Investigation of the pharmacokinetic interactions of deferasirox, a once-daily oral iron chelator, with midazolam, rifampin, and repaglinide in healthy volunteers.
Deferasirox, a newly developed iron chelator, was coadministered orally with either a known inducer of drug metabolism or with cosubstrates for cytochrome P450 (CYP) to characterize the potential for drug-drug interactions. In the induction assessment, single-dose deferasirox pharmacokinetics were obtained in the presence and absence of a repeated-dose regimen of rifampin. In the CYP3A interaction evaluation, midazolam and its active hydroxylated metabolite were assessed after single doses of midazolam in the presence and absence of steady-state concentrations of deferasirox. To test for interaction at the level of CPY2C8, single-dose repaglinide pharmacokinetics/pharmacodynamics were determined with and without repeated-dose administration of deferasirox. After rifampin, a significant reduction (44%) in plasma exposure (AUC) to deferasirox was observed. Upon coadministration of midazolam, there was a modest reduction of up to 22% in midazolam exposure (AUC, C(max)), suggesting a modest induction of CYP3A4/5 by deferasirox. Def erasirox caused increases in repaglinide plasma C(max) and AUC of 1.5-fold to over 2-fold, respectively, with little change in blood glucose measures. Specific patient prescribing recommendations were established when coadministering deferasirox with midazolam, repaglinide, and rifampin. These recommendations may also apply to other substrates of CYP3A4/5 and CYP2C8 or potent inducers of glucuronidation.
Skerjanec
Andrej
A
Novartis Oncology, 104/3K01, Florham Park, NJ 07932, USA. andrej.skerjanec@novartis.com
Wang
Jixian
J
Maren
Kelly
K
Rojkjaer
Lisa
L
D000328:Adult; D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology*; D002219:Carbamates / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D000077588:Deferasirox; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics; D007502:Iron Chelating Agents / Q000494:pharmacology; D008297:Male; D008874:Midazolam / Q000493:pharmacokinetics*; D010880:Piperidines / Q000493:pharmacokinetics*; D012293:Rifampin / Q000493:pharmacokinetics*; D014230:Triazoles / Q000494:pharmacology*
D018686:Anesthetics, Intravenous; D001565:Benzoates; D002219:Carbamates; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007502:Iron Chelating Agents; D010880:Piperidines; D014230:Triazoles; C072379:repaglinide; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; C510164:CYP3A5 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D008874:Midazolam; D000077588:Deferasirox; D012293:Rifampin