Sirolimus pharmacokinetics

Nifedipine [which does not inhibit CYP3A4] is said not to interact, and a study comparing 16 patients taking nifedipine and sirolimus with 10 patients taking sirolimus alone found no significant differences in sirolimus pharmacokinetics between the two groups. ... 

Wu FLL, Tsai M-K, Chen RR-L, Sun S-W, Huang J-D, Hu R-H, Chen K-H, Lee P-H. Effects of calcineurin inhibitors on sirolimus pharmacokinetics during staggered administration in renal ttansplant recipients. Pharmacotherapy (2005) 25, 646-53. 

Schacter AD, Benfield Lfll., Wyatt RJ, Grimm PC, Fennell RS, Herrin JT, Lirenman DS, Mc-Dorrald RA, Munoz-Arizpe R, Harmon WE. Sirolimus pharmacokinetics in pediatric renal trarrsplant recipients receiving ealeineurin inhibitor co-therapy. PeeSatr Transplant (2006) 10, 914-9. 

Cyclosporine, tacrolimus, and sirolimus are all metabolized via the CYP3A4 pathway therefore, it would be anticipated that they would experience similar pharmacokinetic DDIs. Table 52-6 details some clinically relevant DDIs that occur... 

Cattaneo D, Merlini S, Zenoni S, Baldelli S, Gotti E, Remuzzi G Perico N. (2005) Influence of co-medication with sirolimus or cyclosporine on mycophenolic acid pharmacokinetics in kidney transplantation. Am J... 

Lactation It is not known whether sirolimus is excreted in human breast milk. The pharmacokinetic and safety profiles of sirolimus in infants are not known. Because of the potential for adverse reactions in nursing infants from sirolimus, decide whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 

Zimmerman JJ, Patat A, Parks V, Moirand R, Matschke K. Pharmacokinetics of sirolimus (Rapamycin) in subjects with severe hepatic impairment. J Clin Pharmacol 2008 48(3) 285-92. 

BottigerY Sawe J, Brattstrom C, et al. Pharmacokinetic interaction between single oral dose of diltiazem and sirolimus in healthy volunteers. Cli Pharmacol 2001 69 32-40. 

Klugherz BD, Llanos G, Lieuallen W, et al. Twenty-eight-day efficacy and pharmacokinetics of the sirolimus-eluting stent. Coron Artery Dis 2002 13(3) 183-188. 

Kwok OH, Chow WH, Law TC, et al. First human experience with angiopeptin-eluting stent a quantitative coronary angiography and three-dimensional intravascular ultrasound study. Catheter Cardiovasc Interv2005 66(4) 54l-546. Nakamura M, Wada M, Hara H, et al. Angiographic and clinical outcomes of a pharmacokinetic study of sirolimus-eluting stents lesson from restenosis cases. Circ J 2005 69(10) ... 

The pharmacokinetic interaction of a single oral dose of diltiazem 120 mg with a single oral dose of sirolimus 10 mg... 

In 18 healthy subjects, in a randomized, crossover study of the pharmacokinetics of a single oral dose of sirolimus 10 mg, a single dose of diltiazem 120 mg, and the combination, diltiazem increased exposure to sirolimus, presumably by inhibiting its first-pass metabolism (13). 

Zimmerman JJ, Harper D, Getsy J, Jusko WJ. Pharmacokinetic interactions between sirolimus and microemulsion cyclosporine when orally administered jointly and 4 hours apart in healthy volunteers. J Clin Pharmacol 2003 43(10) 1168-76. 

Macdonald A, Scarola J, Burke JT, Zimmerman JJ. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin Therapeutics 2000 22(SupplB) B101-21. 

Zimmerman JJ, Kahan BD. Pharmacokinetics of sirolimus in stable renal transplant patients after multiple oral dose administration. J Clin Pharmacol 1997 37 405-15. 

Zochowska D, Wyzgal J, Paczek L (2012) Impact of CYP3A4 1B and CYP3A5 3 polymorphisms on the pharmacokinetics of cyclosporine and sirolimus in renal transplant recipients. Ann Transplant 17 36 4... 

