Chronopharmacokinetics of Mycophenolic Acid and Its Glucuronide and Acyl Glucuronide Metabolites in Kidney Transplant Recipients Converted From Cyclosporine to Everolimus

Chronopharmacokinetics of Mycophenolic Acid and Its Glucuronide and Acyl Glucuronide Metabolites in Kidney Transplant Recipients Converted From Cyclosporine to Everolimus

Author Tedesco-Silva, Helio Autor UNIFESP Google Scholar
Felipe, Claudia Rosso Autor UNIFESP Google Scholar
Slade, Alan Google Scholar
Schmouder, Robert L. Google Scholar
Medina Pestana, Jose Osmar Autor UNIFESP Google Scholar
Institution Universidade Federal de São Paulo (UNIFESP)
Novartis Inst Biomed Res
Novartis Pharmaceut
Abstract Background: the influence of the conversion from cyclosporine (CsA) to everolimus (EVR) on the chronopharmacokinetics of mycophenolic acid (MPA) and its glucuronide (MPAG) and acyl glucuronide (acyl-MPAG) metabolites in patients receiving enteric-coated mycophenolate sodium (EC-MPS) has not been studied.Methods: We evaluated daytime and nighttime steady-state MPA, MPAG, and acyl-MPAG pharmacokinetics in 24 stable kidney transplant recipients while receiving cyclosporine and 28 days after conversion from CsA to EVR. the effect of concomitant treatment and the circadian difference on AUC(t,ss) and C-max,C-ss were assessed using a linear mixed model.Results: After conversion from CsA to EVR, MPA AUC(t,ss) was 43% higher (29% daytime and 58% during nighttime), whereas MPAG AUC(t,ss) was 33% lower (35% daytime and 30% during nighttime) and acyl-MPAG AUC(t,ss) was 31% lower (36% during daytime and 26% nighttime). Compared with daytime, MPA AUC(t,ss) was 25% lower (32% with CsA and 17% with EVR), MPAG AUC(t,ss) was 24% lower (26% with CsA and 21% with EVR), and acyl-MPAG AUCt, ss was 26% lower (32% with CsA and 21% with EVR) during nighttime. After conversion from CsA to EVR, MPAG: MPA and acyl-MPAG: MPA AUC(t,ss) ratios were 50% lower but were not different during daytime compared with nighttime EC-MPS administration. There was no correlation between CsA or EVR concentrations with MPA, MPAG, and acyl-MPAG exposures during daytime and nighttime. At least 1 adverse event was reported in 70.8% of patients receiving EC-MPS and CsA and in 91.7% receiving EC-MPS and EVR.Conclusion: in stable kidney transplant recipients receiving EC-MPS and steroids, exposures to MPA, MPAG, and acyl-MPAG were lower during nighttime compared with daytime, both with CsA or EVR. This circadian effect on MPA exposure did not correlate with CsA or EVR concentrations or with altered MPAG and acyl-MPAG formation.
Keywords mycophenolic acid
cyclosporine
everolimus
pharmacokinetics
circadian variation
Language English
Sponsor Novartis Pharmaceuticals, Basel, Switzerland
Date 2012-12-01
Published in Therapeutic Drug Monitoring. Philadelphia: Lippincott Williams & Wilkins, v. 34, n. 6, p. 652-659, 2012.
ISSN 0163-4356 (Sherpa/Romeo, impact factor)
Publisher Lippincott Williams & Wilkins
Extent 652-659
Origin http://dx.doi.org/10.1097/FTD.0b013e3182706ef1
Access rights Closed access
Type Article
Web of Science ID WOS:000311147300005
URI http://repositorio.unifesp.br/handle/11600/35586

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