Issue 12 October 2002
New Methods to Induce Transplant Organ Tolerance	New Medications: Benicar™ (olmesartan medoxomil)

New Methods to Induce Transplant Organ Tolerance Reports recently presented at the XIX International Congress of Transplantation Society in Miami provide hope for better methods to control organ rejection and perhaps decrease or eliminate the need for immunosuppressive drugs. Dr. Samuel Strober from Stanford University reported experience with four renal transplant patients who achieved graft tolerance (living donors) without immunosuppressive agents for a few months. This was accomplished by boosting stem cell production in the donors who then donated a kidney and stem cells to the recipient. After kidney transplant, the recipients underwent radiation treatment to the lymph nodes, spleen, and thymus, and then received the stem cell transplants. In two of the patients, immuno- suppressive drugs were completely stopped by one year post-transplant and they were later maintained on low-dose immunosuppression. A third patient was approaching complete discontinuation of immunosuppressants while the fourth was not weaned because of rejection. The stem cell transplants reportedly induced an immunologic “chimerism” between the donor and host. In another report, Dr. Thomas E. Starzl from the University of Pittsburgh recommended a new approach to immunosuppression for organ transplantation. His approach is to deplete T cells in the recipient pre-transplant with antithymocyte globulin and to use low dose tacrolimus for 3 months post-transplant, then discontinue immunosuppressants. Renal, liver, pancreas, and small bowel transplant patients who received this treatment are now receiving just minimal weekly doses of immunsuppressants. The strategy allows for clonal deletion of T cells directed against the graft that is more complete and longer lasting. While these approaches provide hope for improving graft tolerance, there is disagreement among transplant experts as to the utility of these strategies. Dr. Alan Kirk, from the National Institutes of Health, added that patients should not reduce their immunosuppressive regimen based on these encouraging preliminary results. “None of these protocols are ‘ready for prime-time,’” Dr. Kirk said.

New Medications Benicar™ (olmesartan medoxomil) Benicar™ (olmesartan medoxomil), manufactured by Sankyo Pharma Inc., is a selective AT1 subtype angiotensin II receptor antagonist approved by the FDA in April 2002 for the treatment of essential hypertension. The drug is available as a 5, 20, or 40 mg film-coated tablet. Olmesartan medoxomil, an angiotensin II receptor blocker (ARB), prevents angiotensin II from binding to the angiotensin II type 1 (AT1) receptor. Since olmesartan medoxomil blocks the binding and not the synthesis of angiotensin II, it does not inhibit the breakdown of bradykinin. This may decrease the cough and angioedema associated with angiotensin–converting enzyme inhibitors. Olmesartan medoxomil has been shown to be effective in reducing blood pressure. Twenty milligrams per day of olmesartan medoxomil was more effective than irbesartan (150 mg/day), valsartan (80 mg/day), and losartan (50 mg/day). It is also as effective as 5 mg/day of amlodipine (SG Chrysant et al, Am J Hyperten 2002; 15 part 2:57A, abstract P-68; S Oparil et al, J Clin Hypertens 2001; 3:283). In comparison with atenolol 50 or 100 mg/day alone or in combination with 25 mg/day of hydrochlorothiazide, olmesartan medoxomil had similar efficacy in the reduction of diastolic blood pressure for patients with mild-to-moderate hypertension (W Van Mieghern, J Hypertens 2001; 19 suppl 2:S152, abstract P2.174; K Püchler et al, J Hypertens 2001; 19 suppl 2:S153, abstract P2.175). Twenty milligrams once daily is the recommended starting dose of olmesartan medoxomil. If needed, the dose can be increased to 40 mg once daily after two weeks of therapy. Divided daily doses of olmesartan medoxomil showed no differences in response compared with once daily dosing and doses greater than 40 mg showed no additional effect on blood pressure. While there is no dosage adjustments recommended for the elderly (>65 years) or patients with moderate-to-marked hepatic or renal disease, it is recommended that a lower starting dose and a maximum daily dose of 20 mg/day be used in patients with severe renal insufficiency (creatine clearance <20 ml/min) due to elevated concentrations of olmesartan medoxomil in this patient population. There is an association of oliguria and/or progressive azotemia and acute renal failure with the use of ARBs. Patients at risk for hyperkalemia, such as those who are volume depleted, should also be started at a lower dose of olmesartan medoxomil. In clinical trials involving olmesartan medoxomil treated patients, dizziness was the only adverse event that occurred more often than placebo, with an occurrence rate greater than one percent (3% and 1% respectively). Compared with placebo, other adverse events with an occurrence rate greater than 1% without significant differences compared with placebo are increased creatine phosphokinase, hyperglycemia, hypertriglyceridemia, hematuria, headache, diarrhea, back pain, flu-like symptoms, bronchitis, pharyngitis, rhinitis, sinusitis, upper respiratory tract infections and inflicted injury. Facial edema has been reported in five patients receiving olmesartan medoxomil. Similar to all ARBs and angiotensin-converting enzyme inhibitors, the use of olmesartan medoxomil in pregnancy is contraindicated (olmesartan medoxomil has a pregnancy category “C” rating during the first trimester and a pregnancy category “D” rating in the second and third trimesters). A patient assistance program is available for Benicar™. For further information concerning the assistance program, please contact MAP at (706) 721-0131, or Sankyo Pharma at (866) 268-7327. Authored by Chad Mosley

The MAP newsletter is published quarterly to present topics of interest to the transplant community. If you would like to submit material to be considered for publication in the newsletter, please contact MAP at: Medication Access Program University of Georgia at the Medical College of Georgia Clinical Pharmacy Program CJ-1020 Augusta, Georgia 30912-2450 (706) 721-0131 or 1-800-736-2273 ext. 0131 E-mail - map@mapuga.com

The Medication Access Program is a statewide program for solid-organ transplant patients in Georgia that offers information about medication assistance programs and helps with the enrollment into these programs.