At one time, organ failure meant certain death. With the advent of transplantation came the hope of a second chance at life for those who faced organ failure. Today, tens of thousands of people are alive because of the miracle of transplantation. The official word about transplant survival is good: the United Network of Organ Sharing (UNOS) reports that one-year graft and patient survival rates continue to increase each year for all organ types. New immunosuppressants, careful monitoring and an ever-improving technology can be credited for the continuing success. The word about the availability of organs, however, is not good: While the number of transplants increased by 57% between 1988 and 1995, the number of patients waiting for a transplant at the end of each year nearly tripled. A record 50,000 people are now waiting for transplants. People are attacking the problem from different angles: some are working to improve organ donation rates, others are in the lab creating artificial organs and some are exploring the potential of animal-to-human organ transplantation. There are also people striving to maintain a high quality of life for those who have already received transplants. This Stadtlanders LifeTIMES in-depth review looks at a number of areas affecting transplantation today and tomorrow. Through this review we can see that transplant recipients, candidates and professionals are poised to meet the future and all that it might bring.
IMMUNOSUPPRESSANTS OF TODAY
By Daniel H. Hayes, MD - Director, Transplantation, Carolina Medical Center, Medical Director, LifeShare of The Carolinas Organ Procurement Agency, Charlotte, North Carolina
Dramatic advances in medication therapy are the cornerstone of transplantation as we know it today. These drugs which are so vital to successful transplantation are immunosuppressant medications. They weaken the immune system so that it does not recognize the transplanted organ as an invader and attack, or reject it. In the early years of transplantation, immunosuppression consisted of steroids, plus additional drugs to prevent the bone marrow from making cells that cause rejection of the transplanted organ. Steroids are still an important part of most immunosuppressive regimens, with prednisone being the oral steroid most commonly prescribed for transplant recipients. Intravenous forms of steroids, such as Solumedrol", are also used. The most commonly used bone marrow suppressant was and still is azathioprine (Imuran).
The steroid/azathioprine combination was standard until cyclosporine (Sandimmune) was developed. The FDA approved cyclosporine for patient use in 1983 and it became used routinely with prednisone and azathioprine.Cyclosporine, the first transplant-specific drug developed, greatly increased the survival of transplanted organs.
There are three goals of immunosuppressive therapy: induction, maintenance and treatment of acute rejection episodes. Induction immunosuppressants are very potent drugs given for 10 to 14 days around the time of the transplant. The goal of induction therapy, although not always successful, is to `turn off the immune system' for approximately two weeks to reduce the likelihood of immediate rejection (within the first ten days after the transplant) and early rejection (within the first three months after the transplant). The drugs most commonly used for induction are Orthoclone (OKT-3 or muromonab-CD3), which was approved in 1986, and Atgam (anti-thymocyte globulin), approved in 1981.
Maintenance immunosuppression is the long-term use of drugs to reduce the immune system's ability to recognize and reject foreign organs. The past three years have brought exciting developments in maintenance immunosuppression for transplant recipients with three new drugs. In 1994 Prograf" (FK506 or tacrolimus) was approved by the FDA. CellCept" (mycophenolate mofetil) and a new cyclosporine micro-emulsion form, Neoral", were approved by the FDA in 1995. With these key advances came today's most common triple-therapy regimen for maintenance immunosuppression, including a combination of: Neoral or Prograf; azathioprine or CellCept; and prednisone.
The third type of immunosuppressants is used as treatment for acute organ rejection. Rejection treatment is very potent, similar to induction. Drugs used for induction and maintenance treatment can be used, at much higher doses, to reverse rejection. Common drugs to treat cute rejection includes Orthoclone, Atgam, Solumedrol, and occasionally Prograf or CellCept.
Sandimmune, the first form of cyclosporine developed, can be given either as an intravenous injection or oral medication. Oral Sandimmune is available as an oil-based liquid and as a gelatin capsule. The amount of Sandimmune that can be absorbed by the intestine varies and is affected by many factors including diet, general health and intestinal diseases. Because of this, the dosing of this formulation can be difficult.
The Neoral form of cyclosporine is more easily absorbed and may allow a lower dose to be given. Since its approval, many cyclosporine users have been converted to the Neoral formulation. Neoral also comes in an oral solution and soft gelatin capsules.
Cyclosporine is a potent drug. It blocks the function and growth of white blood cells (T-cells) that cause organ rejection. As long as blood levels are monitored closely, cyclosporine is a safe and effective drug. The most common side effects are damage to the kidneys and liver, elevation of blood pressure, overgrowth of the gum tissue, tingling of the hands and feet, tremors and excessive hair growth.
CellCept, which is approved for immunosuppression in kidney transplant patients, was developed from penicillin bacteria. It works by blocking cell division and growth in cells that cause rejection. It can reverse rejection and can also decrease the chance of rejection when taken as a maintenance drug with other immunosuppressive agents. CellCept and azathioprine act in a similar manner and should not be used together.
