Preclinical pharmacokinetic/pharmacodynamic models to predict synergistic effects of co-administered anti-cancer agents.

PURPOSE: Pharmacokinetic/pharmacodynamic (PK/PD) models have been shown to be useful in predicting tumor growth rates in mouse xenografts. We applied novel PK/PD models to the published anticancer combination therapies of tumor growth inhibition to simulate synergistic changes in tumor growth rates. The parameters from the PK/PD model were further used to estimate clinical doses of the combination. METHODS: A PK/PD model was built that linked the dosing regimen of a compound to the inhibition of tumor growth in mouse xenograft models. Two subsequent PK/PD models were developed to simulate the published tumor growth profiles of combination treatments. Model I predicts the tumor growth curve assuming that the effect of two anticancer drugs, AZD7762 and irinotecan, is synergistic when given in combination. Model II predicts the tumor growth curve assuming that the effect of co-administering flavopiridol and irinotecan is maximally synergistic when dosed at an optimal interval. RESULTS: Model I was able to account for the synergistic effects of AZD7762 following the administration of irinotecan. When Model II was applied to the antitumor activity of irinotecan and flavopiridol combination therapy, the modeling was able to reproduce the optimal dosing interval between administrations of the compounds. Furthermore, Model II was able to estimate the biologically active dose of flavopiridol recommended for phase II studies. CONCLUSIONS: The timing of clinical combination therapy doses is often selected empirically. PK/PD models provide a theoretical structure useful in the design of the optimal clinical dose, frequency of administration and the optimal timing of administration between anticancer agents to maximize tumor suppression.

Ultra-low flow nanospray for the normalization of conventional liquid chromatography/mass spectrometry through equimolar response: standard-free quantitative estimation of metabolite levels in drug discovery.

Nanospray experiments were performed on an ensemble of drug molecules and their commonly known metabolites to compare performance with conventional electrospray ionization (ESI) and to evaluate equimolar response capabilities. Codeine, dextromethorphan, tolbutamide, phenobarbital, cocaine, and morphine were analyzed along with their well-known metabolites that were formed via hydroxylation, dealkylation, hydrolysis, and glucuronidation. Nanospray exhibited a distinct trend toward equimolar response when flow rate was reduced from 25 nL/min to less than 10 nL/min. A more uniform response between the parent drug and the corresponding metabolites was obtained at flow rates of 10 nL/min or lower. The largest discrepancy was within +/-50% for plasma samples. Nanospray was used as a calibrator for conventional ESI liquid chromatography/tandem mass spectrometry (LC/MS/MS) and normalization factors were applied to the quantitation of an acyl-glucuronide metabolite of a proprietary compound in rat plasma. A nanospray calibration method was developed with the standard curve of the parent drug to generate quantitative results for drug metabolites within +/-20% of that obtained with reference standards and conventional ESI. The nanospray method provides a practical solution for the quantitative estimation of drug metabolites in drug discovery when reference standards are not available.