Flavopiridol (NSC649890) pharmacokinetics suggest enterohepatic circulation

Flavopiridol is a novel cyclin-dependent kinase inhibitor which is currently in clinical trials at the NCI. Flavopiridol was administered as a 72-hr continuous infusion every 14 days. A total of 55 patients have been treated to date at doses starting at 4mg/m2/dayx3 escalating to 78mg/m²/day x3. Twenty-three patients experienced post-infusional increases in plasma flavopiridol concentration, usually within 12 hrs post infusion. This suggests that flavopiridol undergoes enterohepatic circulation. Pharmacokinetic parameter estimates were determined by non-compartmental methods (NCM) and using an enterohepatic recirculation model (ERM) implemented in ADAPT IIv4. The median (range) of these values are: NCM ERM Clt (L/hr) 31.89 (2.6-153) 30.99 (0.4-168) Vd (L/Kg) 6.47 (1.4-13.9) 8.48 (0.8-320) T_1/2 (hr) 13.21(1-246) 14.02 (2-69) The observation that post-infusional increases occured in close proximity to meals has led to the hypothesis that these meals are influencing the disposition of flavopiridol. We are currently studying the cholecystokinin concentrations associated with the post-infusional peaks, and the effects of diet modification on flavopiridol pharmacokinetics.