been shown to be more effective than
fixed-dose (300 mg) allopurinol in lowering serum uric
acid concentration, it had not been shown to be
clinically more efficacious or cost effective compared
with allopurinol when taken to control uric acid levels
(up to 900 mg). However, the committee recommended
febuxostat for people who are intolerant of allopurinol.
References
• 衛生福利部 • https://secure.pharmacytimes.com/lessons/201104-02.asp#
• Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York,
NY: McGraw-Hill; 2008:chap 96.
• Naproxen [package insert]. Allegan, MI: Perrigo; 2007.
• Allopurinol [package insert]. Huntsville, AL: Qualitest; November, 2007.
• Uloric [package insert]. Deerfield, IL: Takeda Pharmaceuticals America,
Inc; 2010.
• Probenecid [package insert]. Morgantown, WV: Mylan Pharmaceuticals
Inc; 1985.
• 財團法人宏恩醫院痛風治療中心 陳峙仰醫師
Purine metabolism cycle
AmidoPRT = amidophosphoribosyltransferase; ATP = adenosine triphosphate; HPRTase
= hypoxanthine phosphoribosyltransferase; PRPP = phosphoribosylpyrophosphate.
the Kaplan-Meier cumulative incidence function of gout by baseline anemia status,
suggesting that by age 70, the cumulative incidence of gout was 4.4% in those
without anemia and 10.2% in those with anemia.