Is there any known interaction between cyclosporine (Sandimmune), carvedilol (Kredex) or calcium an
Fråga: Is there any known interaction between cyclosporine (Sandimmune), carvedilol (Kredex) or calcium and vitamin D3 (Calcichew D3)?
The question concerns a woman who had a heart transplant one month ago and is being treated with cyclosporine and carvedilol since then. In addition, she has osteoporosis and has been treated with calcium and vitamin D3 for 4-5 weeks. Her calcium levels are normal but her cyclosporine levels have increased. She is known to have a decreased kidney function.
Sammanfattning: Both cyclosporine and carvedilol are metabolized by the cytochrome P450 system. The metabolism of cyclosporine is specifically by CYP3A4 and carvedilol is by CYP2D6 and possibly CYP3A4, CYP1A2, CYP2E1, and CYP2C9. Therefore, due to the metabolism and the one study, administering cyclosporine and carvedilol concomitantly can be assumed to be associated with increased cyclosporine blood levels and decreased doses may be necessary. However, the documentation given was only in renal transplant patients and no other documentation indicated an interaction between cyclosporine and carvedilol. In the present case, it is possible that the carvedilol administration has resulted in the increased cyclosporine blood levels and a decrease in the cyclosporine dose may be advantageous for this patient. Since there is little documentation on this interaction, close monitoring of cyclosporine blood levels would be recommended in patients on cyclosporine when carvedilol is introduced.
Svar: Cyclosporine is an immunosuppressive agent metabolised in the liver by the cytochrome P450 monooxygenase polyenzyme system specifically CYP3A4. Drugs which inhibit this system could potentially increase cyclosporine blood levels (1). Carvedilol is an anti-hypertensive agent which is also known to be metabolised in the liver by the cytochrome P450 system. A paper from 1997 (2) determined that the enzyme primarily responsible for the carvedilol metabolism is CYP2D6. There was some evidence that other cytochrome P450 enzymes may play a role in the carvedilol metabolism such as CYP2C9, CYP1A2, CYP2E1, and CYP3A4. Calcichew D3 is hydroxylated in the liver by the 24, 25 hydroxylation process.
One might also speculate that carvedilol might interact with mdrl which transports cyclosporine from the blood to the gut lumen and thus possibly increasing cyclosporine blood levels (3). In addition, another factor which may alter cyclosporine levels is the time since transplantation and necessary dosing adjustments (4).
One study (5) investigated the pharmacokinetic interactions associated with carvedilol and cyclosporine when administered concomitantly in 21 renal transplant patients suffering from chronic graft rejection. Carvedilol was administered at 6.5 mg or 12.5 mg on the first day and increased in increments up to 50 mg per day based on the patients blood pressure. The patients had cyclosporine levels taken on days one, 14, 30, 90, and 180 days after the introduction of carvedilol. The results determined that as the carvedilol levels slowly began to increase, the cyclosporine doses were gradually decreased to keep the cyclosporine blood levels in the therapeutic range. Of the 21 patients, cyclosporine levels had increased in 13 patients, decreased in 5 patients and was unchanged in 3 patients during the early stage of carvedilol treatment. Cyclosporine levels after 90 days were increasing in 5 of the patients but returned to initial values in all other patients, due to the fact that cyclosporine doses were being lowered to avoid the change in blood levels. Based on the results the authors suggest that a 20 percent reduction in cyclosporine doses is necessary when being administered with carvedilol. However, this type of situation should be evaluated based on each individual´s cyclosporine blood levels.
Other reports could not be found in the literature dealing with the interaction of cyclosporine and carvedilol or calcichew D3.