CellCept is considered to be a safe drug with few side effects. It's currently available only in oral form. The most common side effects are diarrhea, abdominal pain, nausea and a decreased white blood cell count. Lowering the dose of CellCept under the guidance of a doctor can often decrease the side effects.
Prograf is manufactured from a fungus that grows in the soil. It works by blocking the function and growth of T-cells. It can be given both intravenously and orally. Common side effects of Prograf include elevation of blood pressure, damage to the kidneys and liver, nausea, diarrhea, headaches, gastrointestinal problems, tingling of hands and feet, and tremors. As with cyclosporine, measuring blood levels of Prograf is important to determine the most beneficial dose.
All immunosuppressants have side effects and potential complications. In addition to the drug-specific side effects mentioned, immunosuppressed patients are at risk for developing infections, cancers (especially of the lymph system or skin) and diabetes. It is more likely that the combination of drugs contributes to the cause, not any specific immunosuppressant.
CYCLOSPORINE has revolutionized organ transplantation by enhancing the quality and length of long-term survival of transplanted organs. However, cyclosporine often varies from one patient to another in the extent and timing of absorption from the intestinal tract, as well as how quickly it's used and eliminated by the body. Because of this variability, dosage amounts can't be standardized; however, the correct dosage is very important. Too much in the bloodstream might cause side effects, while too little might result in organ rejection.
To determine the correct dose of cyclosporine for a particular patient, doctors look at several things including evidence of rejection, drug-related side effects, particularly renal function and the concentration of cyclosporine in the blood. Traditionally, doctors have only looked at the concentration of cyclosporine in the blood immediately before a dose is taken_ the trough concentration. The cyclosporine trough concentration, however, doesn't provide enough information about how the drug is actually being used by the body. More information can be obtained by taking several blood samples between doses of cyclosporine to determine the pharmacokinetics of the drug.
PHARMACOKINETICS: A NEW EVALUATION IN CYCLOSPORINE THERAPY
By Patrick A. Kelly, PharmD, Research Insturctor in Surgery, Department of Surgery, Division of Immunology and Transplantation, University of Texas-Houston Medical School, Houston, Texas
Pharmacokinetics is the study of ways in which a drug is absorbed, distributed, metabolized and eliminated. The pharmacokinetics describe how the drug is processed by the body over a period of time, usually between doses. To get the clearest pharmacokinetic description possible, blood samples need to be taken from the patient right before the dose is taken and at several points afterwards until the time of the next dose. The concentration of the drug is determined in each sample, and then graphed as a `concentration-time curve' for that patient. This graph shows how much drug was absorbed (`exposure'), as well as the highest and lowest concentrations of the drug in the blood between doses. The same sample graph is an example of a concentration-time curve plot. By applying pharmacokinetic principles to the patient's cyclosporine therapy, transplant physicians, pharmacists and nurse coordinators seek to ensure the safest and most effective use of the drug.
In determining the pharmacokinetics of cyclosporine, clinicians are performing `therapeutic drug monitoring,' which is important for several reasons. First, cyclosporine has a narrow therapeutic window: that is, there is a small range between blood concentrations that are too high and cause side effects and those that are too low and lead to rejection. Second, cyclosporine has widely different pharmacokinetic behavior between patients and even in the same patient who is tested several times. And third, there is not a good single measurement (like a trough concentration) that tells enough information about how much drug the patient has been exposed to between doses. Thus, the total exposure to cyclosporine in the patient's blood over the entire dosing interval has been found to predict who is at risk for rejection (too little cyclosporine) versus side effects (too much cyclosporine).
The sample graph also shows examples of cyclosporine concentration-time curves for two different patients. Both patients have the same trough cyclosporine concentrations. Patient #1 has an average cyclosporine concentration in the therapeutic range, while Patient #2 has an average cyclosporine concentration that is below the therapeutic range. If only trough cyclosporine levels were known, we would think both patients had adequate blood concentrations. But due to the low cyclosporine average concentration, Patient #2 may be at risk for rejection of his transplanted organ due to insufficient cyclosporine exposure between doses.
Therapeutic drug monitoring using pharmacokinetic principles can play an important role in effectively managing cyclosporine therapy in transplant patients. Because Sandimmune" has shown the potential for extreme variances in the amount of cyclosporine in the blood, the use of trough concentrations alone can either over- or underestimate drug exposure for a patient. A pharmacokinetic profile is the best measure to analyze the level of cyclosporine in the blood between doses.
Pharmacokinetic studies show that Neoral has better and more consistent absorption than Sandimmune. Therefore, shorter pharmacokinetic profiles, with less blood sampling, may be used to determine drug exposure with Neoral. Pharmacokinetic profiling is a tool which is still new to many transplant professionals and takes more time and effort than determining trough concentrations alone. However, pharmacokinetics offer transplant professionals much more information to make informed decisions about dosing adjustments of cyclosporine in patients. This can only help to improve the quality and length of survival of the transplanted organ ¥ a precious, limited and life-saving commodity.
