ORAL IDARUBICIN PHARMACOKINETICS - CORRELATION OF TROUGH LEVEL WITH IDARUBICIN AREA UNDER CURVE

Idarubicin is the first anthracycline that can be successfully adminis tered via the oral route and thus may facilitate antineoplastic chemot herapy in an improved quality of life. These perspectives are somewhat hampered by the large variation in bioavailability between individual patients and the obvious requirement to monitor plasma concentration and area-under-the-curve values (AUG) for an appropriate adjustment of idarubicin dose, In this study we describe the pharmacokinetics of id arubicin and its main metabolite idarubicinol in 12 patients after ora l application of 20 mg/m(2) idarubicin on 3 consecutive days and demon strate that the 24 h trough levels show a high correlation with AUC an d may thus allow a rapid and easy determination of individual drug con centrations and an appropriate dose adjustment. The average terminal h alf-life was 30.5 h for idarubicin and 66.9 h for idarubicinol. The AU C for idarubicin and its main metabolite idarubicinol revealed a subst antial interpatient variation with AUC values ranging from 25.7 to 114 ng x h/ml (average 58.1 ng x h/ml) for idarubicin and from 109.4-445. 2 ng x h/ml (average 287.3 ng x h/ml) for idarubicinol. However, the r atio of idarubicin/idarubicinol differed only two folds from 1:3.7 to 1:7.7 with an average of 1:5.1. Both idarubicin and idarubicinol conce ntrations were highly reproducible, however, upon measurements after r epeated applications within individual patients. Moreover, idarubicino l and idarubicin AUCs showed a good correlation with r = 0.78, indicat ing that the interindividual variation of idarubicin AUC reflects diff erences in absorption rather than in metabolism. In order to describe the interindividual bioavailability of idarubicin - represented by the respective AUC - measurement of a single data point with a high corre lation with the AUC would be ideal. Our study demonstrates that the 24 h trough level shows such an excellent correlation (r = 0.96) with AU G, making it the perfect candidate for fast estimates of the individua l bioavailability in a given patient. On this basis, the longitudinal measurement of the 24 h trough level may allow assessment of the impac t of interindividual variations in AUC on clinical outcome and toxicit y.