P2-17-04: Induction of Tamoxifen Metabolism by Rifampicin: A Worrying Drug-Drug Interaction.
Authors: Binkhorst L , Loos WJ , de Jongh FE , Hamberg P , Ghobadi Moghaddam-Helmantel IM , Jager A , Seynaeve C , Verweij J , van Gelder T , Mathijssen RH 
Published: June 2012

Abstract
Background
Tamoxifen (Tam) undergoes extensive biotransformation into several metabolites, including the highly active metabolite endoxifen. Differences in metabolism, influenced by both genetic and environmental factors, largely contribute to the inter-individual variability in endoxifen plasma concentrations, potentially affecting the efficacy of Tam. Conflicting results between CYP2D6 genotype/phenotype and endoxifen concentrations have been observed. A reason for this discrepancy may be that CYP3A4 may have a more crucial role in the formation of endoxifen than previously thought (de Graan et al, JCO, in press). Hypothesizing that induction of CYP3A4 and CYP2D6 could lead to increased endoxifen levels, a prospective study was activated evaluating the effects of enzyme induction by rifampicin (Rif) on the plasma pharmacokinetics (PK) of Tam and its metabolites.
Methods: A randomized cross-over study design was used, with each patient serving as her own control. Breast cancer patients on steady state Tam therapy (20 or 40 mg once daily) were included. Patients underwent two periods of plasma sampling covering 24 hrs each, once using Tam alone, and once after 15 days of oral Rif (600 mg daily) taken in combination with Tam. Patients were randomized for sampling sequence 1) Tam alone followed by Rif/Tam versus 2) Rif/Tam followed by Tam alone. PK sampling in sequence 2 was performed after a 30-day wash-out period of Rif. Tam and its main metabolites ND-Tam, 4-OH-Tam and endoxifen were quantitated by a validated LC-MS/MS method. PK parameters, including area under the plasma-concentration time curve (AUC) and maximum concentration (Cmax) of all four compounds were calculated (WinNonLin program) and compared (with or without Rif) using a two-sided paired t-test. For safety reasons an interim-analysis was performed after 4 patients.
Results: The interim-analysis showed that concentrations of Tam and its metabolites were significantly decreased during Rif/Tam co-administration as compared to Tam administration alone (see table). Especially endoxifen exposure was decreased by a mean of 69%. Based on these data it was decided to stop further enrollment in this study.
Conclusions: Concentrations of Tam and its main metabolites decreased significantly after induction by rifampicin. Potentially contributing factors include further metabolism of Tam-metabolites into other inactive metabolites or conjugates (i.e. glucuronides) or a decreased oral availability of Tam. Further pharmacokinetic analyses, including the analysis of glucuronides and other metabolites, will be performed to better understand the mechanism behind these findings. Based upon these data, combining rifampicin with Tam should be avoided. Similar drug-drug interactions may exist between Tam and other strong CYP inducers, such as St John's wort and phenytoin.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-17-04.