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| |  ICAAC: Blood Levels of Crixivan Boosted By Ritonavir SAN FRANCISCO, CA. -- September 27, 1999 -- A new pharmacokinetic study of once-daily Crixivan® (indinavir sulfate) combined with another protease inhibitor, ritonavir(A), showed that blood levels of Crixivan were boosted to levels that were comparable to those seen in a prior study with the approved dosing of Crixivan (800 mg every eight hours). The three once-daily dosing regimens studied were Crixivan 800 mg combined with 100 mg or 200 mg of ritonavir, and 1,200 mg of Crixivan with ritonavir 100 mg. The blood levels in the Crixivan 1,200 mg and ritonavir 100 mg regimen were actually higher than the levels seen with the approved dosing of Crixivan (800 mg every eight hours). The results of this Merck study were presented at the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). "Based on findings from this once-daily pharmacokinetic study of Crixivan combined with ritonavir, clinical studies in patients are now underway to evaluate the safety and efficacy of once-daily combinations of Crixivan with ritonavir," says Dr. Alfred Saah, associate director, Merck Research Laboratories, who led the study. "Once-daily regimens are important treatment options for patients who have difficulty adhering to frequent dosing schedules, are just starting treatment, or live in unique settings such as prisons." This study was undertaken as a result of the favorable pharmacokinetic profile seen with twice-daily Crixivan (800 mg) combined with ritonavir (100, 200 or 400 mg) in a study that was presented at the Sixth Conference on Retroviruses and Opportunistic Infections in February 1999. Crixivan in combination with other antiretroviral agents is indicated for the treatment of HIV infection. The approved dosage of Crixivan is 800 mg every eight hours. The indication for Crixivan is based on two clinical trials of approximately one-year duration that demonstrated a reduction in the risk of AIDS-defining illnesses or death and a prolonged suppression of HIV RNA.
Blood Levels of Crixivan Boosted By Ritonavir The 14-day study of 33 healthy volunteers evaluated the pharmacokinetics (i.e., the peak level, minimum level and total amount of Crixivan in the bloodstream over a 24-hour period) of the following combinations of Crixivan dosed with ritonavir once-daily: - Crixivan 1,200 mg with ritonavir 100 mg (11 participants); - Crixivan 800 mg with ritonavir 100 mg (11 participants); and - Crixivan 800 mg with ritonavir 200 mg (11 participants). Blood levels were measured on day 14 after study participants took their final dose and ate a meal consisting of a muffin and a glass of milk. These blood levels were then compared to pharmacokinetic data from a previous Merck study with the standard dosing of Crixivan dosed 800 mg every eight hours taken with a light meal or on an empty stomach. Once-daily Crixivan 1,200 mg combined with ritonavir 100 mg produced: - total daily blood levels of Crixivan that were 1.5 times higher than; - peak (i.e., highest over 24 hours) blood levels that were 1.8 higher than; and - minimum (i.e., lowest over 24 hours) blood levels that were comparable to the approved dosing regimen of Crixivan. Crixivan 800 mg dosed once-daily with 100 mg or 200 mg of ritonavir resulted in peak, minimum and total daily blood levels of Crixivan that were comparable to standard therapy with Crixivan. The combinations were generally well-tolerated. The study was partially blinded and volunteers did not know which dosage regimen they received. Adverse events reported include gastrointestinal discomfort, headaches and oral parasthesias (abnormal sensations around the mouth).
Combination Studies of Crixivan With Ritonavir Ongoing The findings from this once-daily pharmacokinetic study with ritonavir are part of Merck’s commitment to explore Crixivan in simplified combination regimens with other protease inhibitors. Merck has initiated a pilot study in patients to investigate the safety and efficacy of once-daily dosing regimens of 1,200 mg of Crixivan combined with 200 mg of ritonavir. Blood levels of Crixivan will be measured as part of this study. Also underway are clinical studies of twice-daily regimens of Crixivan combined with low dosages of ritonavir. The antiviral effects of 800 mg of Crixivan combined with 100 mg of ritonavir in patients who have not previously taken a protease inhibitor, and 800 mg of Crixivan combined with 200 mg of ritonavir in patients who have failed a protease inhibitor-containing regimen, will be evaluated in these studies.
Simplified Dosing Regimens Important For Many Patients Merck’s HIV research efforts are focused on developing treatment options that will offer convenience through twice-daily or once-daily regimens, along with the potent and durable treatment outcomes seen with the standard dosing of Crixivan. "Simplified regimens are critical for patients who have difficulty adhering to regimens that have frequent dosing requirements or that restrict the time or type of meal a patient can eat," says Saah. "Likewise, simplified dosing regimens may be also important treatment options for patients in unique settings, such as prisons, where once-daily dosing could make it easier to treat more HIV-positive patients."
Important information about Crixivan Crixivan can be taken with a light meal or on an empty stomach. There are some common and AIDS-related medications that should not be taken with Crixivan. Crixivan should not be administered concurrently with Seldane® (terfenadine)(B), Propulsid® (cisapride), Hismanal® (astemizole), Halcion® (triazolam), Versed® (midasolam), or ergot derivatives such as Wigraine® and Cafergot®. Taking Crixivan with the above medications could result in serious or life-threatening problems (such as irregular heartbeat or excessive sleepiness). Crixivan is generally well-tolerated. There are side effects associated with protease inhibitors in general and Crixivan in particular. Some patients treated with Crixivan may develop kidney stones. For some, this can lead to more severe kidney problems, including kidney failure. Drinking at least six glasses of water a day may help reduce the chance of forming a kidney stone. Other side effects that have been reported include liver problems and rapid breakdown of red blood cells. As with other protease inhibitors, increased bleeding in some patients with hemophilia and increased blood sugar levels and diabetes have been reported and severe muscle pain and weakness have occurred in patients also taking cholesterol-lowering medicines called "statins".
Worldwide Use of Crixivan More than 180,000 people with HIV/AIDS around the world are on treatment with Crixivan today, and it is approved in more than 80 countries. Merck & Co., Inc. is a global, research-driven pharmaceutical company that discovers, develops, manufactures and markets a broad range of human and animal health products, directly and through our joint ventures, and provides pharmaceutical benefit services through Merck-Medco Managed Care. (A) Ritonavir (Norvir®), Abbott Laboratories (B) The brands listed are the registered trademarks of their respective owners and are not trademarks of Merck & Co., Inc.
Related Links: Crixivan and Merck & Co., Inc..
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