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...

Purpose: To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function. Experimental Design: Thirty-four patients were stratified by 24-h urinary creatinine clearance (CrCL) into four renal dysfunction groups: group A (control, CrCL, z60 mL/min), B (mild, CrCL, 40-59 mL/min), C (moderate, CrCL, 20-39 mL/min), and D (severe, CrCL, <20 mL/min). Patients were treated with 60 to 130 mg/m 2 oxaliplatin infused over 2 h every 3 weeks. Pharmacokinetic monitoring of platinum in plasma, plasma ultrafiltrates, and urine was done during cycles 1and 2. Results: Plasma ultrafiltrate platinum clearance strongly correlated with CrCL (r 2 = 0.712). Platinum elimination from plasma was triphasic, and maximal platinum concentrations (C max ) were consistent across all renal impairment groups. However, only the h-half-life was significantly prolonged by renal impairment, with values of 14.0 F 4.3, 20.3 F 17.7, 29.2 F 29.6, and 68.1h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m 2 , the area under the concentration time curve increased in with the degree of renal impairment, with values of 16.4 F 5.03, 39.7 F 11.5, and 44.6 F 14.6 AgÁh/mL, in groups A, B, and C, respectively. However, there was no increase in pharmacodynamic drug-related toxicities. Estimated CrCL using the Cockcroft-Gault method approximated the measured 24-h urinary CrCL (mean prediction error, -5.0 mL/min). Conclusions: Oxaliplatin pharmacokinetics are altered in patients with renal impairment, but a corresponding increase in oxaliplatin-related toxicities is not observed.

Flurbiprofen pharmacokinetics were studied in 15 normal male subjects after four oral doses. Plasma levels of total (bound + free) drug were monitored for 48 h and urine was collected for 96 h after the doses. All subjects demonstrated linear relationships between administered dose and total flurbiprofen AUC, indicating that oral clearance is independent of dose for the dose range evaluated in this study. Urinary recovery data indicated that the efficacy of absorption was dose independent.

Ibuprofen kinetics were studied in 15 subjects after four oral doses. Plasma levels of both total and free ibuprofen were measured for 12 hr, and urine was collected for 48 hr after the doses. All subjects showed a nonlinear relationship between dose and total ibuprofen plasma AUC. Free ibuprofen plasma AUC, however, was linearly related to the dose, suggesting that oral clearance based on free drug was dose independent. Urinary recovery data indicated that efficiency of absorption was dose independent.

This study was designed to test a proposed dose modification for intravenous milrinone in congestive heart failure patients (CHF, NYHA I-II) with either moderate or severe renal impairment. All the patients were administered an intravenous loading dose of drug at 50 micrograms kg-1 over 10 min. This was followed by an 18 h maintenance infusion of milrinone at 0.45 or 0.35 micrograms kg-1 min-1 for the moderate (chromium-EDTA clearance of 31-75 mL min-1, n = 10) and severe renally impaired subjects (chromium-EDTA of clearance 10-30 mL min-1, n = 11), respectively. Plasma and urine samples were collected for up to 34 h and analysed for parent drug by validated HPLC methods. The mean (+/- s.d.) steady-state plasma concentrations of milrinone were within the therapeutic range (100-300 ng mL-1) for both groups, with values of 239 +/- 71 ng mL-1 and 269 +/- 32 ng mL-1 for the moderate and severe patients, respectively. No statistical differences were observed between the steady-state values for the two groups. With the exception of two patients per group, individual steady-state levels were also within the therapeutic range. Those outside the nominal range showed steady-state levels, ranging between 308 and 353 ng mL-1, that were not associated with any serious adverse events.(ABSTRACT TRUNCATED AT 250 WORDS)

We conclude that SR233377 administered on a 5-day schedule is associated with tolerable clinical symptoms and some activity against a range of solid tumors but dosing is limited by QTc prolongation, a condition that predisposes to ventricular arrhythmias. Phase II development on this schedule is not recommended based on the occurrence of this concentration-dependent effect. Further investigation of alternative schedules of administration and of SR233377 analogues is warranted.