Management of metabolic cytochrome P450 3A4 drug-drug interaction between everolimus and azole antifungals in a renal transplant patient.
We report a case of a 54-year-old male renal transplant patient who received antifungal azole treatment in combination with the recently introduced immunosuppressant agent everolimus to prevent post-transplantation aspergillosis reactivation. Voriconazole was withdrawn after 1 month because of elevated concentrations (5 mg/L trough plasma determination) and hepatotoxicity, and substituted by several months of treatment with posaconazole (observed concentration range 1-2 mg/L). We observed pharmacokinetic drug interactions between both voriconazole and posaconazole, and everolimus cytochrome P450 3A4 metabolism, resulting in 7.5- and 3.8-fold increase, respectively, in everolimus blood trough concentrations. Combined therapeutic drug monitoring (TDM) of both everolimus and azole inhibitors allowed for safe and convenient modification of everolimus dosage, which was tapered to maintain a target range of 5-15 ng/mL during and after antifungal treatments. While significant in their effects, these drug interactions were able to be managed safely through a careful approach to management and use of individual TDM.
Billaud
E M
EM
Pharmacology Unit, Hôpital Européen Georges Pompidou, 20-40 Rue Leblanc, 75908, Paris Cedex 15, France. eliane.billaud@egp.aphp.fr.|Faculty of Medicine, University Paris-Descartes, Paris, France. eliane.billaud@egp.aphp.fr.
Antoine
C
C
Nephrology and Kidney Transplantation Unit, Hôpital Saint Louis, Paris, France.
Berge
M
M
Pharmacology Unit, Hôpital Européen Georges Pompidou, 20-40 Rue Leblanc, 75908, Paris Cedex 15, France.
Abboud
I
I
Nephrology and Kidney Transplantation Unit, Hôpital Saint Louis, Paris, France.
Lefeuvre
S
S
Pharmacology Unit, Hôpital Européen Georges Pompidou, 20-40 Rue Leblanc, 75908, Paris Cedex 15, France.|Faculty of Medicine, University Paris-Descartes, Paris, France.
Benammar
M
M
Pharmacology Unit, Hôpital Européen Georges Pompidou, 20-40 Rue Leblanc, 75908, Paris Cedex 15, France.
Glotz
D
D
Nephrology and Kidney Transplantation Unit, Hôpital Saint Louis, Paris, France.
D000935:Antifungal Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D016903:Drug Monitoring; D000068338:Everolimus; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000493:pharmacokinetics / Q000627:therapeutic use; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D014230:Triazoles / Q000493:pharmacokinetics / Q000627:therapeutic use; D065819:Voriconazole
D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D011743:Pyrimidines; D014230:Triazoles; C101425:posaconazole; D000068338:Everolimus; D051544:Cytochrome P-450 CYP3A; D065819:Voriconazole; D020123:Sirolimus