Effect of a high-calorie, high-fat meal on the bioavailability and pharmacokinetics of PA-824 in healthy adult subjects.

PA-824 is a novel nitroimidazo-oxazine being developed as an antituberculosis agent. Two randomized studies evaluated the pharmacokinetics and safety of a single oral dose of PA-824 administered to healthy adult subjects 30 min after a high-calorie, high-fat meal (fed state) versus after a minimum 10-h fast (fasted state). A total of 48 subjects were dosed in the two studies in a randomized crossover design with PA-824 at dose levels of 50, 200, or 1,000 mg in the fed state or fasted state. After the administration of PA-824, the geometric mean ratios of Cmax and AUC0-∞ revealed an increase in exposure with the addition of a high-calorie, high-fat meal compared to the fasted state by 140 and 145% at 50 mg, 176 and 188% at 200 mg, and 450 and 473% at 50, 200, and 1,000 mg, respectively. The median Tmax in the fed state was 4 h for the 50-mg dose and 5 h for the 200- and 1,000-mg doses. In the fasted state, the median Tmax was 4 h for the 50- and 200-mg doses and 6.5 h for the 1,000-mg dose. All doses were well tolerated, and no serious adverse events occurred in either study. (This study has been registered at ClinicalTrials.gov under registration numbers NCT01828827 and NCT01830439.).

Early bactericidal activity and pharmacokinetics of PA-824 in smear-positive tuberculosis patients.

PA-824 is a novel nitroimidazo-oxazine being evaluated for its potential to improve tuberculosis (TB) therapy. This randomized study evaluated safety, tolerability, pharmacokinetics, and extended early bactericidal activity of PA-824 in drug-sensitive, sputum smear-positive, adult pulmonary tuberculosis patients. Fifteen patients per cohort received 1 of 4 doses of oral PA-824: 200, 600, 1,000, or 1,200 mg per day for 14 days. Eight subjects received once daily standard antituberculosis treatment as positive control. The primary efficacy endpoint was the mean rate of change in log CFU of Mycobacterium tuberculosis in sputum incubated on agar plates from serial overnight sputum collections, expressed as log10 CFU/day/ml (+/-standard deviation [SD]). The drug demonstrated increases that were dose linear but less than dose proportional in serum concentrations in doses from 200 to 1,000 mg daily. Dosing of 1,200 mg gave no additional exposure compared to 1,000 mg daily. The mean daily CFU fall under standard treatment was 0.148 (+/-0.055), consistent with that found in previous studies. The mean daily fall under PA-824 was 0.098 (+/-0.072) and was equivalent for all four dosages. PA-824 appeared safe and well tolerated; the incidence of adverse events potentially related to PA-824 appeared dose related. We conclude that PA-824 demonstrated bactericidal activity over the dose range of 200 to 1,200 mg daily over 14 days. Because maximum efficacy was unexpectedly achieved at the lowest dosage tested, the activity of lower dosages should now be explored.

Safety, tolerability, and pharmacokinetics of PA-824 in healthy subjects.

PA-824 is a novel antibacterial agent that has shown in vitro activity against both drug-sensitive and drug-resistant Mycobacterium tuberculosis. The compound's MIC is between 0.015 and 0.25 microg/ml for drug-sensitive strains and between 0.03 and 0.53 microg/ml for drug-resistant strains. In addition, it is active against nonreplicating anaerobic Mycobacterium tuberculosis. The safety, tolerability, and pharmacokinetics of PA-824 were evaluated in two escalating-dose clinical studies, one a single-dose study and the other a multiple-dose study (up to 7 days of daily dosing). In 58 healthy subjects dosed with PA-824 in these studies, the drug candidate was well tolerated, with no significant or serious adverse events. In both studies, following oral administration PA-824 reached maximal plasma levels in 4 to 5 h independently of the dose. Maximal blood levels averaged approximately 3 microg/ml (1,500-mg dose) in the single-dose study and 3.8 microg/ml (600-mg dose) in the multiple-dose study. Steady state was achieved after 5 to 6 days of daily dosing, with an accumulation ratio of approximately 2. The elimination half-life averaged 16 to 20 h. Overall, PA-824 was well tolerated following oral doses once daily for up to 7 days, and pharmacokinetic parameters were consistent with a once-a-day regimen. The results of these studies, combined with the demonstrated activity of PA-824 against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support the investigation of this novel compound for the treatment of tuberculosis.

