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Antimicrobial Agents and Chemotherapy, May 2006, p. 1881-1883, Vol. 50, No. 5
0066-4804/06/$08.00+0 doi:10.1128/AAC.50.5.1881-1883.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.
Schering-Plough Research Institute, Kenilworth, New Jersey,1 Parkway Research Center, Inc., North Miami, Florida2
Received 3 October 2005/ Returned for modification 7 November 2005/ Accepted 13 February 2006
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Steady-state concentrations are attained by 7 to 10 days of multiple-dose administration. Posaconazole does not appear to have any major circulating phase 1 (cytochrome P450) metabolites; most (77%) of an administered dose is excreted as a parent compound in the feces (9). Of the circulating metabolites, most are glucuronide conjugates of posaconazole (9). Although posaconazole is an inhibitor of liver cytochrome P450 3A4 enzyme activity, it has no effect on the activity of other P450 enzymes (12).
Previous studies have demonstrated that food, particularly meals high in fat content, significantly increases posaconazole bioavailability (2, 3). Systemic exposure to posaconazole increases 4- and 2.6-fold when it is consumed with a high-fat and nonfat meal, respectively, relative to that observed in fasted subjects (2). Therefore, posaconazole should be administered with food whenever possible to ensure optimal absorption (2). However, persons at risk for invasive fungal infection are usually critically ill, and many have difficulty eating solid foods. These patients are commonly given liquid nutritional supplements through an enteral feeding tube.
We have therefore conducted an open-label, single-center, randomized study to evaluate the effect of a liquid nutritional supplement (Boost Plus) on the pharmacokinetics of posaconazole. Healthy male and female subjects between the ages of 18 and 55 years, with a body mass index between 19 and 27 kg/m2, were eligible for enrollment. Subjects were excluded if they used prescription or over-the-counter medications (other than acetaminophen) 2 weeks prior to study initiation. The study was conducted in accordance with the Declaration of Helsinki, and written informed consent from each subject and approval by an accredited institutional review board were obtained before the initiation of the study.
On day 1, subjects received a single 400-mg dose of the posaconazole oral suspension (10 ml) either alone after an overnight fast or in combination with 8 fluid ounces of Boost Plus (batch AMM 74; Mead Johnson & Co., Evansville, IN). The alternate treatment was administered after a 14-day washout period (day 15) in a crossover manner. Subjects were not permitted to eat again until 4 h postdose following assessment of vital signs and blood sample collection. Each 240-ml serving of Boost Plus contained 360 cal, with a caloric distribution of 16% protein, 34% fat, and 50% carbohydrate. Blood samples (4 ml) were collected predose and up to 72 h postdose on days 1 and 15. The collection of blood samples and assay of plasma posaconazole concentrations were performed using a validated liquid chromatography with tandem mass spectrometric assay with a lower limit of quantitation of 1.00 ng/ml and a linear range of 1.0 to 4,000 ng/ml (4).
A noncompartmental pharmacokinetic method was used for the analysis (8). The maximum concentration of drug in serum (Cmax) and time to Cmax (Tmax) were observed values. The area under the concentration-time curve from 0 to 72 h (AUC0-72), terminal phase half-life (t[1/2]), apparent total body clearance, and apparent volume of distribution were calculated using Kinetica 2.5.3. Standard Edition (InnaPhase Corporation, Philadelphia, PA). Safety was assessed on the basis of adverse events, physical examinations, vital signs, clinical assessments of laboratory data, and electrocardiograms.
Summary statistics were prepared, and log-transformed Cmax and AUC values were analyzed using a crossover analysis of variance model. Two-sided 90% confidence interval estimates of the mean ratios of AUC and Cmax were calculated.
Twenty-four subjects (12 men and 12 women) were enrolled in the study and received at least 1 dose of posaconazole. Subjects were between the ages of 24 and 53 years (mean age, 39.4 years), and the overall mean body mass index was 26.2 kg/m2. Of the 24 subjects, 16 were Hispanic, 5 were Caucasian, 2 were black, and one was "other." Twenty-three subjects completed the study and were included in the pharmacokinetic analysis. One subject discontinued the study due to personal reasons. Data from all 24 subjects were used to evaluate safety and tolerability.
Coadministration of posaconazole and Boost Plus increased drug exposure compared to the administration of posaconazole alone in the fasted state (Fig. 1). Mean Cmax and AUC0-72 values were higher in the presence of Boost Plus than in fasted subjects, resulting in increased relative oral bioavailability (Tables 1 and 2). Median Tmax and mean t[1/2] values were similar in fasted subjects and those receiving Boost Plus (Table 1).
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These data demonstrate that coadministration of a liquid nutritional supplement (containing 14 g fat) increases posaconazole bioavailability to an extent similar to that observed with a nonfat meal (2). Concomitant administration of Boost Plus resulted in a statistically significant and marked increase in the bioavailability of the posaconazole suspension relative to Tmax in the fasting state. The similarity in Tmax and t[1/2] values observed in the presence and absence of Boost Plus suggests that coadministration of a liquid nutritional supplement increased the extent of posaconazole absorption.
Previous studies have demonstrated that administering posaconazole with food, regardless of fat content, causes an increase in drug exposure (increase of 164% after a nonfat meal); the inclusion of fat in a meal increases posaconazole exposure only by an additional 48% (2, 3). Collectively, these observations indicate that food increases posaconazole bioavailability independent of the type of food (solid versus liquid) or fat content (nonfat versus high fat). Therefore, posaconazole should be administered with food or a nutritional supplement when possible.
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ACKNOWLEDGMENTS |
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