Single-dose escalation and multiple-dose safety, tolerability, and pharmacokinetics of IDX899, a candidate human immunodeficiency virus type 1 nonnucleoside reverse transcriptase inhibitor, in healthy subjects.

IDX899 is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant strains of human immunodeficiency virus type 1 (HIV-1) and with a high genetic barrier to resistance. Single rising doses of 50 and 100 (given by use of a 50-mg capsule) and 200, 400, 800, and 1,200 mg (given by use of a 200-mg capsule) of IDX899 or matching placebo were administered sequentially to cohorts of healthy male subjects, followed by the administration of multiple doses of 800 mg once daily (QD) or 400 mg twice daily (BID) for 7 days. A single dose of 400 mg was also administered to a cohort of females. IDX899 was administered orally under fasted (50- to 400-mg doses) and then fed (> or = 200-mg doses) conditions. Exposure to IDX899 was dose proportional and comparable in males and females. With a different drug-to-excipient ratio, the 50-mg capsule led to a higher exposure but a shorter mean terminal half-life (t(1/2)) of 6.2 to 6.8 h. The 200-mg capsule resulted in a more sustained exposure with a longer mean t(1/2) of 7.9 to 14.6 h. Food enhanced absorption by approximately twofold, while it delayed the time to the maximum concentration. The mean concentration at 24 h following the administration of a single 200-mg dose under fed conditions exceeded the in vitro protein binding-adjusted 90% inhibitory concentration by fourfold. The levels of plasma exposure were similar between the single dosing and the repeat dosing with 800 mg QD and was approximately twofold higher with 400 mg BID. Mean steady-state trough levels were 0.9 microg/ml (range, 0.2 to 2.5 microg/ml) and 2.1 microg/ml (range, 0.5 to 4.5 microg/ml) for the 800-mg QD and 400-mg BID regimens, respectively. The level of excretion of unchanged drug in urine was negligible. IDX899 was well tolerated; and no serious adverse events, dose-dependent adverse events, or laboratory abnormalities were detected. These favorable safety and pharmacokinetic results support further clinical studies with patients with HIV-1 infection by the use of a QD regimen.

The pharmacokinetics of daptomycin in moderately obese, morbidly obese, and matched nonobese subjects.

Daptomycin pharmacokinetics were studied in adult volunteers who were moderately obese (body mass index [BMI] = 25-39.9 kg/m2) or morbidly obese (BMI > or =40 kg/m2) and a matched (gender, age, renal function) nonobese (BMI between 18.5 and 24.9 kg/m2) control group. All subjects received a dose of 4 mg/kg total body weight (TBW) by intravenous infusion (30 minutes). Daptomycin plasma half-life, the fraction of the dose excreted unchanged in urine, and daptomycin absolute renal clearance (mL/h) were unchanged as a function of obesity. The absolute volume of distribution (Vz and Vss) and plasma clearance (CL) for daptomycin were higher in obese subjects as compared to nonobese matched controls. The rate of change of Vz and CL with increasing BMI was greater when these pharmacokinetic parameters were expressed in absolute terms compared to when they were normalized for TBW or ideal body weight. This suggests that increases in body mass associated with obesity are proportionality higher than the corresponding increases in Vd and CL. Exposure to daptomycin in obese subjects (Cmax, AUC) was increased 25% and 30%, respectively, compared to nonobese matched controls, well within the range that was previously determined to be safe and well tolerated. Daptomycin may be dosed based on total body weight, and no adjustment in daptomycin dose or dose regimen should be required based solely on obesity.

Single-dose pharmacokinetics of daptomycin in young and geriatric volunteers.

Daptomycin is a novel lipoprotein antibiotic that was recently approved for the treatment of complicated skin and skin structure infections caused by aerobic gram-positive bacteria. The pharmacokinetics of daptomycin was evaluated after a single 0.5-hour intravenous infusion of 4 mg/kg to groups of young adult (18-30 years) and geriatric (>or= 75 years) volunteers. Daptomycin was safe and well tolerated. No adverse events related to the infusion were reported. With increased age, there were increases in the area under the plasma concentration-time curve extrapolated to infinity (AUC( infinity )) and the terminal elimination half-life. Systemic (CL) and renal clearance (CL(R)) both decreased with increasing age. The observed changes seen in CL between the two cohorts were most likely a result of changes in renal function, as estimated by creatinine clearance. No statistically significant differences were observed between the two groups in the maximum plasma concentration (C(max)) and volume of distribution at steady state (Vd(ss)). The confidence intervals for the arithmetic mean ratios of the fraction of the dose excreted in the urine as daptomycin (%Fe) (geriatric subjects over younger subjects) were 60% to 101%, indicating that %Fe(dose) was lower in geriatric subjects. These results demonstrate that changes in the pharmacokinetics of daptomycin in the elderly are attributable to changes in renal function, whereas age per se is not a significant factor.