Potential side effects and toxicity: The effect on blood fats have traditionally been of concern with antiviral drugs. However, mean triglyceride decreased and cholesterol levels remained stable over time in all groups of patients on TMC-114 during C202 study. During the study comparing TMC-114 to control groups, there was a high discontinuation rate in the controls (patients in the study not receiving TMC-114, but still taking other protease inhibitors). Thus, due to virologic failure in controls, they had less drug exposure, compared to the patients taking TMC-114. This bias in control failures resulted in a disproportionate incidence of adverse events. However, when Tibotec analyzed the results based on per 100 patient years, side effects of nausea did not demonstrate any difference and diarrhea was lower in TMC-114 arms compared to the control of other protease inhibitors. Headache and fatigue was lower in TMC-114 than control groups. In other words, when adjusted for many more patients taking TMC-114 during the study and large treatment failures in control arm, the analysis did not show any increased side effects due to TMC-114. The take home message should be that TMC-114 has shown very good safety and tolerance.
Additionally, elevated liver enzymes occurred in 2-3% of patients in all TMC-114 groups combined.
Potential drug interactions: The standard drug interactions being seen due to ritonavir should be maintained, thus rifamycins and anticonvulsants have drug interactions. Also erectile dysfunction drugs should be dosed accordingly.
Protease inhibitors increase blood levels of Viagra, Cialis and Levitra. Use with caution. Initially the Viagra dose should be 12.5 mg (1/2 of 25 mg tablet) and increased as needed and tolerated. It’s recommended that people on PIs do not exceed 25 mg of Viagra in a 48-hour period because of potential for serious reaction. Use Cialis at reduced doses of 10 mg every 72 hours and Levitra at reduced doses of no more than 2.5 mg every 72 hours, with increased monitoring for adverse events.
Tips: Expected to be FDA approved in 2006. Became available through an expanded access program in late 2005. Visit www.tibotec.com or www.clinicaltrials.gov, or contact the company toll-free number above. TMC-114 was shown to be very well-tolerated; low side effect profile and low rate of discontinuation due to adverse events. It has also shown to be highly active against a wide range of resistance mutations or multi-drug resistant strains that was unprecedented, compared to other drugs studied for patients with advanced disease or resistance. Finally, a significant increase in CD4 T-cell counts were also seen in the studies of patients on TMC-114. At press time, the proposed brand name was “Darunavir.” For more info see www.tpan.com/publications/pa/mar_apr_05/tmc-114.shtml.—page written by Dan S. Berger, MD
Doctor
TMC-114 is a novel next-generation protease inhibitor that is currently in Phase III clinical trials. It is anticipated to receive FDA approval sometime in late 2006 or early 2007. Similarly to tipranavir, TMC-114 was designed to retain antiviral activity against virus that is resistant to other protease inhibitors. In early phase trials, this drug was given together with a small booster dose (100 mg) of ritonavir, and proved more effective than either placebo or comparator protease inhibitors against virus with three or more primary protease mutations. Overall this drug seems to be generally well-tolerated with the same expected side effects seen with most other protease inhibitors (gastrointestinal intolerance, diarrhea, and nausea).—Chad J. Zawitz, MD
Activist
This new promising PI has not been approved yet but is available through expanded access for those with CD4 cells of 200 or under, and who have failed most drugs available in the market. So far, Phase II data look very good in those patients with multi-drug resistance. It seems to have most of the common PI-related side effects. The most commonly used dose will be 600 mg along with 100 mg of Norvir as a booster, both twice a day. I am looking forward to seeing more data of TMC-114 plus entry inhibitor combinations in salvage patients soon. Tibotec is also starting a combination study of its non-nuke TMC-125 plus TMC-114, a first in the HIV drug development world where two investigational agents are combined prior to approval. I applaud Tibotec for this courageous step, which will set the tone for future research studies encouraging Multi-Experimental Agent Trials (MEAT).—Nelson Vergel
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