Pharmacokinetic Drug Interactions with Vandetanib during Coadministration with Rifampicin or Itraconazole

Abstract

Background: Vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 (VEGFR-2), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET), is a developmental oncology drug, that is in part metabolized by cytochrome P450 (CYP) 3A4. Clinical studies were performed to assess the potential for 3A4 inhibitors and inducers to affect exposure to vandetanib. Objective: The aim of this study was to investigate the effects of a potent CYP3A4 inducer, rifampicin (Study A), and a potent CYP3A4 inhibitor, itraconazole (Study B), on the pharmacokinetics of a single 300 mg dose of vandetanib in healthy subjects. Study Design and Setting: Two phase I, randomized, open-label, two-way crossover, single-center studies. Participants and Intervention: Study A: 18 healthy male subjects aged 21-44 years were randomized to receive each of the following two regimens, separated by a ‡6-week washout period: (i) oral rifampicin 600 mg/day on days 1-31 with a single oral dose of vandetanib 300 mg on day 10; and (ii) a single oral dose of vandetanib 300 mg on day 1. Study B: 16 healthy male subjects aged 20-44 years were randomized to receive each of the following two regimens, separated by a 3-month washout period: (i) oral itraconazole 200 mg/day on days 1-24 with a single oral dose of vandetanib 300 mg on day 4; and (ii) a single oral dose of vandetanib 300 mg on day 1. Main Outcome Measure: Blood samples for measurement of vandetanib (both studies) concentrations and its metabolites, N-desmethylvandetanib and vandetanib N-oxide (Study A only), were collected before and at various timepoints after vandetanib administration for up to 28 days (Study A) and 37 days (Study B). Pharmacokinetic parameters were determined using noncompartmental methods. The area under the plasma concentration-time curve from time 0 to 504 hours (AUC 504 ) and maximum plasma concentration (C max ) of vandetanib were compared in the presence and absence of rifampicin, and in the presence and absence of itraconazole.

Drug‐Drug Interaction Study to Assess the Effect of Cytochrome P450 Inhibition and Induction on the Pharmacokinetics of the Novel Cereblon Modulator Avadomide (CC‐122) in Healthy Adult Subjects

“…This contrasted with the essentially nil effect of the CYP3A inhibitor itraconazole. Similar findings of discordance between CYP3A inhibition and induction have been reported for several drugs, including ixazomib, 17 tivozanib, 18 and vandetanib 19 ; this contrast has 1 of 2 possible main explanations. First, the induction of CYP3A-mediated metabolism by rifampin might cause a significant increase in clearance of avadomide, although the contribution of CYP3A to avadomide clearance is small at baseline.…”

“…In the case of vandetabib such a regime was confirmed by direct measurement of large increases in plasma concentrations of CYP3A4-related metabolites under conditions of induction. 19 Second, rifampin could induce other pregnane X receptor-dependent drug-metabolizing enzymes and transporters. 20,21 Specifically, rifampin induces not only CYP3A4 expression but also intestinal P-glycoprotein (P-gp) 22 and CYP1A2 in vivo, supported by the finding that the rifampin produced a 15% increase in conversion of caffeine to paraxanthine mediated by CYP1A2 in healthy subjects.…”

Long‐Term Effect of Rifampicin‐Based Anti‐TB Regimen Coadministration on the Pharmacokinetic Parameters of Efavirenz and 8‐Hydroxy‐Efavirenz in Ethiopian Patients

“…The present study adopted a conservative approach to allow 2 weeks more than the longest reported period, which was at least 6 weeks. 28,[41][42][43] Certainly, it would be challenging and is beyond the scope of this clinical study to prove the mechanisms contributing to the above observation, given that EFV and 8-OH-EFV undergo both primary and secondary metabolism via several enzymes, whose functionalities are affected by the presence of the anti-TB drugs and the associated genetic polymorphisms in CYP2B6 and NAT2. 44 However, the phenomena might be explained through the following complementing mechanisms.…”

Medullary thyroid carcinoma – Adverse events during systemic treatment: risk-benefit ratio

“…may increase the toxicity of cabozantinib by increasing its plasma concentrations. In contrast, the use of CYP3A4 inducers can reduce the plasma concentrations of vandetanib and, consequently, the efficacy of the drug (23,24).…”