IMMUNOSUPPRESSANTS OF TO TOMORROW
By Teri Wagner, PharmD, Stadtlanders Clinical Pharmacist
Even after the addition of newly approved medications in the past couple of years, the number of immunosuppressant options will continue to increase well into the future. Many new medications are currently being investigated for use as immunosuppressants. How soon any of these products will be commercially available for widespread use is difficult to predict.
First, pre-clinical testing of a new drug candidate is conducted in animals and laboratory-simulated scenarios. Next, Phase I trials examine the safety of the drug in humans to determine the most appropriate dose. Phase II trials study the effectiveness of the drug for the intended purpose. Finally, long-term use of the drug in large numbers of patients is studied in Phase III trials. The entire clinical trial process typically takes an average of seven to 10 years. Results collected from these trials generally form the foundation for a New Drug Application (NDA). Review of the NDA and approval of the new drug product by the FDA can also take years, with the average time being 18-24 months.
ON THE HORIZON
Drug Name Description Use Manufacturer Clinical Trials Comments
sirolimus, Rapamune" (formerly known as rapamycin) Similar to cyclosporine and tacrolimus, sirolimus blocks cellular immune signals which inhibit T-cells¥those responsible for acute rejection episodes Lowers the incidence of acute kidney rejection when used in combination with cyclosporine and steroids May also prove useful in treating autoimmune disorders Wyeth-Ayerst Laboratories, Philadelphia, PA Phase I and II trials demonstrated that Rapamune, in combination with cyclosporine and steroids, reduced the incidence of acute rejection from 40% to less than 10% Rapamune is currently in Phase III trials Initial studies found that steroid therapy may be discontinued when Rapamune is used with cyclosporine-based immunosuppressants It shouldnOt be used with tacrolimus because the two drugs lessen the effectiveness of each other Exhibits a prolonged biological lifespan, indicating infrequent dosing (i.e., once daily) may be possible Approval and availability is anticipated by the end of the decade
anti-thymocyte immunoglobulin, Thymoglobulin" Rabbit-derived polyclonal antibody to T-cells, similar to Atgam" Reversal of acute kidney transplant rejection SangStat Medical Corporation, Menlo Park, CA Phase III trials are complete and found Thymoglobulin to be significantly more effective than Atgam at reversing acute rejection Application is currently under review by the FDA Thymoglobulin is currently approved for use in 39 countries and has been used safely in thousands of transplant patients worldwide FDA approval and product availability is anticipated by the end of 1997
dacliximab, Zenapax" OHumanizedO or OsmartO monoclonal antibody that blocks the IL-2 receptor and in turn inhibits T-cell activity Prevention of acute kidney rejection when used in combination with cyclosporine, prednisone and/or azathioprine Protein Design Laboratories, Mountain View CA; Hoffman LaRoche, Nutley, NJ Phase III trials are complete, which found up to 40% reduction in acute rejection episodes when combined with cyclosporine-based regimens, as compared to a standard triple- or double-drug regimen NDA is expected to be filed in 1997 Humanized compounds, such as Zenapax, contain portions of mouse antibodies genetically engineered with human antibodies, which have highly specific action on the immune system Typically has less severe side effects than conventional monoclonal antibodies Zenapax exhibits a long biological lifespan, allowing administration on an every-two-week schedule Ongoing studies suggest that cyclosporine doses may be greatly reduced or even discontinued in patients receiving Zenapax
SDZ CHI 621, Simulect" OChimericO monoclonal antibody, which blocks the IL-2 receptor and in turn inhibits T-cell activity Prevention of kidney rejection when combined with cyclosporine Novartis, East Hanover, NJ Early Phase I/II studies found Simulect to be well tolerated and effectively reducing incidence of acute rejection initially following kidney transplant Larger trials are underway Like Zenapax, Simulect is a hybrid of both mouse and human antibodies, and is expected to have a low incidence of severe side effects Immunosuppressive activity is prolonged, enabling the drug to be administered less frequently
BTI-322 Rat-derived monoclonal antibody targeted to CD2, a critical target on the T-cell surface Prevention of first-time kidney rejection, as well as treatment of first rejection episodes or resistant rejection BioTransplant Incorporated, Charlestown, MA Phase I/II studies in Belgium found that patients receiving a 10-day course of BTI-322 combined with conventional triple-drug therapy had significantly fewer acute rejection incidents Was highly successful in reversing rejection episodes Phase I/II trials are in progress in the US Clinical advantage of this agent appears to be its specific mechanism for preventing rejection, in addition to a favorable safety profile
enlimomab, BIRR1 Mouse-derived monoclonal antibody to a specific cell surface molecule, ICAM-1, which initiates the rejection response Prevention of renal transplant rejection Additional uses include ischemic strokes and thermal burn injuries Boehringer Ingelheim, Ridgefield, CT Phase I trial found significantly less delayed graft function and rejection in enlimomab treated Ohigh riskO patients Clinical trials are ongoing This agent may be particularly useful in preventing OischemicO injury to donor organs with prolonged preservation times Enlimomab appears to have a favorable safety profile
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