The future is here as genetically engineered drugs enter the hospital

In one vision of the future of drugs and genetic engineering, an elderly patient won’t have to give up a meal in order to take medication because the meal will be the medication. That may sound far-fetched to some — a recent caller to a National Public Radio program dubbed it "Frankenfood" — but researchers say compounding the drugs for this new science will soon become an everyday experience in hospitals.

"Pharmacists will need to know the pharmacodynamics and pharmacokinetics of the new drugs," Robert Piepho, PhD, dean of the school of pharmacy at the University of Missouri-Kansas City, tells Drug Utilization Review.

In one new approach, plants are being studied for possible use as a drug delivery system. Researchers are studying the raising of corn whose kernels would produce and house drugs. "The genetic makeup of the corn is modified," says Piepho. "The kernel is planted, the plant grows, and you get drug produced as part of the plant. The drug is there, and it’s in stable form."

From there, the corn can be used for making cornmeal and other forms of food intended, basically, for dosing of drug. "Some people are asking if we’ll even need drugs 30 years down the road in the way we think of them today," Piepho says. "It may be that we’ll have dietary packages to match to each person. Using plants as machines could cause a big change in the way we view medicine."

As research into new technologies continues to flourish, hospital pharmacists soon will find themselves having to understand the newly unfolding science of genetic engineering and the way it will affect their business.

"All the information will be new," he explains. "Receptor variations will be identified in patients so that metabolism and isoenzymes can be matched perfectly to patients. We’ll list isoenzyme variations down one side of the paper and drug classes down the other side, then match one to the next. Each drug we’ll be able to use in some people but not in others. For example, there are probably many people out there who can safely use terfenadine without a problem. They would have no metabolic issue with ketoconazole. Never a blip in QTc. But we don’t know who those people are. Down the road, we will know who they are."

Roger Dabbah, PhD, associate director of the division of biologics and biotechnology at United States Pharmacopeia in Rockville, MD, and co-author of a general information chapter of the Pharmacopeial Forum on cell and gene therapy products,1 says hospital pharmacists in particular will be affected by the new gene therapy products. "Pharmacists will be part of the team to compound the new drugs," he tells DUR. "The products naturally have a very short half-life, and many have to have the final preparation performed at the patient’s bedside or in the pharmacy."

Repairing clinical damage

New discoveries have enabled medical scientists to identify specific genes whose presence, absence, or alteration can trigger specific diseases. With that information comes the power of gene manipulation and the knowledge of how and where to retrieve a new gene to repair clinical damage. Two new categories of products that resulted from this newfound knowledge are cell therapy and gene therapy products.

"Cell therapy products contain living cells as one of their active ingredients," Dabbah writes, "while gene therapy products contain pieces of nucleic acid, usually deoxyribonucleic acid [DNA] as one of their active ingredients. Some products combine both categories, resulting in a therapy that uses cells that express a new gene product."

Certain cell therapy products already are commonplace. These products involve live cells that "replace, augment, or modify the function of patients’ cells that are diseased, dysfunctional, or missing," Dabbah writes. Bone marrow for transplantation, a well-known example of cell therapy, comes from three sources: autologous, meaning the cells come from the patient; allogeneic, meaning the cells come from a donor human; and xenogeneic, meaning the cell source is an animal.

Each source has positive and negative components. Autologous products are not rejected by the patient because they originate in the patient. However, if the original problem is the absence of or damage to the gene, autologous therapy often is not an option. Allogeneic therapy does not cause as strong a reaction as xenogeneic therapy can, but xenogeneic therapy is an option when human cells are either unavailable or are in short supply.

"Cell therapy products are sometimes encapsulated in a device that prevents the patient’s cells and antibodies from killing the xenogeneic cells," Dabbah writes. "Much research is focused on identifying and propagating stem cells, regardless of the source, because stem cells can be manipulated to differentiate either during manufacturing or after administration."

Already, parents are adding one more child to their families in order to harvest stem cells or bone marrow from the new family member to donate to an older sibling with a life-threatening disease, according to a story in the Oct. 5 Financial Times. One family has become the first to pre-screen a new sibling prior to implantation for in vitro fertilization, ensuring a biological match for transplant of stem cells, the story reports.

Gene therapy products can be classified by their delivery system. Some use viral vectors as their mode of transportation and transduction into cells. Some nucleic acids are in a simple (or naked) formulation, while other nucleic acids are formulated into delivery systems such as liposomes.

