Posaconazole Tablet Pharmacokinetics: Lack of Effect of Concomitant Medications Altering Gastric pH and Gastric Motility in Healthy Subjects.

Posaconazole oral suspension is an extended-spectrum triazole that should be taken with food to maximize absorption. A new posaconazole tablet formulation has demonstrated improved bioavailability over the oral suspension in healthy adults in a fasting state. This study evaluated the effects of concomitant medications altering gastric pH (antacid, ranitidine, and esomeprazole) and gastric motility (metoclopramide) on the pharmacokinetics of posaconazole tablets. This was a prospective open-label 5-way crossover study in 20 healthy volunteers. In each treatment period, a single 400-mg dose (4 100-mg tablets) of posaconazole was administered alone or with 20 ml antacid (2 g of aluminum hydroxide and 2 g of magnesium hydroxide), ranitidine (150 mg), esomeprazole (40 mg), or metoclopramide (15 mg). There was a ≥10-day washout between treatment periods. Posaconazole exposure, time to maximum concentration of drug in serum (Tmax), and apparent terminal half-life (t1/2) were similar when posaconazole was administered alone or with medications affecting gastric pH and gastric motility. Geometric mean ratios (90% confidence intervals [CIs]) of the area under the concentration-time curve from time zero to infinity (AUC0-inf) (posaconazole with medications affecting gastric pH and gastric motility versus posaconazole alone) were 1.03 (0.88-1.20) with antacid, 0.97 (0.84-1.12) with ranitidine, 1.01 (0.87-1.17) with esomeprazole, and 0.93 (0.79-1.09) with metoclopramide. Geometric mean ratios (90% CIs) of the maximum concentration of drug in serum (Cmax) were 1.06 (0.90-1.26) with antacid, 1.04 (0.88-1.23) with ranitidine, 1.05 (0.89-1.24) with esomeprazole, and 0.86 (0.73-1.02) with metoclopramide. In summary, in healthy volunteers, the pharmacokinetics of a single 400-mg dose of posaconazole tablets was not altered to a clinically meaningful extent when posaconazole was administered alone or with medications affecting gastric pH or gastric motility

Development of a PCR Assay to Detect Low Level <i>Trypanosoma cruzi</i> in Blood Specimens Collected with PAXgene Blood DNA Tubes for Clinical Trials Treating Chagas Disease

<div><p>Chagas disease is caused by the parasitic infection of <i>Trypanosoma cruzi</i> (<i>T</i>. <i>cruzi</i>). The STOP CHAGAS clinical trial was initiated in 2011 to evaluate posaconazole in treating Chagas disease, with treatment success defined as negative qualitative PCR results of detecting the parasites in blood specimens collected post-treatment. PAXgene Blood DNA tubes were utilized as a simple procedure to collect and process blood specimens. However, the PAXgene blood specimens challenged published <i>T</i>. <i>cruzi</i> PCR methods, resulting in poor sensitivity and reproducibility. To accurately evaluate the treatment efficacy of the clinical study, we developed and validated a robust PCR assay for detecting low level <i>T</i>. <i>cruzi</i> in PAXgene blood specimens. The assay combines a new DNA extraction method with a custom designed qPCR assay, resulting in limit of detection of 0.005 and 0.01 fg/μl for K98 and CL Brener, two representative strains of two of <i>T</i>. <i>cruzi</i>’s discrete typing units. Reliable qPCR standard curves were established for both strains to measure parasite loads, with amplification efficiency ≥ 90% and the lower limit of linearity ≥ 0.05 fg/μl. The assay successfully analyzed the samples collected from the STOP CHAGAS study and may prove useful for future global clinical trials evaluating new therapies for asymptomatic chronic Chagas disease.</p></div

Improvement in Sensitivity of <i>T</i>. <i>cruzi</i> qPCR Assay in Terms of LOD

<p>Improvement in Sensitivity of <i>T</i>. <i>cruzi</i> qPCR Assay in Terms of LOD</p

Accuracy and Precision of Version 2 <i>T</i>. <i>cruzi</i> kDNA qPCR Assay

<p>Accuracy and Precision of Version 2 <i>T</i>. <i>cruzi</i> kDNA qPCR Assay</p

QC Parameters, Acceptable Values, and Final Results of Analysis of Clinical Samples Collected from the Randomized Patients of the STOP CHAGAS Study

<p>QC Parameters, Acceptable Values, and Final Results of Analysis of Clinical Samples Collected from the Randomized Patients of the STOP CHAGAS Study</p

Improving <i>T</i>. <i>cruzi</i> kDNA qPCR Assay Sensitivity with Version 2 Assay TaqMan Probe.

<p>Fig 3A: Comparison of Version 1 and Version 2 probe with 20 fg/μl of CL Brener; Fig 3B: 20 fg/μl of K98 (each DNA sample having four qPCR technical replicates)</p

Confirming Accuracy of Established <i>T</i>. <i>cruzi</i> kDNA qPCR Standard Curves with NHV PAXgene Blood Samples Spiked with Known Concentrations of <i>T</i>. <i>cruzi</i> DNA.

<p>Fig 4A: CL Brener; Fig 4B: K98; with 3 PAXgene blood samples per concentration per <i>T</i>. <i>cruzi</i> strain</p

Established <i>T</i>. <i>cruzi</i> kDNA qPCR Standard Curve Formulas of the Version 2 Assay

<p>Established <i>T</i>. <i>cruzi</i> kDNA qPCR Standard Curve Formulas of the Version 2 Assay</p