Pharmacodynamics
The proposed mechanism of action for phenformin is an increase in p-AMPK levels. Our intention was to measure changes in PBMC p-AMPK in all patients treated but due to a cell bank malfunction, only samples from patients treated at the highest dose levels (150 and 200 mg twice daily) were available for analysis. Patients treated at these high dose levels experienced frequent AEs requiring phenformin dose interruption, which would be expected to mitigate some of the effects. Despite this, in 3 of 6 patients, there was evidence of p-AMPK increase in PBMC while on phenformin (We also explored the hypothesis that phenformin would decrease peripheral MDSCs. As noted above, we only had PBMCs from patients treated at the two highest dose levels. Effect of treatment on percentage of circulating MDSCs derived from flow cytometric analysis of PBMC samples from patients treated at the 150 and 200 mg bid dose level. Dotted lines indicate times when patient was not taking phenformin. bid, twice daily.