We investigated whether a single plasma midazolam concentration could serve as an accurate predictor of total midazolam clearance, an established in-vivo probe measure of cytochrome P450 3A (CYP3A) activity. In a retrospective analysis of data from 224 healthy volunteers, non-compartmental pharmacokinetic parameters were estimated from plasma concentration-time curves following intravenous (IV) and/or oral administration. Based on statistical moment theory, the concentration at the mean residence time (MRT) should be the best predictor of the total area under the curve (AUC). Following IV or oral midazolam administration, the average MRT was found to be approximately 3.5 h, suggesting that the optimal single sampling time to predict AUC was between 3 and 4 h. Since a 4-h data point was common to all studies incorporated into this analysis, we selected this time point for further investigation. The concentrations of midazolam measured 4 h after an IV or oral dose explained 80 and 91% of the constitutive interindividual variability in midazolam AUC, respectively. The 4-h midazolam measurement was also an excellent predictor of drug-drug interactions involving CYP3A induction and inhibition. Compared with baseline values, the direction and magnitude of change in midazolam AUC and the 4-h concentration were completely concordant for all study subjects. We conclude that a single 4-h midazolam concentration following IV or oral administration represents an accurate marker of CYP3A phenotype under constitutive and modified states. Moreover, the single-point approach offers an efficient means to phenotype and identify individuals with important genetic polymorphisms that affect CYP3A activity.

Oxaliplatin at 130 mg/m2 every 3 weeks is well tolerated by patients with mild to moderate degrees of renal dysfunction. These data strongly support the recommendation that dose reductions of single-agent oxaliplatin are not necessary in patients with a CrCL greater than 20 mL/min.

The efficacy of oral WIN 54954 for the prevention of rhinovirus infection and illness was tested in two randomized, double-blinded, placebo-controlled volunteer challenge studies. Volunteers were inoculated with rhinovirus type 39 (MIC of WIN 54954, 0.17 Lg/ml) or rhinovirus type 23 (MIC, 0.016 ,ug/ml). The volunteers received two doses of drug (600 mg per dose) or placebo on the first day; this was followed by three doses on each of the subsequent 5 days. All volunteers were challenged with virus after the third dose of study drug. No significant antiviral or clinical effect was detected in either study. Pharmacokinetic studies revealed that on the last day of drug administration, 38 of 39 (97%) volunteers had trough levels of WIN 54954 in plasma greater than the MIC for the respective virus. Nasal wash specimens collected on the same day revealed a detectable level in only 6 of 24 (25%) volunteers at the peak (range, 6 to 24 ng/ml) and in only 2 of 14 (14%) volunteers at the trough (range, 6 and 7 ng/ml). These results suggest that the lack of efficacy of WIN 54954 against rhinovirus may be related to an inability to deliver sufficient drug to the site of viral infection.The oxazolines are a class of antipicornavirus compounds which have activity against rhinoviruses and enteroviruses in vitro (4, 6, 16) and against enteroviruses in animal models (4, 5). These compounds bind to a hydrophobic pocket in the picornavirus viral capsid protein (7). Depending on the virus serotype, this interaction inhibits replication either by interfering with uncoating of the virus or by causing a conformational change in the cell receptor site on the viral capsid and inhibiting attachment to the cell (9, 14). WIN 54954 is a representative of the oxazoline compounds and has a broad spectrum of activity against both the human rhinoviruses and enteroviruses in vitro (16). In cell culture, this agent inhibited 80% of 52 rhinovirus serotypes when it was used at a concentration of 0.28 ,ug/ml and 80% of 15 enterovirus serotypes when it was used at a concentration of 0.06 ,ug/ml. The purpose of these two parallel studies done at the University of Virginia (UVa) and at the Medical University of South Carolina (MUSC) was to determine the efficacy of oral WIN 54954 for the prevention of experimentally induced rhinovirus infection and illness.MATERIALS AND METHODS Study design. The clinical trials at both study sites were randomized, double blind, and placebo controlled in design. All volunteers were begun on the study drug or placebo approximately 18 h prior to virus challenge. At UVa the volunteers were isolated in individual motel rooms throughout the treatment period; at MUSC the volunteers were not isolated during the study. The study at UVa was done in January 1990, and the study at MUSC was done in November 1990.Volunteers. Healthy volunteers between 18 and 55 years of age who had a serum neutralizing antibody titer to the study virus of less than 1:8 were selected for participation in the studies. Volunteers who had an upper respir...