Purpose A Phase l trial of intravesical recombinant adenovirus-mediated interferon-α2b gene therapy (rAd-IFNα) formulated with the excipient SCH Syn3 was conducted in patients with non-muscle invasive bladder cancer (NMIBC) who recurred after Bacillus Calmette-Guerin (BCG). The primary objective was to determine the safety of rAd-IFNα/Syn3; secondary endpoints were to demonstrate effective rAd-IFNα gene expression and preliminary evidence of clinical activity at three months. Patients and Methods Seventeen patients with recurrent NMIBC after BCG were enrolled. A single treatment of rAd-IFNα (3×109 to 3×1011 particles/mL) formulated with the excipient Syn3 was administered. Patient safety was evaluated for ≥12 weeks. Efficacy of gene transfer was determined by urine IFNα protein concentrations. Preliminary drug efficacy was determined at 3 months. Results Intravesical rAd-IFNα/Syn3 was well tolerated as no dose limiting toxicity (DLT) was encountered. Urgency was the most common adverse event and all were grade 1 or 2. rAd-IFNα DNA was not detected in the blood, however, transient low serum IFNα and Syn3 levels were measured. High and prolonged dose-related urine IFNα levels were achieved with the initial treatment. Of the 14 patients treated at doses ≥ 1010 particles/mL with detectable urine IFNα, 6 (43%) experienced a complete response at 3 months and 2 remained disease free at 29.0 and 39.2 months respectively. Conclusion Intravesical rAd-IFNα/Syn3 was well tolerated with no DLT encountered. Dose dependent urinary IFNα concentrations confirmed efficient gene transfer and expression. Intravesical rAd-IFNα/Syn3 demonstrated promising clinical activity in NMIBC recurring after BCG.

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Whereas all doses were well tolerated and produced significant declines in plasma HIV RNA, total oral daily doses of 50 or 100 mg vicriviroc monotherapy for 14 days appeared to provide the most potent antiviral effect in this study.

This study evaluated the safety, tolerability, and pharmacokinetics of a posaconazole i.v. (intravenous) solution. This was a single-center, 2-part, randomized, rising single-and multiple-dose study in healthy adults. In part 1, subjects received 0 (vehicle), 50, 100, 200, 250, or 300 mg posaconazole in a single dose i.v. by 30-min peripheral infusion (6 cohorts of 12 subjects each [9 active and 3 placebo], making a total of 72 subjects). Blood samples were collected until 168 h postdose. In part 2, subjects were to receive 2 peripheral infusions at a 12-h interval on day 1 followed by once-daily infusion for 9 days. However, part 2 was terminated early because of high rates of infusion site reactions with multiple dosing at the same infusion site. The pharmacokinetics results for part 1 (n ‫؍‬ 45 subjects) showed that the mean posaconazole exposure (area under the concentration-time curve from time zero to infinity [AUC 0 -ؕ ]) ranged from 4,890 to 46,400 ng · h/ml (range of coefficient of variation values, 26 to 50). The dose-proportionality slope estimate (90% confidence interval) for AUC 0 -ؕ was 1.30 (1.19 to 1.41), indicating a greater-thandose-proportional increase. The data for safety in part 1 show that 29/72 subjects had >1 adverse event. Infusion site reactions were reported in 2/9 vehicle subjects, 0/18 placebo subjects, and 7/45 i.v. posaconazole subjects. The data for safety in part 2 show that infusion site reactions were reported in 1/4 (25%) placebo subjects, 3/9 (33%) vehicle control subjects, and 4/5 (80%) i.v. posaconazole (100 mg) subjects (3 posaconazole recipients subsequently developed thrombophlebitis and were discontinued from treatment). In conclusion, the posaconazole i.v. solution showed a greater-than-dose-proportional increase in exposure, primarily at doses below 200 mg. When administered peripherally at the same infusion site, multiple dosing of i.v. posaconazole led to unacceptably high rates of infusion site reactions. Intravenous posaconazole was otherwise well tolerated. Single doses of i.v. posaconazole were tolerated when given through a peripheral vein over 30 min. P osaconazole (Noxafil) formulated as an oral suspension is a systemic triazole antifungal approved in more than 80 countries for use as therapy for refractory invasive fungal infection (IFI), prophylaxis of IFI in patients at high risk, and therapy for oropharyngeal candidiasis (1-5). The precise approved indications differ across the various countries in which posaconazole is available (6, 7). To enhance its gastric absorption, posaconazole oral suspension must be taken multiple times per day with a meal, a nutritional supplement, or an acidic carbonated beverage (8, 9). Although a new tablet formulation of posaconazole with improved absorption characteristics has been developed (10) and was recently approved in the United States and Europe, a limitation of any oral formulation is that patients at risk for IFI may be unable to take any formulation through the oral route because of vomiting, prohibition of ente...

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