By Alice Goodman
Medscape Medical News

October 29, 2009 (Philadelphia, Pennsylvania) — New dosing guidelines for colchicine (Colcrys) provide important information about drug–drug interactions with calcium-channel blockers commonly used to treat hypertension. These guidelines are also applicable to other drugs that inhibit CYP450 3A4 and P-glycoprotein when used concomitantly with colchicine.

"This study is an extension of a previous study that looked at verapamil and diltiazem for drug–drug interactions. Gout affects more than 5 million adults in the United States, and 50% of people with gout have hypertension, so this information can affect a huge number of patients. These data provide critical guidance for physicians about previously unknown drug–drug interactions and will help prevent toxicity and optimize use of this drug," said Robert Terkeltaub, MD, who presented the results of this and a related study here at American College of Rheumatology (ACR) 2009. Dr. Terkeltaub is section chief of rheumatology/allergy at the VA Medical Center in San Diego and professor at the University of California at San Diego.

Colcrys is the only form of colchicine approved by the US Food and Drug Administration for the treatment of acute gout. Generic forms of colchicine have been used off-label for several years. The results of this study on verapamil are similar to those on drug interactions between diltiazem and colchicine, Dr. Terkeltaub explained.

The first study to evaluate drug–drug interactions between verapamil and colchicine found that verapamil increased the blood concentration of colchicine by 30%, increased exposure by 99%, and increased clearance by 52%.

Thus, when treating an acute flare of gout, the dose of oral colchicine should be reduced from 3 to 2 tablets for patients receiving verapamil or diltiazem. When administered chronically, colchicine doses should be reduced by 50% in patients receiving concomitant verapamil or diltiazem.

"The dose [of colchicine] should be adjusted for tolerance, age, and renal function," Dr. Terkeltaub added.

The phase 1 open-label 2-period study was an analysis of blood samples from healthy volunteers taking a single oral dose of colchicine 0.6 mg on day 1. Blood samples were obtained on days 2, 3, 4, and 5. After a washout period, subjects received verapamil once daily for 5 days on day 15, followed by a second dose of colchicine on day 19. Blood samples were obtained again on days 20, 21, 22, and 23.

Based on this study, similar dose adjustments should be made when colchicine is given concomitantly with strong CYP3A4 inhibitors like verapamil, clarithromycin, ketoconazole, and nefazodone, Dr. Terkeltaub emphasized.

"This study represents the first evidence-based dosing guidelines in a regular prophylactic setting where colchicine is given for 6 months or more," he added.

"These new guidelines are very important because many patients with gout have a great deal of comorbidity and are taking other medications, which limits their treatment options. These guidelines will help optimize the use of this drug for patients with gout," said

Anthony Reginato, PhD, from Rhode Island Hospital in Providence, made these remarks while giving attendees a tour of important poster presentations, including these studies.

Dr. Terkeltaub was also first author of a separate study of 75 healthy volunteers showing that low-dose (1.2 mg + 0.6 mg after 1 hour) and high-dose (1.2 mg + 0.6 mg for 6 doses) colchicine achieved similar steady-state plasma concentrations and blood levels. Following a gout flare, peak colchicine blood levels of around 6 ng/mL provide adequate pain relief within the first 24 hours. Dr. Terkeltaub said that on the basis of this study, low-dose colchicine is recommended for early acute gout flare treatment, and that additional exposure to high-dose colchicine could increase unwanted adverse effects.

The study was sponsored by URL Pharma. Dr. Terkeltaub reports financial relationships with NIH, Altus, Ardea, BioCryst, Novartis Pharmaceutical Corporation, Pfizer Inc, Proctor and Gamble, Regeneron, Savient, EnzymeRx, Takeda, URL Pharma, and UCB. Dr. Reginato has disclosed no relevant financial relationships.

American College of Rheumatology (ACR) 2009. Abstract 1107. Presented October 19, 2009.

新的Cochicine(Colcrys)給藥劑量指引提供有關併用經常用於降血壓的鈣離子阻斷劑相關藥物與藥物交互作用重要資訊。這些指引也適用於與Colchicine併用的其他抑制CYP450 3A4與P醣蛋白藥物。
  這項研究是過去一項針對verapamil與diltiazem藥物交互作用研究的延伸。在美國,痛風影響了超過5百萬位成人病患,其中50%痛風病患同時罹患高血壓,因此這樣的資訊將會影響非常多病患。Robert Terkeltaub醫師指出,這些數據提供了醫師們有關過去未知藥物與藥物交互作用的重要指引,且將協助預防這些藥物的毒性,並且最佳化這些藥物的使用;Terkeltaub醫師是聖地牙哥VA醫學中心風濕學/免疫學科主任,也是聖地牙哥加州大學的教授,他在美國風濕醫學會(ACR)2009年會發表上述發現及一項相關研究結果。
  這項第一期、開放標記的兩段研究是採自健康志願者血液樣本,這些志願者在第1天服用單一劑量的colchicine 0.6 mg。接著,在第2、3、4與5天採集血液樣本。從第15天後,藥物排出期後,志願者們接受每天一次的verapamil,持續5天,接著在第19天時,服用第二次劑量的colchicine。在第20、21、22與23天再次採集血液樣本。
  Terkeltaub醫師強調,根據這項研究,當colchicine併用其他CYP450 3A4強烈抑制劑時,例如verapamil、clarithromycin、ketoconazole與nefazodone時,可以進行類似的劑量調整。
  來自普洛登維士羅德島醫院的Anthony Reginato博士在與聽眾介紹重要壁報發表時,包括這些研究,提供這些評論。
  Terkeltaub醫師也是另一項收納75位健康受試者研究的第一作者,該項研究結果顯示,低劑量(1.2 mg與1小時後投予0.6 mg)及高劑量(1.2 mg與0.6 mg投予6次)colchicine達到相似的穩定血清與血液濃度。在痛風急性發作後,colchicine最高血中濃度大約是6 ng/ml,可以在24小時內提供足夠的疼痛緩解。Terkeltaub醫師表示,根據這項研究,低劑量colchicine建議用於急性痛風發作初期處理,而額外暴露在高劑量的colchicine會增加不必要的副作用。
  這項研究由URL Pharma公司贊助。Terkeltaub醫師報告與NIH、Altus、Ardea、BioCryst、Novartis Pharmaceutical Corporation、Pfizer Inc、Proctor與Gamble、Regeneron、Savient、EnzymeRx、Takeda、URL Pharma與UCB有相關資金上的往來。Reginato醫師表示已無相關資金上的往來。



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