Pharmacokinetics of darunavir at 900 milligrams and ritonavir at 100 milligrams once daily when coadministered with efavirenz at 600 milligrams once daily in healthy volunteers.

Ritonavir-boosted darunavir with efavirenz may be considered a nucleoside-sparing regimen for treatment-naïve HIV-infected patients. However, the pharmacokinetics of this combination administered once daily have not been studied. We conducted a three-period interaction study with healthy volunteers. The subjects were given darunavir at 900 mg with ritonavir at 100 mg once daily for 10 days. Efavirenz at 600 mg once daily was added for 14 days. Darunavir-ritonavir was then stopped and efavirenz alone was given for 14 days. At the end of each period, blood was taken predosing and for up to 24 h postdosing to measure the drug concentrations. We recruited seven males and five females ages 24 to 49 years and weighing 50 to 83 kg. The darunavir trough concentrations were reduced after efavirenz administration (geometric mean ratio [GMR], 0.43; 90% confidence interval [CI], 0.32 to 0.57]; P < 0.001). The mean darunavir trough concentrations were 1,180 ng/ml (standard deviation, 1,138 ng/ml) after efavirenz administration, but all darunavir trough concentrations were above the 50% effective concentration (EC(50)) of 55 ng/ml for the wild-type virus. For darunavir, the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) (GMR, 0.86; 90% CI, 0.75 to 0.97; P = 0.05) and the half-life (GMR, 0.56; 90% CI, 0.49 to 0.65; P < 0.001) were also significantly reduced. The darunavir peak concentrations were not significantly changed (GMR, 0.92; 90% CI, 0.82 to 1.03; P = 0.23). The ritonavir trough concentrations (GMR, 0.46; 90% CI, 0.33 to 0.63; P = 0.001), AUC(0-24) (GMR, 0.74; 90% CI, 0.64 to 0.86; P = 0.004), and half-life (GMR, 0.80; 90% CI, 0.75 to 0.86; P < 0.001) were also significantly reduced. The efavirenz half-life was significantly longer when it was coadministered with darunavir-ritonavir than when it was given alone (GMR, 1.66; 90% CI, 1.24 to 2.23; P = 0.01), but there were no differences in the efavirenz trough or peak concentration or AUC(0-24) when it was coadministered with darunavir-ritonavir. Efavirenz reduced the trough concentrations of darunavir significantly, but the concentrations remained above the EC(50) for the wild-type virus. This regimen should be evaluated with treatment-naïve patients with no preexisting resistance.

Induction of chemoprotective phase 2 enzymes by ginseng and its components.

Phase 2 detoxification enzymes protect against carcinogenesis and oxidative stress. Ginseng ( PANAX spp.) extracts and components were assayed for inducer activity of NQO1 (quinone reductase), a phase 2 enzyme, in Hepa1c1c7 cells. Ginseng extracts were analyzed for ginsenosides and panaxytriol. Korean red PANAX GINSENG extracts demonstrated the most potent phase 2 enzyme induction activity (76,900 U/g dried rhizome powder and 27,800 U/g for two similar preparations). The ginsenoside-enriched HT-1001 American ginseng ( PANAX QUINQUEFOLIUS) extract was the next most potent inducer, with activity of 15,900 U/g, followed by raw American ginseng root with activity of 8700 U/g. Neither a polysaccharide-enriched extract of American ginseng nor a commercial white PANAX GINSENG preparation showed any inducer activity. Pure ginsenosides showed no inducer activity. Protopanaxadiol and protopanaxatriol, deglycosylated ginsenoside metabolic derivatives, showed potent induction activity (approximately 500,000 U/g each). Synthetic panaxytriol was over 10-fold more potent (induction potency 5,760,000 U/g). There was no correlation between ginsenoside content and phase 2 enzyme induction. The most potent inducing red ginseng extract also had the highest panaxytriol content, 120.8 microg/g. We found that ginseng induced NQO1 and that polyacetylenes are the most active components.

Darunavir/ritonavir and efavirenz exert differential effects on MRP1 transporter expression and function in healthy volunteers.

BACKGROUND: The efflux transporter MRP1 actively transports antiretrovirals and reduces intracellular accumulation in peripheral blood mononuclear cells (PBMCs). We studied MRP1 expression and function in healthy volunteers treated with darunavir/ritonavir and efavirenz. METHODS: Seven healthy HIV-negative volunteers were recruited. PBMCs were collected at baseline, 9 days after administration of darunavir (900 mg) and ritonavir (100 mg) once daily, 9 days after coadministration of darunavir/ritonavir and efavirenz (600 mg) once daily and 13 days after administration of efavirenz alone. MRP1 expression was measured in PBMCs using flow cytometry with fluorescein isothiocyanate-conjugated antibody against MRP1m6. MRP1 expression was also measured in CD4(+) T-cells with a phycoerythrin-conjugated antibody against CD4. MRP1 efflux function was assessed by incubating PBMCs with carboxyfluorescein diacetate (CFDA) and comparing CFDA fluorescence with and without the modulators MK571 and probenecid. RESULTS: MRP1 expression was reduced after darunavir/ritonavir administration (geometric mean ratio [GMR] 0.58, 95% confidence interval [95% CI] 0.51-0.65; P<0.001) and darunavir/ritonavir plus efavirenz coadministration (GMR 0.74, 95% CI 0.64-0.84; P=0.001), but not after efavirenz administration alone (GMR 0.82, 95% CI 0.64-1.06; P=0.10). MRP1 protein expression was 41% higher in CD4(+) T-cells. MRP1 efflux function was increased after efavirenz administration (GMR 3.13, 95% CI 2.73-3.59; P<0.001) and darunavir/ritonavir plus efavirenz coadministration (GMR 4.35, 95% CI 3.35-5.68; P<0.001), but not after darunavir/ritonavir administration (GMR 1.06, 95% CI 0.80-1.42; P=0.42). CONCLUSIONS: Darunavir/ritonavir and efavirenz treatment exerted differential effects on MRP1 expression and function. These effects could potentially alter antiviral activity, especially in CD4(+) T-cells.