University of Florida Health researchers are investigating whether a generic form of a common heart medicine used for high blood pressure, heart failure and many other conditions works as well as the brand-name prescription.
Through a $2.3 million, three-year grant from the U.S. Food and Drug Administration, UF Health researchers hope to learn if patients taking a generic form of the drug Toprol XL for high blood pressure and other heart conditions are receiving the same effective treatment they would get from the brand-name prescription. The researchers will compare the generic and brand name treatments by investigating drug concentrations in the blood and the effect the drugs have on blood pressure and heart rate.
More than 80 percent of U.S. drugs offer an approved generic option, saving patients more than $150 billion a year in medical costs, according to the FDA. Extended-release drugs are designed to release the drug in the body over a longer period of time, so patients don't have to take the drug as often. For some extended-release drugs, the rate at which the drug enters the blood may affect treatment outcomes in patients, and the formulation is often more challenging to copy. The FDA is proactively conducting a post-market clinical trial regarding generic extended-release products.
Approved by the FDA in 1992, Toprol XL, a beta-blocker, has been effective in treating patients with high blood pressure, heart failure and other heart diseases. Generic formulations of the drug later became available, offering a cost savings of up to $2,000 a year to patients. In 2013, Toprol XL, or metoprolol, was the fourth most commonly prescribed drug in the United States, with about 84 million prescriptions.
When switching from a brand name to a generic drug, the FDA looks for bioequivalence, meaning the same amount of drug is absorbed from a given dose whether the medication be brand name or its generic counterpart. Similarly, the bioequivalence of other extended-release drugs, such as those used for treating depression and epilepsy, also have been examined recently by the FDA.
"Our study will employ state-of-the-art approaches for determining drug levels in the bloodstream, gastric pH and genetic makeup to address questions regarding the bioequivalence of various extended-release metoprolol products," said Larisa Cavallari, Pharm.D., an associate professor of pharmacotherapy and translational research in the UF College of Pharmacy.
Led by Cavallari, the UF Health study will look at levels of different drug formulations in the blood to understand how the body absorbs and metabolizes each generic drug compared with the brand-name product. The research team also will evaluate the effects of each formulation on the body, including their ability to lower blood pressure and affect heart rate. Julie A. Johnson, Pharm.D., a distinguished professor and dean of the UF College of Pharmacy, is the co-principal investigator on this study.
Cavallari and Johnson also will work closely with other health researchers and practitioners to further demonstrate the drug's stability and release into the intestinal tract. Physiological factors, including pH levels and gastric motility, might cause differences in blood levels between brand name and generic products. Varying with each patient, these and other factors may determine how much of the drug's active ingredient actually becomes available in the bloodstream after metabolism.
"A collaborative team of UF Health researchers in the colleges of Pharmacy and Medicine and a cardiologist from The Ohio State University allows our study to apply our combined experience in pharmacology, cardiology and gastrointestinal medicine to clearly define any differences between products," said Cavallari, who also directs the UF Center for Pharmacogenomics.
The researchers will use patient facilities at the UF Clinical and Translational Science Institute to conduct studies on 30 to 40 volunteers who have participated in Johnson's previous pharmacogenomics studies of common antihypertensive drugs. Funded by the National Institutes of Health, the earlier studies sought genetic predictors of patient responses to blood pressure-lowering medications. Siegfried Schmidt, M.D., Ph.D., a professor of community health and family medicine at UF, participated in the earlier studies and will oversee the clinical components of the FDA-funded study.
In the new study, the patient volunteers, who are being treated for chronic high blood pressure, will undergo three overnight hospital stays that will allow doctors to monitor blood pressure and heart rate and take blood samples to track drug levels. They also will track pH levels in the gastrointestinal system.
The researchers are also investigating how common genetic variations in the drug metabolizing enzyme CYP2D6 - which acts on one-quarter of all prescription drugs - may affect the brand and generic forms of the drug in its ability to lower blood pressure and regulate heart rate.
To better understand the combined effects of genotype and gastric pH on drug performance in the study patients, mathematical modeling will be used to understand the movement of the drug in the body to determine how much of the drug is in the blood. The amount of medication in the body will be linked with the effect it is having on the patient, such as lowering blood pressure or heart rate.
"The results of this study will help the FDA determine the criteria necessary for improving generic extended-release metoprolol products to ensure safe and high-quality generic alternatives for patients," Cavallari said.
Funding for this study was made possible, in part, by the Food and Drug Administration through grant1U01FD005235-01.