Assessment of the effects of the nitroimidazo-oxazine PA-824 on renal function in healthy subjects.

The mechanism underlying a dose-dependent, reversible increase in serum creatinine (SC) caused by the administration of PA-824, a novel nitroimidazo-oxazine, was evaluated in 47 healthy male and female volunteers. Subjects were administered either 800 or 1,000 mg PA-824 or matching placebo once daily for 8 days. The following renal function parameters were determined before and during dosing and after a 7-day washout: SC, glomerular filtration rate (GFR; measured as the iohexol clearance), effective renal plasma flow (ERPF; measured as the para-amino hippurate clearance), filtration fraction (FF), creatinine clearance (CrCl), extraglomerular creatinine excretion (EGCE; defined as CrCl minus GFR), blood urea nitrogen (BUN), and uric acid (UA) levels. Eight days' administration of 800 or 1,000 mg PA-824 was associated with increased SC and a trend toward decreased CrCl and EGCE. SC, CrCl, and EGCE values returned to normal/baseline within 1 week's washout. GFR, ERPF, FF, BUN, and UA values were similar across groups during treatment and washout. The reversible increase in SC observed in this and earlier trials of PA-824, thus, did not appear to be the result of a pathological effect on renal function (as measured by GFR, ERPF, FF, BUN, or UA). Pharmacokinetic analyses confirmed that PA-824 exposures were similar to those in previous healthy-volunteer clinical studies. That EGCE declined maximally when drug levels were highest suggests that PA-824 causes creatinine levels to rise by inhibiting renal tubular creatinine secretion. Such an effect, considered clinically benign, has been described for several marketed drugs.

Regulation of cholesterol homeostasis by the liver X receptors in the central nervous system.

The nuclear oxysterol receptors liver X receptor-alpha [LXRalpha (NR1H3)] and LXRbeta (NR1H2) coordinately regulate genes involved in cholesterol homeostasis. Although both LXR subtypes are expressed in the brain, their roles in this tissue remain largely unexplored. In this report, we show that LXR agonists have marked effects on gene expression in murine brain tissue both in vitro and in vivo. In primary astrocyte cultures, LXR agonists regulated several established LXR target genes, including ATP binding cassette transporter A1, and enhanced cholesterol efflux. In contrast, little or no effect on gene expression or cholesterol efflux was detected in primary neuronal cultures. Treatment of mice with a selective LXR agonist resulted in the induction of several LXR target genes related to cholesterol homeostasis in the cerebellum and hippocampus. These data provide the first evidence that the LXRs regulate cholesterol homeostasis in the central nervous system. Because dysregulation of cholesterol balance is implicated in central nervous system diseases such as Alzheimer's and Niemann-Pick disease, pharmacological manipulation of the LXRs may prove beneficial in the treatment of these disorders.

Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines.

A potent, selective, orally active LXR agonist was identified from focused libraries of tertiary amines. GW3965 (12) recruits the steroid receptor coactivator 1 to human LXRalpha in a cell-free ligand-sensing assay with an EC(50) of 125 nM and profiles as a full agonist on hLXRalpha and hLXRbeta in cell-based reporter gene assays with EC(50)'s of 190 and 30 nM, respectively. After oral dosing at 10 mg/kg to C57BL/6 mice, 12 increased expression of the reverse cholesterol transporter ABCA1 in the small intestine and peripheral macrophages and increased the plasma concentrations of HDL cholesterol by 30%. 12 will be a valuable chemical tool to investigate the role of LXR in the regulation of reverse cholesterol transport and lipid metabolism.