title: Sirolimus and everolimus in kidney transplantation.
abstract: The mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus have shown their efficacy in kidney transplantation, but their wider introduction has been limited by relative high discontinuation rates. Their main advantage compared with calcineurin inhibitors (CNIs) is their relative lack of nephrotoxicity. They differ mainly in pharmacokinetic characteristics and have variable inter- and intra-individual pharmacokinetics. They are metabolized by cytochrome (CYP)-3A4/5 and CYP2C8 enzymes and are substrates for P-glycoprotein (P-gp). Their most important adverse effects are thrombocytopenia, leukopenia, hypercholesterolemia, stomatitis, diarrhea, and, although rare, interstitial pneumonitis. The narrow therapeutic window makes therapeutic drug monitoring (TDM) essential to prevent toxicity or rejection. As we discuss here, the main future challenge is to further optimize mTOR inhibitor (mTORi)-based immunosuppressive therapy.
authors.affiliation: Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. Electronic address: d.j.a.r.moes@lumc.nl.
authors.forename: Dirk Jan A R
authors.initials: DJ
authors.lastname: Moes
authors.affiliation: Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Department of Nephrology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: Johan W
authors.initials: JW
authors.lastname: de Fijter
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D065095:Calcineurin Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D016903:Drug Monitoring / Q000379:methods; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D016030:Kidney Transplantation / Q000379:methods*; D020123:Sirolimus / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus