title: Increased inhibition of cytochrome P450 3A4 with the tablet formulation of posaconazole.
abstract: Being a substrate of the cytochrome P450 3A4 (CYP3A4) isoenzyme, sirolimus metabolism is decreased when posaconazole is administered concomitantly. However, because of the poor bioavailability of the oral suspension of posaconazole with which low plasma concentrations are obtained, CYP3A4 inhibition is weak and a 50-75% dose reduction of sirolimus is sufficient to avoid sirolimus overdosage. The new tablet formulation allows reaching posaconazole concentrations 3-4 fold higher than those obtained with the oral suspension. Based on a case of sirolimus overdosage following posaconazole tablets administration, we modelled the inhibition of sirolimus clearance by posaconazole, and then simulated several dosage regimens of sirolimus taken together with posaconazole tablets. We were able to describe well the interaction, and found a value of IC50 of posaconazole towards sirolimus clearance of 0.68 μg/mL. The simulations showed that even a 80% decrease of the daily dose of sirolimus is unsuitable in many cases with trough concentrations of posaconazole of 2 μg/mL. A decrease of 40% of the dose with spacing administrations of 3 days may be considered. The clinicians and pharmacologists must be warned that the use of posaconazole tablets may result in an inhibition of CYP3A4 of greater magnitude than with the oral suspension.
authors.affiliation: Rennes University Hospital, Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Rennes, France; Rennes 1 University, Faculty of Medicine, Laboratory of Experimental and Clinical Pharmacology, Rennes, France; Inserm, CIC-P 1414 Clinical Investigation Center, Rennes, France. Electronic address: antoine.petitcollin@chu-rennes.fr.
authors.forename: A
authors.initials: A
authors.lastname: Petitcollin
authors.affiliation: Rennes University Hospital, Department of Nephrology, Rennes, France.
authors.forename: R
authors.initials: R
authors.lastname: Crochette
authors.affiliation: Rennes University Hospital, Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Rennes, France; Rennes 1 University, Faculty of Medicine, Laboratory of Experimental and Clinical Pharmacology, Rennes, France; Inserm, CIC-P 1414 Clinical Investigation Center, Rennes, France.
authors.forename: C
authors.initials: C
authors.lastname: Tron
authors.affiliation: Rennes University Hospital, Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Rennes, France; Rennes 1 University, Faculty of Medicine, Laboratory of Experimental and Clinical Pharmacology, Rennes, France; Inserm, CIC-P 1414 Clinical Investigation Center, Rennes, France.
authors.forename: M-C
authors.initials: MC
authors.lastname: Verdier
authors.affiliation: Rennes University Hospital, Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Rennes, France.
authors.forename: C
authors.initials: C
authors.lastname: Boglione-Kerrien
authors.affiliation: Rennes University Hospital, Department of Nephrology, Rennes, France.
authors.forename: C
authors.initials: C
authors.lastname: Vigneau
authors.affiliation: Rennes University Hospital, Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Rennes, France; Rennes 1 University, Faculty of Medicine, Laboratory of Experimental and Clinical Pharmacology, Rennes, France; Inserm, CIC-P 1414 Clinical Investigation Center, Rennes, France.
authors.forename: E
authors.initials: E
authors.lastname: Bellissant
authors.affiliation: Rennes University Hospital, Department of Clinical and Biological Pharmacology and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Rennes, France; Rennes 1 University, Faculty of Medicine, Laboratory of Experimental and Clinical Pharmacology, Rennes, France; Inserm, CIC-P 1414 Clinical Investigation Center, Rennes, France.
authors.forename: F
authors.initials: F
authors.lastname: Lemaitre
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000627:therapeutic use*; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical / Q000379:methods; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D013535:Suspensions / Q000493:pharmacokinetics / Q000627:therapeutic use; D013607:Tablets / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014230:Triazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D013535:Suspensions; D013607:Tablets; D014230:Triazoles; C101425:posaconazole; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: Cytochrome P-450 CYP3A; Drug–drug interaction; Pharmacokinetics; Posaconazole; Sirolimus