HEALTH-SYSTEM EDITION
CLINICAL PRACTICE

Here's a preview of new drugs for 2004 and beyond

Clinicians will soon be able to offer patients with cardiovascular diseases, oncologic disorders, and infectious diseases drugs that take novel approaches to treating these conditions. Several sessions at the recent American College of Clinical Pharmacy annual meeting in Atlanta titled Through the Crystal Ball: Agents in the Pipeline gave pharmacists a sneak preview of the new agents they can expect to see in the near future.

Ximelagatran (Exanta, AstraZeneca) has been through several phase III clinical trials and is likely to receive approval soon, said Robert Parker, Pharm.D., FCCP, associate professor at the University of Tennessee College of Pharmacy. Compared with other anticoagulants, such as warfarin, ximelagatran has an expedient onset of action of approximately two hours, he said. In addition, it is not affected by the cytochrome P450 system or food and is excreted almost entirely by the renal system. No monitoring of the anticoagulant activity is necessary, because it is available as a fixed dose, he added. (For more on ximelagatran, see "Drugs linked to QT syndrome now grouped by risk level".)

Ranolazine (Ranexa, CV Therapeutics) is a partial inhibitor of fatty acid oxidation that reduces myocardial oxygen demand, Parker said. In clinical trials, it was found to prolong exercise duration, time to onset of angina, time to ST depression, and frequency of angina episodes compared with placebo or when added to standard background antianginal therapy. Unlike standard treatments for angina, ranolazine does not have an effect on blood pressure or heart rate, he noted.

Ranolazine therapy was found to cause a dose-related prolongation of QT interval and is likely to have a black box warning regarding QT prolongation, Parker cautioned. He said the Food & Drug Administration Renal & Cardiovascular Drugs Advisory Committee review for September 2003 was canceled and rescheduled and should be occurring very soon.

The greatest progress in new oncologic therapies is directed at the capacity of tumor cells for self-sufficient growth signaling and their ability to evade apoptosis and sustain angiogenesis, said Lisa Davis, Pharm.D., FCCP, BCPS, BCOP, associate professor of clinical pharmacy at the University of the Sciences in Philadelphia. Cetuximab (Erbitux, ImClone/ Bristol-Myers Squibb) is a chimeric monoclonal antibody that binds to the epidermal growth factor receptor (EGFR) on cell membranes with high affinity and prevents ligand binding to the EGFR. This stimulates receptor internalization and degradation and downregulates EGFR expression, she said, so receptor dimerization, tyrosine kinase phosphorylation, and signal transduction are blocked. Cetuximab is in phase III trials, and a Biological License Application has been submitted, she said.

Erlotinib (Tarceva, OSI/Genentech) is an orally bioavailable quinazoline, said Davis. It is a competitive inhibitor at the tyrosine kinase ATP binding site that inhibits ligand-induced cell growth. The results of the phase III trials of erlotinib have not yet been published.

Then there is bevacizumab (Avastin, Genentech), a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF), Davis said. It binds to the VEGF ligand directly to prevent VEGF signaling via VEGF receptor 1 and VEGF receptor 2.

In a phase III trial, the median survival of metastatic colorectal cancer patients who received bevacizumab plus the standard therapy of irinotecan (Camptosar, Pfizer), 5-fluorouracil, and leucovorin was prolonged compared with that of persons who received placebo plus the standard regimen. This drug will probably be approved within the next year, Davis concluded.

The number of new anti-infectives that will become available over the next several years is very limited, said Diane Cappelletty, Pharm.D., associate professor of pharmacy practice at the University of Toledo College of Pharmacy in Ohio. Telithromycin (Ketek, Aventis Pharmaceuticals) should receive approval sometime in the spring, she said. It will be the first in the ketolide class of antibiotics. Telithromycin is active against macrolide-susceptible and resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), and S. pyogenes, she said. Potential adverse events associated with telithromycin include difficulty focusing and QTc prolongation similar to that associated with macrolide therapy.

Cappelletty said that garenoxacin (Toyama Chemical) will be the first in the des-6-fluoroquinolone class of antibiotics. It is more active against Staphylococcus and Streptococcus compared with other bacteria, and minimal inhibitory concentrations are low even for MRSA and enterococci.

Preclinical trials and drug development are focused more on immunomodulation or immunotherapies, compared with treatments for an existing infection, Cappelletty said.

Charlotte LoBuono

 

Charlotte LoBuono. Here's a preview of new drugs for 2004 and beyond. Drug Topics Dec. 8, 2003;147:HSE2.