Time above threshold plasma concentrations as pharmacokinetic parameter in the comparison of oral and intravenous docetaxel treatment of breast cancer tumors

Abstract

Background Prolonging the time which plasma concentrations of antimitotic drugs, such as the taxanes, exceed cytotoxic threshold levels may be beneficial for their efficacy. Orally administered docetaxel offers an undemanding approach to optimize such time above threshold plasma concentrations (tC>threshold). Methods A nonsystematic literature screen was performed to identify studies reporting in-vitro half-maximal inhibitory concentration (IC50) values for docetaxel. Pharmacokinetics of intravenously (i.v.) docetaxel (75 mg/m2) and orally administered docetaxel (ModraDoc006) co-administered with ritonavir (r) given twice daily (30 + 20 mg concomitant with 100 mg ritonavir bis in die) were simulated using previously developed population models. TC>threshold was calculated for a range of relevant thresholds in terms of in-vitro cytotoxicity and plasma concentrations achieved after i.v. and oral administration of docetaxel. A published tumor growth inhibition model for i.v. docetaxel was adapted to predict the effect of attainment of time above threshold levels on tumor dynamics. Results Identified studies reported a wide range of in vitro IC50 values [median 0.04 µmol/L, interquartile range (IQR): 0.0046–0.62]. At cytotoxic thresholds <0.078 µmol/L oral docetaxel shows up to ~7.5-fold longer tC>threshold within each 3-week cycle for a median patient compared to i.v.. Simulations of tumor dynamics showed the increased relative potential of oral docetaxel for inhibition of tumor growth at thresholds of 0.075, 0.05 and 0.005 µmol/L. Conclusion ModraDoc006/r is superior to i.v. docetaxel 75 mg/m2 in terms of median time above cytotoxic threshold levels <0.078 µmol/L. This may indicate superior cytotoxicity and inhibition of tumor growth compared to i.v. administration for relatively docetaxel-sensitive tumors.