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Pharmacokinetic Drug Interactions with Vandetanib during Coadministration with Rifampicin or Itraconazole

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 300mg dose of vandetanib in healthy subjects. Study Design and Setting: Two phase I, randomized...

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Autores principales: Martin, Paul, Oliver, Stuart, Robertson, Jane, Kennedy, Sarah-Jane, Read, Jessica, Duvauchelle, Thierry
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586143/
https://www.ncbi.nlm.nih.gov/pubmed/21410294
http://dx.doi.org/10.2165/11586980-000000000-00000
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author Martin, Paul
Oliver, Stuart
Robertson, Jane
Kennedy, Sarah-Jane
Read, Jessica
Duvauchelle, Thierry
author_facet Martin, Paul
Oliver, Stuart
Robertson, Jane
Kennedy, Sarah-Jane
Read, Jessica
Duvauchelle, Thierry
author_sort Martin, Paul
collection PubMed
description 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 300mg 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 600mg/day on days 1–31 with a single oral dose of vandetanib 300mg on day 10; and (ii) a single oral dose of vandetanib 300mg 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 200mg/day on days 1–24 with a single oral dose of vandetanib 300mg on day 4; and (ii) a single oral dose of vandetanib 300mg 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. Results: Study A: coadministration of vandetanib with rifampicin resulted in a statistically significant reduction in AUC(504) (geometric least square [GLS]mean ratio [vandetanib + rifampicin/vandetanib alone] 0.60; 90% CI 0.58, 0.63). There was no significant difference in C(max) of vandetanib (GLSmean ratio 1.03; 90% CI 0.95, 1.11). AUC(504) and C(max) of N-desmethylvandetanib increased by 266.0% and 414.3%, respectively, in the presence of rifampicin compared with vandetanib alone. Exposure to vandetanib N-oxide was very low compared with that of vandetanib, but was increased in the presence of rifampicin. Study B: coadministration of vandetanib with itraconazole resulted in a significant increase in AUC(504) (GLSmean ratio [vandetanib + itraconazole/vandetanib alone] 1.09; 90% CI 1.01, 1.18) and no significant change in C(max) (GLSmean ratio 0.96; 90% CI 0.83, 1.11). Vandetanib was well tolerated in both studies. Conclusions: Exposure to vandetanib, as assessed byAUC(504) in healthy subjects, was reduced by around 40% when a single dose was given in combination with the potent CYP3A4 inducer rifampicin. Because of this, it may be appropriate to avoid coadministration of potent CYP3A4 inducers with vandetanib. Vandetanib exposure was increased by about 9% when it was taken in combination with the CYP3A4 inhibitor itraconazole. It is unlikely that coadministration of vandetanib and potent CYP3A4 inhibitors will need to be contraindicated.
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spelling pubmed-35861432013-03-07 Pharmacokinetic Drug Interactions with Vandetanib during Coadministration with Rifampicin or Itraconazole Martin, Paul Oliver, Stuart Robertson, Jane Kennedy, Sarah-Jane Read, Jessica Duvauchelle, Thierry Drugs R D Original Research Article 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 300mg 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 600mg/day on days 1–31 with a single oral dose of vandetanib 300mg on day 10; and (ii) a single oral dose of vandetanib 300mg 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 200mg/day on days 1–24 with a single oral dose of vandetanib 300mg on day 4; and (ii) a single oral dose of vandetanib 300mg 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. Results: Study A: coadministration of vandetanib with rifampicin resulted in a statistically significant reduction in AUC(504) (geometric least square [GLS]mean ratio [vandetanib + rifampicin/vandetanib alone] 0.60; 90% CI 0.58, 0.63). There was no significant difference in C(max) of vandetanib (GLSmean ratio 1.03; 90% CI 0.95, 1.11). AUC(504) and C(max) of N-desmethylvandetanib increased by 266.0% and 414.3%, respectively, in the presence of rifampicin compared with vandetanib alone. Exposure to vandetanib N-oxide was very low compared with that of vandetanib, but was increased in the presence of rifampicin. Study B: coadministration of vandetanib with itraconazole resulted in a significant increase in AUC(504) (GLSmean ratio [vandetanib + itraconazole/vandetanib alone] 1.09; 90% CI 1.01, 1.18) and no significant change in C(max) (GLSmean ratio 0.96; 90% CI 0.83, 1.11). Vandetanib was well tolerated in both studies. Conclusions: Exposure to vandetanib, as assessed byAUC(504) in healthy subjects, was reduced by around 40% when a single dose was given in combination with the potent CYP3A4 inducer rifampicin. Because of this, it may be appropriate to avoid coadministration of potent CYP3A4 inducers with vandetanib. Vandetanib exposure was increased by about 9% when it was taken in combination with the CYP3A4 inhibitor itraconazole. It is unlikely that coadministration of vandetanib and potent CYP3A4 inhibitors will need to be contraindicated. Springer International Publishing 2012-11-27 2011-03 /pmc/articles/PMC3586143/ /pubmed/21410294 http://dx.doi.org/10.2165/11586980-000000000-00000 Text en © Martin et al., publisher and licensee Adis Data Information BV 2011
spellingShingle Original Research Article
Martin, Paul
Oliver, Stuart
Robertson, Jane
Kennedy, Sarah-Jane
Read, Jessica
Duvauchelle, Thierry
Pharmacokinetic Drug Interactions with Vandetanib during Coadministration with Rifampicin or Itraconazole
title Pharmacokinetic Drug Interactions with Vandetanib during Coadministration with Rifampicin or Itraconazole
title_full Pharmacokinetic Drug Interactions with Vandetanib during Coadministration with Rifampicin or Itraconazole
title_fullStr Pharmacokinetic Drug Interactions with Vandetanib during Coadministration with Rifampicin or Itraconazole
title_full_unstemmed Pharmacokinetic Drug Interactions with Vandetanib during Coadministration with Rifampicin or Itraconazole
title_short Pharmacokinetic Drug Interactions with Vandetanib during Coadministration with Rifampicin or Itraconazole
title_sort pharmacokinetic drug interactions with vandetanib during coadministration with rifampicin or itraconazole
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586143/
https://www.ncbi.nlm.nih.gov/pubmed/21410294
http://dx.doi.org/10.2165/11586980-000000000-00000
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