ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, July 2009, p. 2960–2964 0066-4804/09/$08.00⫹0 doi:10.1128/AAC.01178-08 Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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Pharmacokinetics of Posaconazole Administered Orally or by Nasogastric Tube in Healthy Volunteers䌤 Elizabeth S. Dodds Ashley,1 Jay B. Varkey,1 Gopal Krishna,2* Donna Vickery,2 Lei Ma,2 Xin Yu,2 Darshana Malavade,2 Megan Goodwin,1 John R. Perfect,1 and Eddie Power2 Duke University Medical Center, Durham, North Carolina,1 and Schering-Plough Research Institute, Kenilworth, New Jersey2 Received 4 September 2008/Returned for modification 6 January 2009/Accepted 4 May 2009
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. Absorp-
tion 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.
* Corresponding author. Mailing address: Early Clinical Research and Experimental Medicine, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033. Phone and fax: (908) 740-6564. E-mail:
[email protected]. 䌤 Published ahead of print on 11 May 2009.
Inclusion and exclusion criteria. Eligible subjects were men or women of any race aged between 18 and 45 years who had a body mass index between 18 and 29 kg/m2. They were required to be in good health based on their medical history, physical examination findings, laboratory determinations (including complete
MATERIALS AND METHODS
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blood count, blood chemistry, and urinalysis), and electrocardiogram (ECG) results. At the screening ECG, QT intervals corrected for heart rate (QTc intervals) were to be less than 450 ms for women and less than 430 ms for men. Female subjects were required to be of non-childbearing potential or to have negative pregnancy test results at screening and on days ⫺1 and 7. In addition, women of childbearing potential were to use a medically accepted method of contraception from the time of screening through 30 days after stopping the medication. Male subjects were required to use an accepted method of contraception during the treatment period and for 30 days after completing treatment. Subjects were excluded from the study if they had undergone major surgery within 6 months of study initiation or if they had a history of peptic or gastric ulcers or of substance abuse within 1 year of study initiation. They could not be enrolled if they had a history of sinus disease, sinus surgery, rhinoplasty, or any surgery of the nose, septum, or nasal passages. They were also excluded if they had taken medication or substances via inhalation through the nasal passages within 3 months of study enrollment or if they had a history of prolonged use of medication or other substances inhaled through the nasal passages. Subjects who were positive for human immunodeficiency virus or hepatitis B or C were excluded, as were those who were positive for alcohol or illicit drug use based on routine screening tests. Women who were nursing or who intended to become pregnant or to nurse during the study period or within 30 days after the study’s completion were also excluded. The study was conducted in accordance with principles of good clinical practice and the Declaration of Helsinki and was approved by the Duke University Health System Institutional Review Board. The study was also reviewed and approved by the Scientific Advisory Committee of the Duke University Clinical Research Unit. All study participants gave written informed consent prior to undergoing any study-related procedures. Study design. This was a phase 1, open-label, single-center, crossover study. Healthy volunteers were randomized in a 1:1 ratio to receive two single 400-mg doses of posaconazole suspension (10 ml), one administered orally and one administered by nasogastric tube, with a 7-day washout period between doses. Subjects were randomly assigned to receive treatments in one of two treatment sequences (oral followed by nasogastric tube administration or nasogastric tube followed by oral administration). Following an initial screening visit to determine eligibility, subjects were confined to the study center from day ⫺1 to day 1. After receiving their first dose of study medication on day 1, they remained at the center for 12 additional hours for pharmacokinetic blood draws. Following their discharge, they returned for outpatient visits on days 2, 3, 4, and 6 for additional pharmacokinetic sampling, a review of safety data, and to determine adherence to protocol-required procedures. Subjects were readmitted to the center to begin phase 2 of the study on the evening of day 7 and remained until day 8. After receiving their second dose of study medication on day 8, they remained at the center for 12 additional hours for pharmacokinetic blood draws. As in the first dosing period, they returned for additional blood draws on days 9, 10, 11, and 13. Thirty days after