Effects of Rifampin and Ketoconazole on the Pharmacokinetics of Nilotinib in Healthy Participants

Abstract

Nilotinib (Tasigna), an orally bioavailable second-generation BCR-ABL tyrosine kinase inhibitor, is approved for use in patients with chronic myeloid leukemia in chronic phase and accelerated phase who are resistant or intolerant to prior therapy, including imatinib. Previous in vitro studies indicated that nilotinib metabolism is primarily mediated by CYP3A4. To investigate the effect of CYP3A4 induction and inhibition on nilotinib pharmacokinetics, 2 studies were conducted in healthy volunteers prior to and following treatment with a strong inducer (rifampin) or inhibitor (ketoconazole). In the induction study, administration of rifampin 600 mg once daily for 8 days significantly increased urinary 6β-hydroxycortisol/ cortisol ratio, from a preinduction baseline of 5.8 ± 2.7 to 18.0 ± 10.2 after 8 days of rifampin treatment, confirming an inductive effect on CYP3A4. Nilotinib oral clearance was increased by 4.8-fold, and the maximum serum concentration (C(max)) and area under the serum concentration-time curve (AUC) were decreased by 64% and 80%, respectively, in the induced state compared with baseline. In the inhibition study, ketoconazole 400 mg once daily for 6 days increased the C(max) and AUC of nilotinib by 1.8- and 3-fold, respectively, compared with nilotinib alone. These results indicate that concurrent use of strong CYP3A4 inducers or inhibitors may necessitate dosage adjustments of nilotinib and should be avoided when possible.

Variability in bioavailability of small molecular tyrosine kinase inhibitors

“…Whatever the cause, a low F is associated with an increased intra-and interpatient variability in drug plasma concentration [18]. Registration texts and other studies, as far as could be accessed, show significant inter-individual variation in important pharmacokinetic parameters of all smTKIs [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. This may result in possibly dangerous situations for patients that experience extensively low, or high, exposure to the substances.…”

Choosing the Best Second-Line Tyrosine Kinase Inhibitor in Imatinib-Resistant Chronic Myeloid Leukemia Patients Harboring Bcr-Abl Kinase Domain Mutations: How Reliable Is the IC50?

“…Food has been shown to influence nilotinib bioavailability [54]. Interactions with cytochrome p450 (CYP) isoform 3A4 and 3A5 (CYP3A4, CYP3A5) enzyme inducers (dexamethasone, phenobarbital, progesterone, rifampin) are known to be able to decrease imatinib (and also nilotinib) plasma concentrations to subtherapeutic levels [55]. Even more importantly, pharmacogenomics postulates that a significant degree of interpatient variability in therapeutic response lies in single nucleotide polymorphisms influencing the expression level and/or activity of drug-metabolizing enzymes and drug transporters.…”

Effect of rifampin on the pharmacokinetics of bosutinib, a dual Src/Abl tyrosine kinase inhibitor, when administered concomitantly to healthy subjects

“…Rifampin is an oral semisynthetic antibiotic that potently induces CYP3A4 and several other CYP enzymes [26][27][28] and is used for evaluating potential drug-drug interactions [24]. In healthy subjects receiving the Bcr-Abl TKIs imatinib [29] and nilotinib [30], coadministration of rifampin resulted in both reduced TKI exposure and increased TKI clearance.…”