Study urges caution with Lenalidomide dosage

An early stage multiple myeloma process unexpectedly has shown that the drug lenalidomide communicates with another protein in cells that affect the dose level in the body, say researchers from the Ohio State University Comprehensive Cancer Center-Arthur g. James Cancer Hospital and Richard j. Solove Research Institute (OSUCCC-James) that the study conducted.

Lenalidomide is an anti-inflammatory drug, and more than 390 clinical trials have been initiated to study its activities in a number of forms of cancer and other diseases.

The study found that lenalidomide communicates with P-glycoprotein (Pgp), a molecule that are potentially toxic chemicals from cells and aids in the removal of these chemicals from the body pump. Abnormally high levels of Pgp in cancer cells can be a major cause of drug resistance for many cancer patients.

The findings, published online in the Journal of Clinical Oncology, may lead to safer dosing of lenalidomide in a variety of diseases.

"This is the first report indicating that lenalidomide communicates with Pgp, and our clinical data this can be an important consideration suggests for the proper dosage of the drug," says study leader and researcher Dr. Mitch Phelps, Assistant professor at the Ohio State College of pharmacy. "Some toxicities induced by lenalidomide can serious and life threatening."

The phase I clinical trial in relapsed, resulting in the safety of a new drug or drug combination, involved 21 patients with multiple myeloma, a deadly disease that affects more than 20,000 Americans each year and kills more than 10,600 of them.

The process lenalidomide combined with temsirolimus, a drug which the researchers knew from the beginning in interaction with Pgp. lenalidomide during the study, blood levels in patients were often higher than expected, and some patients experience side effects such as electrolyte imbalances and rashes that were larger than expected.

To the surprise of researchers showed laboratory experiments that lenalidomide was removed from the cells by Pgp, and disposal was reduced when temsirolimus was included in the experiments. That data was proof that the two drugs through Pgp, which a potential explanation for the observed in patients ' blood samples changed lenalidomide levels interact, Phelps explains.

"Although this was a relatively small study, we saw an important pharmacokinetic interaction between the two agents," says Phelps. "That, along with side effects that were larger than expected, brought us to the conclusion that the interaction of the agents with Pgp may be the cause of this increased toxicity," says Phelps.

Phelps notes that many medicines interact with Pgp. "this is indicated on the labels of drugs approved by the Food and Drug Administration, which helps prevent the administration of drugs that inhibit interaction with Pgp or Pgp that, one of those to negative drug-drug interactions may lead," says Phelps.

The Food and Drug Administration (FDA) approved in 2005 lenalidomide for the treatment of myelodysplastic syndrome syndromes and in 2006 for multiple myeloma.

"It is unusual to discover a few years after approval by the FDA that a drug with Pgp cooperates," says Phelps. Probably the delay occurred because the drug primarily by the kidneys in the urine excreted, says Phelps. To this it had been assumed by filtration, which is a passive process independent of Pgp or other carrier proteins. "Although the kidneys can have the primary task of eliminating lenalidomide, our findings indicate that the Pgp and other factors also can make a significant contribution," he says.

"We must now studies confirm these findings to determine their meaning when lenalidomide is combined with other substrates Pgp in various disease populations," says Phelps.

Article reference:
Ohio State University Medical Center