receiving their last dose of posaconazole, on day 38 (⫾2 days), subjects returned to the study center for a final blood collection, follow-up, and safety evaluation. Subjects received each dose of posaconazole after an overnight fast, at approximately 8:00 a.m. During the oral phase of the study, they consumed 8 fluid ounces of Boost Plus within a 20-min period and received 400 mg (10 ml) of posaconazole 5 to 10 min after finishing the nutritional supplement. Following oral administration of posaconazole, the dosing syringe was rinsed twice with approximately 60 ml of tap water that was given to the subject to drink. During the nasogastric tube phase, subjects received 8 fluid ounces of Boost Plus via a 16-French (5 mm) nasogastric tube that was inserted into the stomach. The tube was then flushed with 2 oz of tap water to clear residual nutritional supplement from the tube. Within 5 to 10 min after ingestion of the nutritional supplement, the dose of posaconazole was administered by drawing the drug into a syringe and using an adapter to transfer the drug to the nasogastric tube. The inside of the syringe was rinsed twice with 2 oz of tap water, and the rinse was then transferred to the nasogastric tube. Subjects continued to fast until the 4-h postdose pharmacokinetic blood sample had been obtained. In addition, subjects were instructed to refrain from drinking alcohol from 48 h prior to the first dose of posaconazole (day 1) through 24 h after the second dose of posaconazole on day 8. Thereafter, they were not required to refrain from alcohol. Pharmacokinetic assessment. There was a 7-day washout between posaconazole doses (more than 5 times the previously published elimination half-life [t1/2] value of 24.1 h for a single 400-mg posaconazole dose) (3). On the days of posaconazole administration (days 1 and 8), pharmacokinetic blood draws were obtained predose (at 0 h) and at 1, 2, 3, 4, 5, 6, 8, and 12 h postdose. Additional pharmacokinetic blood draws were obtained at 24 h (days 2 and 9), 48 h (days 3
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and 10), 72 h (days 4 and 11), and 120 h (days 6 and 13) after each posaconazole dose. A 10-ml sample was collected at each time point and processed within 30 min. Samples were centrifuged for 10 min at approximately 4°C and 1,500 ⫻ g. Plasma samples were immediately frozen to ⫺20°C or below and kept frozen until assayed. Samples were assayed for determination of posaconazole concentrations using a validated liquid chromatography-tandem mass spectrometry method (22). The assay had a lower limit of quantitation of 1.00 ng/ml, calibration range of 1.00 to 4,000 ng/ml, accuracy (mean % difference) of ⫺7.28 to ⫺0.384, and precision (coefficient of variation [CV]) of 4.43% to 6.64%. The following pharmacokinetic parameters were assessed: observed maximum plasma concentration (Cmax), time of observed maximum plasma concentration (Tmax), area under the plasma concentration-time curve (AUC) to the last measurable concentration (AUCtf), AUC to time infinity (AUC0-⬁), apparent total body clearance (CL/F), t1/2, and terminal elimination rate constant (k). Individual plasma concentrations for posaconazole were used to estimate the derived pharmacokinetic parameters using model-independent methods. The observed values were Cmax and Tmax. The linear trapezoidal method was used to calculate the AUCtf value. Summary statistics were calculated for pharmacokinetic parameters, and individual and summary statistics were calculated for the individual ratios of Cmax, AUCtf, and AUC0-⬁ pharmacokinetic parameters. Safety assessment. Safety was assessed on the basis of adverse events; vital sign measurements; clinical laboratory (hematology and clinical chemistry) tests (screenings on day 6 and the follow-up visit); urinalysis (screenings on day 7 and the follow-up visit); and 12-lead ECG measurements (screenings on days 8 and 13 and the follow-up visit). Adverse events were tabulated by body system or organ class, severity, and relationship to the study medication and summarized by treatment assignment. Statistical analysis. Safety analyses were performed on all subjects who received at least 1 dose of study medication. The primary pharmacokinetic analyses were performed on the intent-to-treat (ITT) population, which included all members of the safety analysis population who provided at least one valid postbaseline pharmacokinetic assessment. The pharmacokinetic parameters AUCtf, AUC0-⬁, and Cmax were analyzed based on the natural log-transformed scale using an analysis of variance model with sequence, subject within sequence, treatment (oral or nasogastric administration), and period (i.e., dosing period). The 90% confidence intervals (CIs) for the treatment ratio estimate (percent) were also determined, and the two treatments were considered bioequivalent if the 90% CIs were contained in the 80%-to-125% range.