Le Meur, Y., and Marquet, P. (2006) A comparison of the efiect of cyclosporine and sirolimus on the pharmacokinetics of mycophenolate in renal transplant patients. British Journal of Clinical Pharmacology, 62, 477-484. 

Kaplan B, Meier-Kriesche HU, Napoli KL, Kahan BD. The effects of relative timing of sirolimus and cyclosporine microemulsion formulation coadministration on the pharmacokinetics of each agent. Clin Pharmacol Ther 1998 63 48-53. 

C. Dansirikul, R. G. Morris, S. E. Tett, and S. B. DuffuU, A Bayesian approach for population pharmacokinetic modeling of sirolimus. Br J Clin Pharmacol 62 420-434 (2006). 

McAlister VC, Mahalati K, Peltekian KM, et al. A cUnical pharmacokinetic study of tacrolimus and sirolimus combination iimnunosuppression comparing simultaneous to separated administration. Ther Drug Monit 2002 23 346-350. 

Fodder FI, Stepkowski SM, Napoli KL, Clark J, Verani RR, Chou TC, Kahan BD. Pharmacokinetic interactions augment toxicities of sirolimus/cydosporine combinations. J Am Soc Nephrol 2001 12 1059-1071. 

Disposition and Pharmacokinetics After oral administration, sirolimus is absorbed rapidly and reaches a peak blood concentration within 1 hour after a single dose in healthy subjects and within 2 hours after multiple oral doses in renal transplant patients. Systemic availability is 15%, and blood concentrations are proportional to doses between 3 and 12 mg/m. A high-fat meal decreases peak blood concentration by 34% sirolimus therefore should be taken consistently either with or without food, and blood levels should be monitored closely. About 40% of sirolimus in plasma is protein bound, especially to albumin. The drug partitions into formed elements of blood, with a blood plasma ratio of 38 in renal transplant patients. Sirolimus is extensively metabolized by CYP3A4 and is transported by P-glycoprotein. Although some of its metabolites are active, sirolimus itself is the major active component in whole blood and contributes >90% of the immunosuppressive effect. The blood tj after multiple doses in stable renal transplant patients is 62 hours. A loading dose of three times the maintenance dose usually provides nearly steady-state concentrations within 1 day. 

Clinical uses and pharmacokinetics Use of these immunosuppressants is a major factor in the success of solid organ transplantation. Cyclosporine is used in solid organ transplantation and in graft-versus-host syndrome in bone marrow transplants. Tacrolimus is used in liver and kidney transplant recipients and may be effective as rescue therapy in patients who fail standard therapy. Sirolimus is used alone or in combination with cyclosporine in kidney and heart transplantation. The agents, particularly cyclosporine, may also be effective in immune diseases, including rheumatoid arthritis, uveitis, psoriasis, asthma, and type 1 diabetes. 

A single-dose study found that the pharmacokinetics of an oral contraceptive (ethinylestradiol/norgestrel 30/300 micrograms) were unaffected by sirolimus. This suggests that the efficacy of the contraceptive is likely to be unchanged, but the UK manufacturer cautiously points out that the effects of long-term sirolimus on oral contraception are unknown. They advise that contraception should be continued for 12 weeks after sirolimus is stopped. 

Picard, N, Premaud, Rousseau A, Le Meur Y, Marquet P. A comparison of the effect of ciclosporin and sirolimus on the pharmacokinetics of mycophenolate in renal tran lant patients. Br J Clin Pharmacol (200Q 62,477-84. 

Perron GM, Mishina EV, Zimmerman JJ, Jusko WJ, Population pharmacokinetics of sirolimus in kidney transplant patients, ClinPhamacol Ther(l997) 61,416-28,... 

In a study in kidney transplant patients taking eielosporin and prednisone 5 to 20 mg daily, only minor to moderate changes occurred in the pharmacokinetics of prednisolone when sirolimus 6 to 13 mg/m daily was given for 2 weeks. The maximum plasma prednisolone levels were raised by... 

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