Cyclosporine dosing

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

Drug can be given concurrentlywith cyclosporine, which mayenable reduced cyclosporine doses and lower toxicity, or potential cyclosporine substitute in patients developing cyclosporine toxicity... 

Ketoconazole has been used in cardiac and renal transplant recipients to lower cyclosporine doses. 

Turgeon DK, Leichtman AB, Lown KS, et al. P4503A activity and cyclosporine dosing in kidney and heart transplant recipients. Clin Pharmacol Ther 1994 56 253-260. 

Bunke M, Sloan R, Brier M, Ganzel B. An improved glomerular filtration rate in cardiac transplant recipients with once-a-day cyclosporine dosing. Transplantation 1995 59(4) 537-40. 

First MR, SchroederTJ, Alexander JW, Stephens GW, Weiskittel P, Myre SA, and Pesce AJ. 1991. Cyclosporine dose reduction by ketoconazole administration in renal transplant recipients. Transplantation 51 365-370. 

Nakamura T, Nozu K, lijima K, Yoshikawa N, Moriya Y, Yamamori M, Kako A, Matsuo M, Sakurai A, Okamura N, Ishikawa T, Oku-mura K, Sakaeda T. Association of cumulative cyclosporine dose with its irreversible nephrotoxicity in Japanese patients with pediatric-onset autoimmune diseases. Biol Pharm Bull 2007 30 2371-2375. 

Cyclosporine is biotransformed primarily in the liver by CYP3A4 however, alternate metabolic pathways may yield toxic metabolites. Most of the cyclosporin dose is excreted in bile as an active metabolite. Less than 1% is excreted as unchanged drug. Inducers of CYP3A increase cyclosporine metabolism, whereas competitors may increase cyclosporine to potentially toxic levels. 

For example, LK is a 50-year-old, 75-kg, 5-ft, 11-in male renal transplant recipient who is receiving oral cyclosporine 400 mg every 12 hours. The current steady-state blood cyclosporine concentration is 375 ng/mL. To compute a cyclosporine dose that will provide a steady-state concentration of 200 ng/mL, linear pharmacokinetic equations can be used. The new dose to attain the desired concentration should be proportional to the old dose that produced the measured concentration (total daily dose = 400 mg/dose x 2 doses/day = 800 mg/day) ... 

Ferguson RM, Mulgaonkar S, Tedesco Ft, et al. Ftigh efficacy of FTY720 with reduced cyclosporine dose in preventing rejection in renal transplantation 12-month prehminary results (abstract 624). Am J Transplant 2003 3(suppl5) 311. 

Wandel C, Bohrer H, Bocker R. Rifampicin and cyclosporine dosing in heart tran lant patients. J Cartioihorac Vase Anestii (1995) 9, 621-2. 

Rossi SJ, Hariharan S, Schroeder T J, First MR. Cyclosporine dosing and blood levels in renal transplants receiving Procardia XL. Clin Pharmacol Ther 993 ) 53,238. 

Howard RL, Shapiro JI, Babcock S, Chan L. The effect of calcium channel blockers on die cyclosporine dose requirement inrenal tran lantrecipients.RewFai/(1990) 12, 89-92. 

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