RESULTS Patients. Of 16 randomized healthy volunteers, 15 completed both treatment phases and 1 discontinued after receiving the first dose of the study drug (via the oral route) due to an adverse event. Subjects included 10 women and 6 men who ranged from 20 to 36 years of age and had a mean age of 25 years (Table 1). Most subjects (81%) were white. Pharmacokinetics. Figure 1 shows the plasma concentration-time profile of posaconazole after oral and nasogastric tube administration. The arithmetic mean (%CV) plasma concentration-time data and arithmetic mean pharmacokinetic parameters for posaconazole following nasogastric tube and oral administration are presented in Table 2. The arithmetic means of k and t1/2 were essentially the same for oral and nasogastric tube administration, as were the median Tmax values. In addition, CL/F was 20% higher when posaconazole was administered via the nasogastric tube. The primary statistical results for the Cmax, AUCtf, and AUC0-⬁ of posaconazole after oral and nasogastric tube administration are summarized in Table 3. The ratio (%) estimate of the ITT population suggests that posaconazole nasogastric tube administration Cmax values were 81%, AUCtf values were 76%, and AUC0-⬁ values were 77% of the least-square mean values of the corresponding oral administration values. The 90% CIs for Cmax, AUCtf, and
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TABLE 1. Demographic characteristics of the study group Value for treatment sequence group Nasogastric tube followed by oral administration
Characteristic
Sex 关no. (%)兴 Female Male
Oral followed by nasogastric tube administration
4 (50) 4 (50)
6 (75) 2 (25)
6 (75) 1 (13) 1 (13)
7 (88) 0 0
0
1 (13)
0 8 (100)
1 (13) 7 (88)
Age (yr) Mean (SD) Median (range)
25.3 (1.9) 25.0 (23–29)
24.8 (4.9) 23.5 (20–36)
Weight (kg) Mean (SD) Median (range)
73.54 (14.89) 71.60 (51.9–101.7)
68.89 (11.90) 70.60 (50.8–86.4)
Height (cm) Mean (SD) Median (range)
175.33 (10.15) 175.50 (160.0–190.5)
169.53 (6.80) 171.50 (157.5–177.8)
Body mass index Mean (SD) Median (range)
23.67 (2.35) 23.55 (20.3–28.0)
23.80 (2.54) 23.65 (20.5–27.3)
Race 关no. (%)兴 White Asian Black or African American Multiracial Ethnicity 关no. (%)兴 Hispanic or Latino Not Hispanic, Latino, or Japanese
AUC0-⬁ were all outside the 80-to-125% range. No period or sequence effects were noted (P values ⬎ 0.20). In order to further assess potential explanations for the differences in total drug exposure, a follow-up experiment was performed and the results confirmed that the concentration of posaconazole was not altered when it was administered via nasogastric tube (data not shown). A scatter plot for Cmax shows an inconsistency between subjects with respect to treatments (Fig. 2). While most subjects
TABLE 2. Arithmetic means and %CV values of posaconazole pharmacokinetic parameters in healthy volunteersa Values for: Parameter
Cmax (ng/ml) Tmax (hr) AUCtf (ng 䡠 hr/ml) AUC0-⬁ (ng 䡠 hr/ml) t1/2 (hr) CL/F (ml/hr) k (hr⫺1)
Oral administration
Nasogastric tube administration
Mean
%CV
Mean
%CV
324 4.0b 10,441 10,866 21.6 49,345 0.035
49.7 3.0–12.0c 52.3 53.4 38.9 54.2 23.5
266 4.0b 8,030 8,402 23.7 59,410 0.031
45.2 2.0–6.0c 43.7 44.8 30.7 52.3 25.7
a Posaconazole pharmacokinetic parameters in healthy volunteers were obtained following a single 400-mg dose of an oral suspension of posaconazole administered orally or via a nasogastric tube 5 to 10 min after the subject received a nutritional supplement. b Median. c Range.
had a nasogastric tube Cmax that was less than that observed for oral administration, these results were not universal. Five subjects showed a fairly large positive difference (⬎30%), and one subject showed a fairly large negative difference (20%) between results with oral and nasogastric tube administration. The remaining subjects had smaller differences in Cmax for the administration routes. Individual results for AUCtf and AUC0-⬁ also demonstrated intersubject variability with respect to nasogastric versus oral administration. Five subjects showed fairly large positive differences (⬎30%), 1 subject showed fairly large negative differences of 20% in AUCtf and of 24% in AUC0-⬁; and the remaining subjects showed smaller differences between AUCtf and AUC0-⬁ values for the oral and nasogastric tube routes. The scatter plot for AUC0-⬁ demonstrates this intersubject variability (Fig. 3). Safety. A total of 21 treatment-emergent adverse events (TEAEs) were reported in 12 individual subjects; in 7 subjects (7/16 [44%]) these followed oral administration and in 8 subjects (8/15 [53%]) they followed nasogastric tube administration. TEAEs in most subjects were rated as mild in severity (with oral administration, 8 of 9 events in 6 of 7 subjects, and with nasogastric tube administration, 11 of 12 events in 7 of 8 subjects), and none was considered severe or life threatening. Headache was the only mild TEAE reported by more than 1 subject (oral administration, 3 of 16 subjects; nasogastric tube administration, 2 of 15 subjects). Gastrointestinal adverse events were reported for
TABLE 3. Primary statistical analysis of posaconazole pharmacokinetic parameters in the ITT populationa Parameter
Cmax (ng/ml) AUCtf (ng 䡠 hr/ml) AUC0-⬁ (ng 䡠 hr/ml) FIG. 1. Means ⫾ standard deviations of plasma concentration-time profiles of posaconazole following a single 400-mg dose administered orally or via a nasogastric tube.
