Pharmacokinetics and pharmacodynamics of the non-nucleoside reverse-transcriptase inhibitor etravirine in treatment-experienced HIV-1-infected patients.

The pharmacokinetics and pharmacodynamics of the antiretroviral agent etravirine were evaluated in two phase III clinical trials. Pharmacokinetic data were available in 577 patients randomized to receive etravirine. The mean (SD) population-pharmacokinetics-derived area under the concentration-time curve at 12 h (AUC(12 h)) and concentration at 0 h (C(0 h)) were 5,501 (4,544) ng·h/ml and 393 (378) ng/ml, respectively. Hepatitis C coinfection raised etravarine exposure, and concomitant use of tenofovir disoproxil fumarate lowered etravirine exposure, but these changes were not considered clinically relevant. Etravirine apparent oral clearance was not affected by age, weight, sex, race, hepatitis B coinfection status, creatinine clearance, or concomitant use of enfuvirtide. Virologic response (<50 copies/ml) at week 24 was 59% in patients randomized to etravirine vs. 41% in those receiving placebo (P < 0.0001). There was no apparent relationship between etravirine pharmacokinetics and either efficacy or safety. Factors other than the pharmacokinetics of etravirine such as the characteristics of the patients and the disease, as well as characteristics of the treatment regimen, predict virologic response.

Assessment of the steady-state pharmacokinetic interaction between etravirine administered as two different formulations and tenofovir disoproxil fumarate in healthy volunteers.

OBJECTIVE: Two open-label, randomized, cross-over trials in healthy volunteers were conducted to investigate the pharmacokinetic interaction between etravirine and tenofovir disoproxil fumarate. METHODS: Etravirine was administered as either 800 mg twice a day (bid) (phase II formulation in Study 1) or 200 mg bid (phase III formulation in Study 2) for 8 days followed by a 12 h pharmacokinetic evaluation. After a minimum of 14 days washout, tenofovir disoproxil fumarate 300 mg once a day was administered for 16 days. Volunteers were randomized to receive co-administration of etravirine with tenofovir disoproxil fumarate on either days 1-8 or days 9-16 followed by a 12 h pharmacokinetic evaluation for etravirine on day 8 or 16, respectively. Plasma and urine tenofovir concentrations were determined on days 8 and 16 over 24 h. RESULTS: The least square mean (LSM) ratio [90% confidence interval (CI)] for the area under the plasma concentration-time curve from 0 to 12 h (AUC(12 h)) for etravirine co-administered with tenofovir disoproxil fumarate vs. etravirine alone was 0.69 (0.61-0.79) and 0.81 (0.75-0.88) in Studies 1 and 2, respectively. The LSM ratio (90% CI) for the effect of etravirine on tenofovir AUC(24 h) was 1.16 (1.09-1.23) in Study 1 and 1.15 (1.09-1.21) in Study 2. CONCLUSIONS: These alterations are not considered clinically relevant for either drug and no dose adjustment is necessary when etravirine and tenofovir disoproxil fumarate are co-administered.

Impact of reverse transcriptase resistance on the efficacy of TMC125 (etravirine) with two nucleoside reverse transcriptase inhibitors in protease inhibitor-naïve, nonnucleoside reverse transcriptase inhibitor-experienced patients: study TMC125-C227.

OBJECTIVES: TMC125-C227, an exploratory phase II, randomized, controlled, open-label trial, compared the efficacy and safety of TMC125 (etravirine) with an investigator-selected protease inhibitor (PI) in nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant, protease inhibitor-naïve, HIV-1-infected patients. METHODS: Patients were randomized to TMC125 800 mg twice a day (bid) (phase II formulation; n=59) or the control PI (n=57), plus two nucleoside reverse transcriptase inhibitors (NRTIs). RESULTS: In an unplanned interim analysis, patients receiving TMC125 demonstrated suboptimal virological responses relative to the control PI. Therefore, trial enrolment was stopped prematurely and TMC125 treatment discontinued after a median of 14.3 weeks. In this first-line NNRTI-failure population, baseline NRTI and NNRTI resistance was high and reduced virological responses were observed relative to the control PI. No statistically significant relationship was observed between TMC125 exposure and virological response at week 12. TMC125 was better tolerated than a boosted PI for gastrointestinal-, lipid- and liver-related events. CONCLUSIONS: In a PI-naïve population, with baseline NRTI and NNRTI resistance and NRTI recycling, TMC125 was not as effective as first use of a PI. Therefore the use of TMC125 plus NRTIs alone may not be optimal in PI-naïve patients with first-line virological failure on an NNRTI-based regimen. Baseline two-class resistance, rather than pharmacokinetics or other factors, was the most likely reason for suboptimal responses.

