Abstract
PurposeTo overcome cytochrome P450 2D6 (CYP2D6) mediated tamoxifen resistance in postmenopausal early breast cancer, CYP2D6 phenotype-adjusted tamoxifen dosing in patients with impaired CYP2D6 metabolism and/or the application of endoxifen, the most potent tamoxifen metabolite, are alternative treatment options. To elucidate both strategies comprehensively we used a physiologically-based pharmacokinetic (PBPK) modeling approach.MethodsFirstly simulation of increasing tamoxifen dosages was performed by a virtual clinical trial including populations of CYP2D6 poor (PM), intermediate (IM) and extensive metabolizers (EM) (N = 8,000). Secondly we performed PBPK-simulations under consideration of tamoxifen use plus concomitant increasing dosages of endoxifen (N = 7,000).ResultsOur virtual study demonstrates that dose escalation of tamoxifen in IMs resulted in endoxifen steady-state plasma concentrations similar to CYP2D6 EMs whereas PMs did not reach EM endoxifen levels. Steady-state plasma concentrations of tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen were similar in CYP2D6 IMs and PMs versus EMs using once daily dosing of 20 mg tamoxifen and concomitant CYP2D6 phenotype-adjusted endoxifen dosing in IMs and PMs (1 mg/d and 3 mg/d, respectively).ConclusionIn conclusion, we suggest that co-administration of endoxifen in tamoxifen treated early breast cancer women with impaired CYP2D6 metabolism is a promising alternative to reach plasma concentrations comparable to CYP2D6 EM patients.
Highlights
The efficacy of the selective estrogen receptor modulator tamoxifen, the backbone of the treatment of estrogen receptor positive early breast cancer in postmenopausal women, is based on its bio-activation to 4-hydroxylated metabolites by hepatic cytochrome P450 (CYP) enzymes (Brauch et al 2009)
The physiologically-based pharmacokinetic (PBPK) model parameterization of the cytochrome P450 2D6 (CYP2D6) intermediate metabolizers (IM) phenotype was based on one functional CYP2D6 allele (acc. to (Mürdter et al 2011; Coller et al 2002))
Since the PBPK model adequacy is sufficiently assessed, simulated median trough Css levels of tamoxifen, NDMTAM, 4OH-TAM and endoxifen as well as the percentiles 5 and 95 for the CYP2D6 extensive metabolizers (EM) phenotype were used as reference ranges to elucidate alternative dosing regimens of tamoxifen together with endoxifen in CYP2D6 IMs and poor metabolizers (PM) by PBPK simulation
Summary
The efficacy of the selective estrogen receptor modulator tamoxifen, the backbone of the treatment of estrogen receptor positive early breast cancer in postmenopausal women, is based on its bio-activation to 4-hydroxylated metabolites by hepatic cytochrome P450 (CYP) enzymes (Brauch et al 2009). Based on clinical studies there is an increasing body of evidence that the in vivo metabolism of tamoxifen in postmenopausal early breast cancer depends on CYP2D6, thereby altering tamoxifen response (Brauch et al 2013a, 2013b; Brauch and Schwab 2013). Direct administration of endoxifen to bypass CYP2D6-dependent bio-activation and to reduce inter-individual variability of endoxifen Css levels (Ahmad et al 2010) may be an attractive alternative in treatment of postmenopausal breast cancer
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