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In vitro–in vivo extrapolations to evaluate the effect of concomitant drugs on tacrolimus (FK506) exposure

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The effect of concomitant drugs having a cytochrome P450 (CYP) 3A inhibitory potency on tacrolimus exposure was predicted from in vitro metabolism results. In this study, the IC50 values of concomitant drugs on the formation of M‐I, the major metabolite of tacrolimus, were determined, and the effect on oral exposure (AUC p.o.) of tacrolimus was assessed from static models. When an absorbed fraction (F a) of 0.97, intestinal wall availability (F g) of 0.27 and fraction metabolized by CYP3A (f m(CYP3A)) of 0.8 were used, the least bias was observed for the prediction of the AUC p.o. of tacrolimus. The relationship of the IC50 values of 11 inhibitors between tacrolimus and typical CYP3A substrates (midazolam and testosterone) was also analysed. A strong correlation was found between the IC50 values of tacrolimus and typical CYP3A substrates (r 2 ≥ 0.85). The predictability of the effect of inhibitors on tacrolimus AUC p.o. was investigated based on the same static models with the use of published IC50 values for midazolam and testosterone. The bias for the prediction of tacrolimus AUC p.o. was minimal with the use of IC50 values determined using tacrolimus itself as a substrate. These results suggest that tacrolimus itself is still the best choice for predicting the AUC p.o. of tacrolimus, although our findings suggest that midazolam or testosterone may be used instead of tacrolimus to estimate roughly (predicted AUC p.o. within an approximately 2‐fold range of observed values) the effect of CYP3A inhibitors on the tacrolimus AUC p.o.. Copyright © 2015 John Wiley & Sons, Ltd.
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Keywords: FK506; drug–drug interaction; microsomes; prediction; tacrolimus

Document Type: Research Article

Publication date: 01 July 2015

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