Population Pk/Pd Analysis Of The Pan-Hdac Inhibitor Resminostat

e13527 Background: Resminostat, an oral pan-HDAC inhibitor, was investigated in various oncological indications. To investigate pharmacokinetic (PK) and pharmacodynamic (PD) properties of resminostat, a population PK/PD model was established to quantitatively describe the time course of HDAC inhibition. Methods: PK and PD data from a clinical Phase I study in patients with solid tumors were included in the analysis. Single dose PK data of 100 mg, 200 mg, 400 mg, 600 mg and 800 mg dose groups were fitted simultaneously to a two-compartment model. A transit compartment model captured a delayed drug input. Collected PD data comprised pan-HDAC inhibition measured ex vivo in leukocytes of 18 patients using the fluorogenic substrate Boc-K(Ac)-AMC. Deacetylation results in trypsin cleavage and released AMC dye is quantified. Several PD models were explored. Model selection and diagnosis was performed applying information criteria, goodness-of-fit plots and visual predictive checks. Results: Ex vivo measured pan-...