Pharmacokinetics of Posaconazole Administered Orally or by Nasogastric Tube in Healthy Volunteers |
| |
| Authors: | Elizabeth S. Dodds Ashley Jay B. Varkey Gopal Krishna Donna Vickery Lei Ma Xin Yu Darshana Malavade Megan Goodwin John R. Perfect Eddie Power |
| |
| Affiliation: | Duke University Medical Center, Durham, North Carolina,1. Schering-Plough Research Institute, Kenilworth, New Jersey2. |
| |
| Abstract: | The use of a nasogastric tube is one means of administering antifungal therapy to critically ill patients unable to receive medication via the oral route. This was a phase 1, open-label, single-center, randomized, crossover study of posaconazole administered via nasogastric tube in healthy volunteers. Each subject received two 400-mg single doses of posaconazole, one administered orally and one administered by nasogastric tube, with a 7-day washout period between each dose. Posaconazole was administered 5 to 10 min after subjects received a nutritional supplement. Blood samples for pharmacokinetic analysis were obtained up to 120 h postdose. The analysis of variance estimate of the study population suggests that the posaconazole nasogastric tube administration least-square mean values of observed maximum concentration (Cmax), area under the plasma concentration-time curve (AUC) to the last measurable concentration, and AUC to time infinity were 81%, 76%, and 77%, respectively, of the corresponding oral administration values. The reason for lower Cmax and AUC values when posaconazole is administered via the nasogastric tube route is not known. Oral and nasogastric tube administration of a single 400-mg dose of posaconazole suspension was safe and well tolerated in healthy adult subjects. The incidence and nature of treatment-emergent adverse events were similar with both administration routes, and no serious adverse events or clinically significant laboratory test or vital sign abnormalities were reported. Obtaining plasma posaconazole concentrations may be warranted when posaconazole is given to patients via a nasogastric tube to ensure adequate posaconazole exposure. Strategies that have been shown to enhance posaconazole exposure (such as splitting the dose and minimizing the use of proton pump inhibitors) may also be used.Posaconazole is a triazole antifungal that has shown potent in vitro and in vivo activities against an extended spectrum of clinically important yeasts and molds (9). Posaconazole prevented invasive fungal infections (IFIs) more effectively than did either fluconazole or itraconazole and improved overall survival in patients undergoing chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome (2). Posaconazole was as effective as fluconazole in preventing all IFIs and was superior to fluconazole in preventing invasive aspergillosis and reducing the rate of IFI-attributable death in hematopoietic stem cell transplant recipients with severe graft-versus-host disease (23). Salvage treatment with posaconazole has been shown to be effective in the treatment of invasive aspergillosis (25), fusariosis (18), and zygomycosis (8, 24).Critically ill patients who are unable to take oral nutrition are often administered alternative nutrition via nasogastric tube (5). Nasogastric feeding is most common in the intensive care unit (ICU) and is also used for cancer patients who are unable to eat (e.g., those with mucositis) or do not want to eat due to severe nausea (16). In these cases, alternates to oral drug administration, including intravenous or nasogastric tube administration, may be sought.Currently, posaconazole is available only as an oral suspension, and intravenous administration is not possible. Absorption data obtained in healthy volunteers support that posaconazole is well absorbed and extensively distributed to many tissue sites following oral administration (3). Exposure can be increased by administration with a high-fat meal (4) or a nutritional supplement (20) and by dividing the total daily dosage into multiple doses per day (6). Data from stem cell transplant patients with graft-versus-host disease have demonstrated that oral posaconazole administered prophylactically results in concentrations of posaconazole likely to be effective against pathogenic fungi in this patient population despite concurrent gastrointestinal disease (10). Little is known, however, about alternate routes of posaconazole administration.The present study was conducted with healthy volunteers to determine the effect, if any, of nasogastric tube administration on the pharmacokinetic profile of posaconazole. The primary objective was to compare the systemic exposure from a single 400-mg dose of posaconazole suspension administered orally with that of the same dose administered via nasogastric tube. The secondary objective was to monitor the safety and tolerability of two single doses of posaconazole, one administered orally and the other via nasogastric tube. Since a previous study had demonstrated the bioavailability of posaconazole when coadministered with Boost Plus (20), posaconazole was administered with the same nutritional supplement in this trial. |
| |
| Keywords: | |
|
|
