Saturday, October 24, 2009

Caution Urged on Dose-Dumping Drugs

Manufacturers should consider ethanol vulnerability at design stage

A Swedish researcher has concluded that controlled release drugs that are vulnerable to alcohol-induced “dose dumping”—releasing the drug faster and in higher concentrations than is safe—should be withheld from the market or reformulated.

Hans Lennernäs, PhD, professor of biopharmaceutics, department of pharmacy, Uppsala University, Uppsala, Sweden, recommends that pharmaceutical companies “avoid developing and marketing oral controlled release products whose in vivo dissolution and/or absorption is sensitive to intake of alcoholic beverages.”

Further, “before any work and investment of a new oral controlled release product is initiated, it is crucial [that manufacturers] consider the ethanol vulnerability of the pharmaceutical formulation that is on the design table,” Dr. Lennernäs told Pharmaceutical Formulation & Quality. The research was published recently in Molecular Pharmaceutics.

an important Problem

Matthew Traynor, PhD, a senior lecturer in pharmaceutics in the school of pharmacy at the University of Hertfordshire in Hatfield, England, agrees this is an important problem. “I strongly believe that no more formulations of this type should be made or approved without full and rigorous checking for this problem,” Dr. Traynor told Pharmaceutical Formulation & Quality.

The problem does not appear to be widespread, however, he said. “The number of potentially problematic formulations reported, combined with the fact that alcohol is generally contraindicated with these formulations anyway, means that this is not a widespread problem that will have a significant impact on a large number of patients,” Dr. Traynor said.

Further, although several authors have reported in vitro data with isolated examples of alcohol-induced dose dumping at concentrations relevant to real-life alcohol consumption, the number of adverse events reported for products currently on the market is low, Dr. Traynor said. “A problem exists. No more formulations of these type with excipients susceptible to alcohol should be approved without more rigorous testing—perhaps at all—but a full recall of all products is an over reaction.

“However, in light of the numerous reports of this phenomenon that have been observed in vitro, a more rigorous examination of new products in development and seeking regulatory approval is a wise move,” he added. “The FDA is actively seeking a solution as to what is the best, most robust method for performing such studies.”

Keys to Dose-Dumping Risk

According to Dr. Lennernäs, several key factors determine a drug’s dose-dumping risk:

  • the solubility of the pharmaceutical excipients;
  • the solubility of the drug;
  • the formulation’s drug release mechanism;
  • the pharmacological effects of the drug; and
  • the gastrointestinal factors critical for dissolution, transit, and absorption.
  • The risk for dose dumping is high when these factors are in interplay,” he said.

If a formulation proves susceptible to alcohol as described by the U.S. Food and Drug Administration’s established in vitro guideline, the next step is in vivo testing in human volunteers, Dr. Lennernäs said.

The manufacturer should reformulate the product if in vivo testing reveals an increased absorption rate in healthy people who have consumed alcohol, Dr. Lennernäs said. Reformulation would increase the safety of any drug arsenal in any country.

This testing is important because it is impossible to predict when and in which patients dose dumping will occur, Dr. Lennernäs said. The alcohol-drug interaction depends on drinking behavior and highly variable gastrointestinal factors critical for dissolution, transit, and absorption.

The patient who takes an ethanol-vulnerable controlled release drug just before bedtime with a large volume of strong alcohol—say, two double whiskeys—is at the greatest risk, he said. “In this case, the patient’s reclining posture may prolong the gastric residence of the drug, making a harmful interaction more likely. If the ethanol-vulnerable drug is an opioid, the effect of the opioid itself may also prolong gastric residence.” Elderly patients are at substantial risk for dose dumping because they have less stable gastrointestinal function that may be exacerbated by the effects of other drugs they are taking.

Cord Blood Cells Converted into Embryonic-Like Cells

Cells free of genetic mutations found in converted adult cells

Reprogramming cells is not new science. Researchers have been taking adult cells and converting them into embryonic-like cells for several years. In a new twist on a familiar theme, however, a research team has reprogrammed human cord blood cells into embryonic-like cells.

Cord blood induced pluripotent stem cells (iPSC) offer two advantages, said Juan Carlos Izpisúa Belmonte, PhD, a professor in the gene expression laboratory at the Salk Institute for Biological Studies.

First, reprogrammed cord blood cells are mutation free. “When we become adults, we develop mutations in our cells. If you reprogram those cells, the mutation will stay there,” Dr. Izpisúa Belmonte told Pharmaceutical Formulation & Quality. “[Cord blood cells] have not accumulated any genetic stress because of living.”

Second, cord blood cells require less immunological matching, said Dr. Izpisúa Belmonte, who led the study. When reprogrammed cells taken from the skin and hair are used, they must be immunologically matched to the receiving patient or they will be rejected. Cord blood cells do not stimulate rejection by the immune system. “You don’t need to have a full matching requirement between the patient and donor for the graft to work,” he said. The research was published recently in Cell Stem Cell.

Cord Blood Readily Available

These cells offer a practical advantage, too. Currently, there are more than 400,000 cord blood units available worldwide. By now, the cord blood banks around the globe cover most people with regard to immunological matching, Dr. Izpisúa Belmonte said. “If you were to need a cord blood transplant, the right one for you is probably already in a bank, whether it is in London or New York.”

This easy accessibility would allow researchers to reprogram the most common haplotypes, making them available for most of the world’s population, Dr. Izpisúa Belmonte said. This would significantly reduce the number of cell lines needed for human leukocyte antigen matching. “I’m not certain about the exact number, but I think to cover 60% to 70% of the world’s population, you would only have to reprogram 500 cord blood cell types,” he said. “That’s manageable.” These embryonic stem cells could be stored in a bank, much like the cord blood bank model.

Reprogrammed cord blood cells offer great promise, said another researcher. “Although all therapeutic options are highly speculative and premature at this time, because umbilical cord blood cells are so widely banked, generating iPSC from them might make them even more valuable as a source of pristine, versatile stem cells,” said George Q. Daley, MD, PhD, an associate professor in the department of biological chemistry and molecular pharmacology at Harvard Medical School.

Only Two Factors Needed

It takes about two weeks to reprogram cord blood cells, which is quicker than reprogramming adult cells. In addition, Dr. Izpisúa Belmonte and colleagues were able to reduce the number of factors needed from four to two. “This is a technical advancement. The four factors we used to reprogram cells, they are oncogenes—they can induce cancer. So if we eliminate some of them, well, we reduce the risk of cancer.”

It remains unclear exactly how these factors reprogram a cell. Until researchers solve the “black box” of reprogramming, the field cannot advance, Dr. Izpisúa Belmonte said. “Yes, you’ve reprogrammed cord blood cells, you generate a bank, but if these cells have an ability to induce cancer, you are not going to transplant that cell into a human being.” These cells demonstrate enormous potential, but they are still years from clinical use,

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