Pharmacokinetic and Pharmacodynamic Properties of SB1317, a Potent and Orally Active Multi-Kinase Inhibitor.

Abstract

Key physicochemical properties such as solubility, lipophilicity (logD7.4, logP) and pKa (the negative log of the acid dissociation constant) can be used to predict protein binding, tissue distribution, and gastrointestinal (GI) absorption. More recent application of computational methods allows even better prediction of compound oral bioavailability from in vitro and/or in silico properties. During the lead optimization process in our multi-kinase inhibitor program a good correlation between physicochemical properties like logD and solubility (determined experimentally at pH 7) versus AUC(0-inf) (Area Under the Curve) was observed for a series of kinase inhibitors. A calculated logD*solubility value between 200 to 400 predicted a reasonably high oral AUC(0-inf) in mouse PharmacoKinetic (PK) studies for this series of compounds, with correlation coefficient of >0.9. The correlation of logD*solubility vs. AUC(0-inf) enabled us to prioritize compounds for PK studies. SB1317, a novel pyrimidine derivative, is an orally active multi-kinase inhibitor that evolved as a lead drug candidate from in vitro and in vivo pharmacokinetic studies. SB1317 is a highly permeable compound, does not undergo active P-glycoprotein transport, and has a solubility of 75 μg/ml. It is metabolically stable in dog and human liver microsomes and unstable in rodent liver microsomes. No P450 inhibition was observed up to 10 μM towards CYP3A4, CYP1A2, CYP2C9 and CYP2C19. In vivo pharmacokinetics in nude mice and Beagle dogs resulted in %F of 12 and 37% respectively. Tumor pharmacokinetics of SB1317 shows increased exposure in tumor than in plasma with a AUC(0-t) tumor/plasma ratio of 3. Excellent oral dose proportionality (10, 20 and 40mg/kg) was observed in both plasma and tumor. SB1317 has exhibited uniformly high plasma protein binding (>99%) across the preclinical species and human. It is the free or unbound portion of the compound in the plasma or at the tissue level that would yield effective anti-tumor activity. (AUC0-inf)unbound/GI50 and Cmax-unbound/GI50 were used as PK/PD surrogates for the measure of SB1317 efficacy. A factor of SB1317 unbound AUC (0-inf)/GI50 above 0.5 results in significant pharmacodynamic (PD) effects in hematological tumor models (MV4-11 and HL-60 engraft model). Linear pharmacokinetic extrapolation from preclinical species to human was determined by allometric scaling (predicted human % F = 36). PK/PD relationships established for SB1317 in preclinical species could form the basis of a PK/PD-driven clinical development program.