Pre-clinical pharmacokinetics of UK-453,061, a novel non-nucleoside reverse transcriptase inhibitor (NNRTI), and use of in silico physiologically based prediction tools to predict the oral pharmacokinetics of UK-453,061 in man

1. UK-453,061 is a novel second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI). Following intravenous bolus administration of UK-453,061 in male rat and infusion administration in dog, UK-453,061 had the following mean pharmacokinetic properties: elimination T-1/2 of 1.6 and 2.4h, CLp of 26 and 10 mlmin(-1) kg(-1) and V-ss of 1.6 and 21 kg(-1), respectively. 2. The half-lives of UK-453,061 disappearance in recombinant human CYPs 2C8, 2C9, 2A6, 2E1, 1A2, 2C19, 2D6 and 3A4 were 71, 100, 56, 101, 61, 34, 60 and 8min, respectively. The disappearance half-life of UK-453,061 in human liver microsomes in the presence of UDPGA was 90 min. 3. Human clearance values were predicted using single-species scaling from in vivo data and from in vitro data using SimCYP. The human distribution of UK-453,061 was estimated using an in silico, physiologically based pharmacokinetics (PBPK) methodology and absorption was predicted from measured physicochemical, permeability, and solubility data using GastroPlus and SimCYP. The C-max was predicted to be 68, 185, 149% of the actual mean value using rat, dog and in vitro predicted values of human clearance at 30mg and 53, 150, 29% of actual at 500mg. The area under the curve (AUC) was predicted to be 73, 285 and 142% of the actual mean value using rat, dog and in vitro predicted values of human clearance at 30 mg and 52, 212 and 35% of actual at 500 mg. 4. This study demonstrates the utility of using in silico PBPK approaches to make predictions of human pharmacokinetics before dosing for the first time in humans.