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Jan 2, 2019

Predicting the Effects of Different Triazole Antifungal Agents on the Pharmacokinetics of Tamoxifen

Abstract

Tamoxifen is an antiestrogen drug that is widely used in the adjuvant chemotherapy of estrogen receptor-α (ERα)-positive breast cancer. Chemotherapy could suppress immune function in breast cancer patients, which may cause invasive fungal infections (IFIs). Triazoles (voriconazole, fluconazole, and itraconazole) were commonly used for IFI. The physiologically based pharmacokinetic (PBPK) models were developed to investigate the influence of different triazoles on tamoxifen pharmacokinetics in this paper. To investigate the influence of different triazoles (voriconazole, fluconazole, itraconazole) on tamoxifen pharmacokinetics. Adjusted physicochemical data and pharmacokinetic parameters of voriconazole, fluconazole, itraconazole, and tamoxifen were obtained from published literatures. PBPK models were built and verified in healthy subjects using GastroPlus™. Voriconazole, itraconazole, and tamoxifen were administered orally. Fluconazole was administered intravenously. Simulated plasma concentration–time curves of the voriconazole, fluconazole, itraconazole, and tamoxifen showed good agreement with the observed profiles, respectively. The DDI simulations showed that the pharmacokinetic parameters of tamoxifen were increased by various degrees when coadministered with different triazoles. In healthy subjects, the area under the plasma concentration–time curve from 0 to t h (AUC0–t) of tamoxifen was increased by 41%, 5%, and1% when coadministrated with voriconazole, fluconazole, and itraconazole, respectively. The PBPK models adequately characterized the pharmacokinetics of tamoxifen and triazoles. Among the three triazoles, voriconazole exhibited the greatest effect on tamoxifen pharmacokinetics. In clinical practice, an effective dosage adjustment of tamoxifen may need to be considered and TDM for tamoxifen is advisable to guide dosing and optimize therapy when coadministered with voriconazole.

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