痛風新藥 -- febuxostat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.


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.


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.


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.


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


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.


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


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.

痛風新藥 -- febuxostat痛風是因尿酸排泄減少或尿酸產生增加所造成 的疾病。...

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痛風新藥 -- febuxostat痛風是因尿酸排泄減少或尿酸產生增加所造成的疾病。...