Pharmacokinetics and Safety Study of Posaconazole Intravenous Solution Administered Peripherally to Healthy Subjects

Abstract

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...

Synergistic drug combination effectively blocks Ebola virus infection

“…Posaconazole has a half-life of 20 hrs in humans. The peak concentration in human plasma is 2,840 ng/ml (4.05 μM) (Kersemaekers et al, 2015). Posaconazole blocks the synthesis of the fungal cell membrane to inhibit growth of the fungi (Munayyer et al, 2004).…”

Pharmacologic and clinical evaluation of posaconazole

“…Initially, a single-center, two-part rising single- and multiple-dose study in healthy adults was performed to evaluate the pharmacokinetics and safety of intravenous posaconazole [32]. For the first part of the study, six cohorts covered a single-dose posaconazole range from 50 to 300 mg by 30 min peripheral infusion.…”

“…Infusion site reactions, specifically thrombophlebitis, were clinically acceptable at 30 min compared with 90 min for single-dose peripheral administration [32]. However, a decrease in infusion time from 90 to 30 min did not reduce infusion site reactions for multiple-dose administrations.…”

Determination of Posaconazole in Plasma/Serum by High-Performance Liquid Chromatography with Fluorescence Detection

“…The pharmacokinetics and pharmacodynamics of each formulation have been outlined extensively [6][7][8][9][10][11]. The oral formulations have exhibited significant inter-patient and intra-patient variations in bioavailability due to inconsistent absorption, metabolism, elimination, or drug-drug interactions.…”