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

• Published in: Biopharmaceutics & drug disposition Vol. 36; no. 5; pp. 265 - 274
• Main Authors: Oda, Kazuo, Yamano, Katsuhiro, Otsuka, Yukio
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.07.2015; Wiley Subscription Services, Inc
• Subjects: Area Under Curve; Cytochrome P-450 CYP3A - metabolism; Cytochrome P-450 CYP3A Inhibitors - pharmacology; Drug Interactions; drug-drug interaction; FK506; Humans; Immunosuppressive Agents - pharmacology; microsomes; Microsomes, Liver - metabolism; Midazolam - pharmacology; Models, Biological; prediction; tacrolimus; Tacrolimus - pharmacology; Testosterone; Testosterone - pharmacology; prediction; FK506; drug-drug interaction; tacrolimus; microsomes
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.1938

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 (AUCp.o.) of tacrolimus was assessed from static models. When an absorbed fraction (Fa) of 0.97, intestinal wall availability (Fg) of 0.27 and fraction metabolized by CYP3A (fm(CYP3A)) of 0.8 were used, the least bias was observed for the prediction of the AUCp.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 (r2 ≥ 0.85). The predictability of the effect of inhibitors on tacrolimus AUCp.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 AUCp.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 AUCp.o. of tacrolimus, although our findings suggest that midazolam or testosterone may be used instead of tacrolimus to estimate roughly (predicted AUCp.o. within an approximately 2‐fold range of observed values) the effect of CYP3A inhibitors on the tacrolimus AUCp.o.. Copyright © 2015 John Wiley & Sons, Ltd.