Cell and gene therapy products face unique manufacturing challenges, including scalability, yield, cost, and stability, but the same principles and good manufacturing practices that apply to pharmaceutical and biological products also apply to cell and gene therapy production.

"Pharmacists must have an understanding of what they’re doing with these new technologies," Dabbah says. "They must do analytical work, as some gene therapy products can change their entire character within an hour’s time."

In his chapter, Dabbah states that the ideal gene therapy vector is described as "one capable of efficient transduction, targeted delivery, and controlled gene expression. The level, timing, and duration of gene expression required will depend on the clinical indication." Further, "vectors are designed and selected for disease states on the basis of the following criteria:

• "capacity to accommodate the DNA for the therapeutic gene and its transcription cassette;

• "host-vector interactions, both cellular and humoral;

• "capacity to target intended cells;

• "control of therapeutic gene expression;

• "vector replication status;

• "capacity for integration into chromosomes of target cells (p43)."

Biotechnology is changing the way drug discovery and development are performed and the way drugs are delivered. "Final formulations for vector products are still in early development," writes Dabbah. "Aseptic filling of large numbers of vials by using classical manufacturing processes may be problematic because viral vectors are thermally sensitive, and storage at ultra-low temperatures is often required. Progress is being made in vector lyophilization and in the use of stabilizers for liquid formulations."

Final product modifications and preparative steps often are required prior to administration of cell or gene therapy products to patients. Because they are usually done close to the time of administration, they are performed under conditions not within control of the original manufacturer. Modifications can include thawing, washing, filtering, transfer to an infusible solution, or compounding.

Right drug, right patient

Before administration to the patient, cell or gene therapy products often require one or more manipulations that pharmacists may perform. As Dabbah writes, those may include:

• "change in final container;

• "change in physical state or temperature (e.g., thawing, warming);

• "change in solution or suspension;

• "addition to biocompatible material;

• "admixture or compounding with other nonstructural materials;

• "filtration or washing;

• "sampling."

Dabbah writes that such products undergoing on-site preparations and manipulations must be properly checked or tested to "ensure that all quality specifications are met prior to release for patient administration." Those requirements, before patient administration, include:

• physical inspection of the product such as for proper color and absence of particulate matter;

• review of process records to ensure completeness and accuracy;

• clerical checking for those patient-specific products to be sure product labeling and records line up with the identity of the intended recipient.

Never before has it been as important as it will be with cell and gene therapy products to get the right drug to the right patient. Many of those products are patient-specific to the point of being autologous or selected allogeneic treatments. Therapeutic products given to the wrong patient could initiate an immune response that would endanger the patient.

"Systems must be in place to prevent administration of such a product to the wrong patient," writes Dabbah. "Recommended systems include procedures similar to those used for administration of human blood products, with special attention given to the correct identification of the patient and patient-specific product by at least two people immediately prior to administration.

"In addition," writes Dabbah, "patient considerations, such as the need to dose the product according to patient weight or blood volume, may influence these steps. All product modifications performed between the time of initial product manufacture and final administration to the patient should be viewed as a part of the overall manufacturing process. The practical implications of this concept are that the process controls must be established for all product storage intervals, transport steps, and modifications, starting with clear definition of critical control points. Operational requirements for performing any of these steps after initial product manufacture include defined physical space with appropriate environmental controls, trained personnel, detailed standard operating procedures, and a comprehensive quality program."

Then there must be close patient follow-up, Dabbah says. Immune-mediated responses can occur with these products, especially allogeneic and xenogeneic products. The same patient monitoring, follow-up, care to avoid medication errors, and reporting of any medication errors and/or adverse events that occur are important to implement when dispensing cell and gene therapy products. Written policies and procedures for monitoring patient outcomes and managing reports of adverse events and medication errors should be in place and implemented as needed.

Regarding changes to pharmacy school curriculum and training of students for all of the new technologies, drug development, and drug delivery systems, Piepho says, "We teach students the fundamentals now, but we need to put this information in the context of the genomic drugs. We need to teach more pharmacogenomics in general."

Reference

1. Dabbah R. Cell and gene therapy products. Pharmacopeial Forum 2000; 26:1-110.

Sources

Robert Piepho, PhD, Dean, School of Pharmacy, University of Missouri-Kansas City, 5005 Rockhill Road, Kansas City, MO 64110. Telephone: (816) 235-1000.

Roger Dabbah, PhD, Associate Director, Division of Biologics and Biotechnology, United States Pharmacopeia, 12601 Twinbrook Parkway, Rockville, MD 20852. Telephone: (301) 816-8336.