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Clinical Pharmacokinetics

Erschienen in:

01.02.2004 | Review Article

Clinical Pharmacokinetics of Everolimus

verfasst von: Dr Gabriele I. Kirchner, Ivo Meier-Wiedenbach, Michael P. Manns

Erschienen in: Clinical Pharmacokinetics | Ausgabe 2/2004

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Abstract

Abstract Everolimus is an immunosuppressive macrolide bearing a stable 2-hydroxy-ethyl chain substitution at position 40 on the sirolimus (rapamycin) structure. Everolimus, which has greater polarity than sirolimus, was developed in an attempt to improve the pharmacokinetic characteristics of sirolimus, particularly to increase its oral bioavailability. Everolimus has a mechanism of action similar to that of sirolimus. It blocks growth-driven transduction signals in the T-cell response to alloantigen and thus acts at a later stage than the calcineurin inhibitors ciclosporin and tacrolimus. Everolimus and ciclosporin show synergism in immunosuppression both in vitro and in vivo and therefore the drugs are intended to be given in combination after solid organ transplantation. The synergistic effect allows a dosage reduction that decreases adverse effects.

For the quantification of the pharmacokinetics of everolimus, nine different assays using high performance liquid chromatography coupled to an electrospray mass spectrometer, and one enzyme-linked immunosorbent assay, have been developed.

Oral everolimus is absorbed rapidly, and reaches peak concentration after 1.3–1.8 hours. Steady state is reached within 7 days, and steady-state peak and trough concentrations, and area under the concentration-time curve (AUC), are proportional to dosage. In adults, everolimus pharmacokinetic characteristics do not differ according to age, weight or sex, but bodyweight-adjusted dosages are necessary in children.

The interindividual pharmacokinetic variability of everolimus can be explained by different activities of the drug efflux pump P-glycoprotein and of metabolism by cytochrome P450 (CYP) 3A4, 3A5 and 2C8. The critical role of the CYP3A4 system for everolimus biotransformation leads to drug-drug interactions with other drugs metabolised by this cytochrome system. In patients with hepatic impairment, the apparent clearance of everolimus is significantly lower than in healthy volunteers, and therefore the dosage of everolimus should be reduced by half in these patients.

The advantage of everolimus seems to be its lower nephrotoxicity in comparison with the standard immunosuppressants ciclosporin and tacrolimus. Observed adverse effects with everolimus include hypertriglyceridaemia, hypercholesterolaemia, opportunistic infections, thrombocytopenia and leucocytopenia.

Because of the variable oral bioavailability and narrow therapeutic index of everolimus, blood concentration monitoring seems to be important. The excellent correlation between steady-state trough concentration and AUC makes the former a simple and reliable index for monitoring everolimus exposure. The target trough concentration of everolimus should range between 3 and 15 µg/L in combination therapy with ciclosporin (trough concentration 100–300 µg/L) and prednisone.

Use of tradenames is for product identification only and does not imply endorsement.

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Titel: Clinical Pharmacokinetics of Everolimus
verfasst von: Dr Gabriele I. Kirchner
Ivo Meier-Wiedenbach
Michael P. Manns
Publikationsdatum: 01.02.2004
Verlag: Springer International Publishing
Erschienen in: Clinical Pharmacokinetics / Ausgabe 2/2004
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI: https://doi.org/10.2165/00003088-200443020-00002

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

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Clinical Pharmacokinetics of Everolimus

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Live-Webinar "Urologie und Sexualmedizin in der Praxis"

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