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 2.4 h, CL(p) of 26 and 10 ml min(-1) kg(-1) and V(ss) of 1.6 and 2 l 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 8 min, 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 30 mg and 53, 150, 29% of actual at 500 mg. 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.

Attenuated responses to CO2 and hypoxia in parents of threatened sudden infant death syndrome infants.

Ventilatory and heart rate responses to hypercapnia and hypoxia were measured in the following three groups: group I, controls (n equals 15); group II, parents of threatened sudden infant death syndrome (SIDS) infants (n equals 10); and group III, parents of SIDS infants (n equals 17). We found significantly reduced heart rate responses to carbon dioxide and hypoxia in group II (1.4 plus or minus 1.9 percent and 16.0 plus or minus 4.0 percent; mean plus or minus SEM) compared with controls (7.1 plus or minus 1.4 percent and 26 plus or minus 2.4 percent; P less than .025). Ventilatory responses to hypoxia in groups II and III were not significantly different from controls. Two group II mothers had a greatly reduce ventilatory response to carbon dioxide. Four other parents in group II had abnormally low heart rate responses to hypoxia or carbon dioxide. We concluded that parents of threatened SIDS infants had reduced heart rate responses to carbon dioxide and hypoxia and may have reduced ventilatory responses to carbon dioxide.