Least-square meanb PO
NG
289 9,098 9,390
233 6,954 7,208
Treatment comparison
Ratio (%) estimate
90% CI
NG vs PO NG vs PO NG vs PO
81 76 77
71–91 69–85 69–86
a Posaconazole pharmacokinetic parameters in 16 healthy volunteers in the ITT population were obtained following a single 400-mg dose of posaconazole administered orally or via a nasogastric tube 5 to 10 min after the subject received a nutritional supplement. b PO, oral administration; NG, nasogastric tube administration.
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FIG. 2. Individual observed posaconazole (POS) Cmax values for assessment of relative bioavailability in healthy subjects following a single 400-mg dose administered orally (PO) or via nasogastric tube (NG) 5 to 10 min after the subject received a nutritional supplement.
FIG. 3. Individual posaconazole (POS) AUC0-⬁ values for assessment of relative bioavailability in healthy volunteers following a single 400-mg dose administered orally (PO) or via a nasogastric tube (NG) 5 to 10 min after the subject received a nutritional supplement.
one subject (two events total) following nasogastric tube administration (abdominal pain and nausea). Events of moderate severity were rash, reported by one subject following oral administration, and arthralgia, reported by one subject following nasogastric tube administration. The instance of rash was the only event that resulted in study drug discontinuation. It occurred in a subject with a history of allergies and periorbital rash, was considered possibly related to the study drug, and resolved after 11 days. The event of arthralgia was considered unlikely to be related to the study drug. No serious adverse events or clinically significant laboratory or vital sign abnormalities were reported. Noteworthy ECG findings were reported for three subjects, one with a QTc change and two with QT changes. One female subject had a change in the QTc interval from 433 ms at screening to 473 ms a few minutes after receiving the second dose of posaconazole (via nasogastric tube). The investigator reported this change as an adverse event of mild severity that was possibly related to the study drug. No action was taken, and the event resolved by the follow-up ECG taken 7 days later and did not recur.
inconclusive in terms of explaining the overall AUC results of the current study. Analysis of posaconazole in the recovered solutions revealed the same concentration on a per-milliliter basis before and after passing posaconazole through the tube; therefore, the difference in AUC seen in the current study is apparently not a qualitative one related to the tube itself. Several published reports discuss the use of nasogastric and other types of enteral feeding tubes to administer azole antifungals, including fluconazole (1, 14, 19), itraconazole (15), and voriconazole (7, 12, 13). In a randomized single-dose study, surgical ICU patients received 100 mg of fluconazole intravenously (n ⫽ 10) or by the administration of crushed tablets through a nasogastric or nasojejunal feeding tube (n ⫽ 8) (19). The mean changes following enteral administration were modest, with Cmax increasing by 5% and AUC decreasing by 24%, although substantial weight-associated variability was observed for both parameters. A case report documented the attainment of a therapeutic blood concentration of itraconazole (1.5 g/ml) after a patient with invasive aspergillosis received extended treatment via nasogastric tube with a solution of cranberry juice and the contents of itraconazole capsules (200 mg three times daily) (15). A prospective observational study examined the pharmacokinetic effects of administering a suspension of crushed voriconazole tablets via nasogastric tube to eight mechanically ventilated ICU patients with suspected or documented IFIs (13). After a mean duration of 16 days of treatment, the means ⫾ 1 standard deviation of trough and peak voriconazole concentrations were 4.6 ⫾ 2.8 mg/liter and 6.4 ⫾ 4.3 mg/liter, respectively, higher than the mean peak voriconazole concentrations seen in another study of patients at risk from aspergillosis who were given 200 or 300 mg of voriconazole orally twice daily for 14 days (Cmax, 3.00 and 4.66 mg/liter, respectively) (package inserts for VFEND I.V. [voriconazole] for injection, VFEND tablets [voriconazole], and VFEND [voriconazole] for oral suspension; Pfizer, Inc.). Because of the diversity of formulations and subjects, it is impossible to make a direct comparison of the findings of the reports on fluconazole, itraconazole, and voriconazole with those of the present posaconazole study. Safety and tolerability of posaconazole. A single 400-mg dose of posaconazole was similarly safe and well tolerated when administered orally or via nasogastric tube in healthy volunteers. No clinically relevant effects of posaconazole on