Reclamation of treated domestic wastewater using biological membrane assisted carbon filtration (BioMAC).

Membrane processes are increasingly used as an advanced treatment technique for the reclamation of treated domestic wastewater. Despite their inherent advantages, fouling remains an operational problem, while the removal of dissolved organic components such as volatile organic compounds is negligible. In the present work, the addition of a partially non-submerged biological granular activated carbon filtration to a microfiltration lab-scale reactor was investigated. It was observed that the reactor could be operated under stable flux conditions although regular hydraulic backwashing was necessary. Preferential attached growth of nitrifiers on the activated carbon particles allowed for a complete and very stable nitrification, with permeate total ammonium nitrogen and nitrite levels below 0.2 mg l(-1) regardless of influent concentrations. Chemical oxygen demand of the permeate averaged 5.26 mg O2 l(-1) which is below the Environmental Protection Agency guideline for wastewater reuse. Using an electronic nose, elimination of volatile compounds was assessed. The combined process resulted in complete odour removal, with the permeate odour levels equaling the reference samples (tap water), even during periods of increased reactor load (shock load experiment). A 4.2 log10 CFU and 3.7 log10 CFU removal were observed for total coliforms and E. coli, respectively.

Experimental study of the flammability limits of toluene-air mixtures at elevated pressure and temperature.

The flammability limits of toluene-air mixtures are experimentally determined at pressures up to 500 kPa and temperatures up to 250 degrees C in a closed spherical vessel. The results at atmospheric pressure are compared with the results obtained in a glass tube. The flammability limits depend linearly upon temperature. A twilight zone characterized by weak pressure rises is observed for toluene at all pressures, while soot is formed at elevated pressures only. The explosion characteristics of toluene are compared with those of methane. Despite their chemical differences, the explosion characteristics of toluene and methane are similar.

Comparison of two standard test methods for determining explosion limits of gases at atmospheric conditions.

A comparison is made between two internationally accepted methods to determine the explosion limits of gases at atmospheric pressure and room temperature (20 l sphere - DIN 51649). Significant differences (about 1 vol.%) in the upper explosion limits (UEL) values are found for four hydrocarbons tested. A new criterion is proposed which leads to close agreement between the UEL values obtained by the two methods.

The impact of peritonitis on peritoneal and systemic acid-base status of patients on continuous ambulatory peritoneal dialysis.

OBJECTIVE: To assess the possible effects of peritonitis on peritoneal and systemic acid-base status. DESIGN: pH, pCO2, lactate, and total leukocyte and differential count were simultaneously determined in the overnight dwell peritoneal dialysis effluent (PDE) and arterial blood in noninfected patients (controls) and on days 1, 3, and 5 from the onset of peritonitis. SETTING: University multidisciplinary dialysis program. PATIENTS: Prospective analysis of 63 peritonitis episodes occurring in 30 adult CAPD patients in a single center. RESULTS: In controls, mean (+/- SD) acid-base parameters were pH 7.41 +/- 0.05, pCO2 43.5 +/- 2.6 mm Hg, lactate 2.5 +/- 1.5 mmol/L in the PDE, and pH 7.43 +/- 0.04, PaCO2 36.8 +/- 3.8 mm Hg, lactate 1.4 +/- 0.7 mmol/L in the blood. In sterile (n = 6), gram-positive (n = 34), and Staphylococcus aureus (n = 9) peritonitis PDE pH's on day 1 were, respectively, 7.29 +/- 0.07, 7.32 +/- 0.07, and 7.30 +/- 0.08 (p < 0.05 vs control). In gram-negative peritonitis (n = 14) PDE pH was 7.21 +/- 0.08 (p < 0.05 vs all other groups). A two-to-threefold increase in PDE lactate was observed in all peritonitis groups, but a rise in pCO2 was only seen in gram-negative peritonitis. Acid-base profile of PDE had returned to control values by day 3 in sterile, gram-positive and Staphylococcus aureus peritonitis and by day 5 in gram-negative peritonitis. Despite a slight increase in plasma lactate on the first day of peritonitis, arterial blood pH was not affected by peritonitis. CONCLUSION: PDE pH is decreased in continuous ambulatory peritoneal dialysis (CAPD) peritonitis, even in the absence of bacterial growth. In gram-negative peritonitis, PDE acidosis is more pronounced and prolonged, and pCO2 is markedly increased. Arterial blood pH is not affected by peritonitis.