Cyclosporine and sirolimus pharmacokinetics and drug-to-drug interactions in kidney transplant recipients

Cyclosporine and sirolimus pharmacokinetics and drug-to-drug interactions in kidney transplant recipients

Author Felipe, Claudia R. Autor UNIFESP Google Scholar
Park, Sung-In Autor UNIFESP Google Scholar
Pinheiro-Machado, Paula G. Autor UNIFESP Google Scholar
Garcia, Riberto Autor UNIFESP Google Scholar
Casarini, Dulce E. Autor UNIFESP Google Scholar
Moreira, Silvia Autor UNIFESP Google Scholar
Tedesco-Silva, Helio Autor UNIFESP Google Scholar
Medina-Pestana, Jose O. Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Abstract This study was conducted to evaluate the pharmacokinetics (pk) and drug interactions between cyclosporine (CsA) and sirolimus (SRL) in kidney transplant recipients. the morning (a.m.) and evening (p.m.) pk of CsA (4-5 mg/kg/dose) and SRL (2 mg, n = 20; 5 mg, n = 33) were evaluated on day 7 (n = 53). CsA showed circadian variation when comparing a.m. and p.m. administration [AUC: 8066 vs. 6699, P < 0.001 (CI 970.9; 1763.6); C0: 272 vs. 245, P = 0.007 (CI 7.5; 46.1)]. SRL showed dose-proportional pk. Significant and drug-to-drug concentration-dependent pk interactions were observed within a narrow concentration range for both drugs. A fivefold increase in SRL AUC (from a mean of 130 to 538 ng h/mL) was associated with a 25% increase in mean a.m. CsA AUC [7021 to 8811 ng h/mL, P = 0.037, CI (-3461.2; -118.9)] and with a 42% increase in mean p.m. CsA AUC [5386-7639, P = 0.024, CI (-4164.4; -340.7)]. A twofold increase in a.m. CsA AUC (from 5860 to 10 974 ng h/mL) was associated with a 70% increase in mean SRL AUC [223 to 380 ng h/mL, P = 0.0026, CI (-291.7; -22.8)]. A twofold increase in p.m. CsA AUC (from 4573 to 9692 ng h/mL) was associated with a 63% increase in mean SRL AUC [246 to 400 ng h/mL, P = 0.032, CI (-290.7; -16.6)]. CSA shows circadian pk regardless of sirolimus dose or blood concentration. Significant drug-to-drug interactions occur within narrow blood drug concentrations. the magnitude of the effect of CsA on SRL blood concentration is higher than that of SRL on CsA blood concentrations. These findings emphasize the need for therapeutic drug monitoring using this drug combination.
Keywords cyclosporine
drug interaction
kidney transplantation
pharmacokinetics
sirolimus
Language English
Date 2009-10-01
Published in Fundamental & Clinical Pharmacology. Malden: Wiley-Blackwell Publishing, Inc, v. 23, n. 5, p. 625-631, 2009.
ISSN 0767-3981 (Sherpa/Romeo, impact factor)
Publisher Wiley-Blackwell
Extent 625-631
Origin http://dx.doi.org/10.1111/j.1472-8206.2009.00699.x
Access rights Closed access
Type Article
Web of Science ID WOS:000269577700016
URI http://repositorio.unifesp.br/handle/11600/31877

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