DISCUSSION In healthy adults, nasogastric tube administration of posaconazole resulted in Cmax, AUCtf, and AUC0-⬁ values that were about 80% of those observed after oral administration. The study also showed that the arithmetic means of k and t1/2 were essentially the same between oral and nasogastric tube administration, a not-unexpected result since the disposition of posaconazole would be expected to be similar regardless of the route of administration. The median Tmax values were the same with oral and nasogastric tube administration, suggesting no important differences between the two routes of administration for the rates of posaconazole absorption. The CL/F arithmetic mean was 20% greater with the nasogastric tube route than with the oral route, a difference that is likely due to the different amounts of posaconazole absorbed with the different routes of administration. The reason for the finding of lower Cmax and AUC values when posaconazole was administered by the nasogastric tube route as opposed to the oral route is not currently known. In further in vitro experiments conducted after this study, some differences in recovery volumes of Boost Plus, posaconazole, and rinse water were noted (data not shown). In these follow-up experiments, analyses of the amounts recovered were
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blood chemistry, hematology, urinalysis, or vital signs were observed. The spectrum of TEAEs reported in this study, including headache, gastrointestinal adverse events, and rash, is similar to that reported in other posaconazole studies with healthy volunteers (3, 4, 6, 21) or patients with or at risk for IFIs (2, 17, 18, 23, 25). Events similar to the mild, transient, and possibly treatment-related adverse event of QTc prolongation reported in one subject in this study were reported in approximately 1% of patients with refractory IFIs or febrile neutropenia who received posaconazole during clinical trials and for whom ECG data were available (17). Implications of this study for posaconazole administration. The effects of nasogastric tube administration on posaconazole pharmacokinetics remain to be evaluated in ill patients. However, in an externally controlled salvage study, patients with invasive aspergillosis or other IFIs received posaconazole at a dose of 800 mg/day in divided doses, orally or via an enteral feeding tube (25). The overall success rate in patients with invasive aspergillosis was 42% for posaconazole recipients and 26% for control patients (odds ratio, 4.06; 95% CI, 1.50 to 11.04; P ⫽ 0.006), although the specific success rate in patients who received posaconazole via feeding tube was not reported. If the reduction in absorption that appears to occur when posaconazole is administered via nasogastric tube to healthy volunteers is also observed in patients, the clinical consequence is unknown. It is possible, however, that the reduced absorption associated with this route of administration, combined with other factors associated with reduced absorption, might result in inadequate exposure in some individuals. The nasogastric route may still provide reasonable exposure, especially if strategies are used that have been shown to enhance exposure to posaconazole, such as splitting the dose and minimizing the use of proton pump inhibitors (11). Obtaining posaconazole plasma concentrations as an indicator of adequate exposure may also be warranted. Conclusion. In healthy adult volunteers who received a single 400-mg dose of an oral suspension of posaconazole 5 to 10 min after receiving a liquid nutritional supplement, nasogastric tube administration led to Cmax, AUCtf, and AUC0-⬁ values that were approximately 20% lower than those observed following oral administration. Oral and nasogastric tube administration of a 400-mg oral suspension of posaconazole to healthy adult subjects was safe and well tolerated, and nasogastric tube administration offers another option for those patients who cannot take drugs orally. ACKNOWLEDGMENTS Funding for the study was provided by Schering-Plough. In addition, this publication was made possible by grant number 5UL1RR024128-03 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. The contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. REFERENCES 1. Buijk, S. L. C. E., I. C. Gyssens, J. W. Mouton, H. A. Verbrugh, D. J. Touw, and H. A. Bruining. 2001. Pharmacokinetics of sequential intravenous and enteral fluconazole in critically ill surgical patients with invasive mycoses and compromised gastro-intestinal function. Intensive Care Med. 27:115–121. 2. Cornely, O. A., J. Maertens, D. J. Winston, J. Perfect, A. J. Ullmann, T. J. Walsh, D. Helfgott, J. Holowiecki, D. Stockelberg, Y.-T. Goh, M. Petrini, C. Hardalo, R. Suresh, and D. Angulo-Gonzalez. 2007. Posaconazole vs. flu-
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