The pharmacokinetics of posaconazole oral suspension in neutropenic patients undergoing high-dose chemotherapy and stem cell transplantation were evaluated, and the association of plasma posaconazole exposure with the presence and severity of oral mucositis was explored in this nonrandomized, open-label, parallelgroup, multiple-dose pharmacokinetic study. Thirty patients were enrolled and received one of three regimens (group I, 200 mg once daily; group II, 400 mg once daily; group III, 200 mg four times daily) for the duration of neutropenia. The mean total exposure for day 1, as shown by the area under the concentration-time curve from 0 to 24 h (AUC 0-24 ), was 1.96 mg · h/liter in group I and was 51% higher in group II and in group III. Increases in AUC 0-24 and maximum plasma concentration (C max ) in groups II and III were dose related. The AUC 0-24 and C max values on day 1 were similar between groups II and III. There was interpatient variability of up to 68% in the pharmacokinetic values for our study population. Steady state was attained by days 5 to 6. Average steady-state plasma posaconazole trough values were 192, 219, and 414 ng/ml in groups I, II, and III, respectively. The AUC 0-24 and apparent oral clearance increased by increasing dose and dosing frequency. Mucositis appeared to reduce exposure but did not significantly affect mean total posaconazole exposure (AUC and C max ) at steady state (P ‫؍‬ 0.1483). Moreover, this reduction could be overcome by increasing the total dose and dosing frequency. Posaconazole was safe and well tolerated.

These findings suggest that the dosage of cyclosporine or tacrolimus should be reduced when posaconazole therapy is started and that plasma levels of the immunosuppressant should be monitored during and at the discontinuation of posaconazole therapy so that dosages are adjusted accordingly. This recommendation is consistent with current standard of care for patients receiving cyclosporine or tacrolimus with concomitant azole antifungal therapy.

Posaconazole is an orally bioavailable triazole antifungal agent for the treatment and prophylaxis of invasive fungal infection. We evaluated plasma posaconazole concentration data from juvenile (younger than 18 years; n ‫؍‬ 12) and adult (18 to 64 years; n ‫؍‬ 194) patients who participated in a multicenter, phase 3, open-label study that assessed the efficacy and safety of posaconazole treatment for persons who were intolerant of or had invasive fungal infection refractory to standard antifungal therapies. With the exception of one juvenile patient who received 400 mg/day as a divided dose on the day of sample collection, all patients received posaconazole at 800 mg/day as an oral suspension in divided doses. Plasma samples were analyzed through a validated liquid chromatographic-tandem mass spectrometric method with a lower limit of quantitation of 1 ng/ml. Because plasma posaconazole concentrations are relatively constant at steady state, the average of all plasma concentrations (C av ) for each patient was calculated to provide a single steady-state plasma posaconazole concentration. A blinded data review committee reviewed all treatment outcomes. Variable posaconazole plasma concentrations were observed within both the juvenile and adult populations. Mean (median [range]) C av values for juvenile and adult patients were 776 ng/ml (579 ng/ml [85.3 to 2,891 ng/ml]) and 817 ng/ml (626 ng/ml [0 to 3,710 ng/ml]), respectively. Overall success rates and adverse event profiles were comparable. In conclusion, posaconazole concentrations in plasma were similar for juvenile and adult patients, suggesting that clinical outcomes are expected to be similar in adults and children with refractory invasive fungal infection.

Posaconazole is a triazole antifungal for prophylaxis of invasive fungal infection and treatment of oropharyngeal candidiasis. We evaluated the effects of gender, age, and race/ethnicity (black or white) on the steady-state pharmacokinetics of posaconazole in two studies on healthy adult subjects (>18 years of age). Additionally, we explored the effect of P-glycoprotein expression and MDR1 genotype on posaconazole pharmacokinetics in black and white subjects. Age, gender, and race/ethnicity had no clinically relevant effects on posaconazole pharmacokinetics. No association was observed between any MDR1 single-nucleotide polymorphism and the area under the concentration-time curve for posaconazole. Posaconazole was safe and well tolerated regardless of age, gender, or race/ethnicity. In conclusion, age, gender, and race/ethnicity have no clinically relevant effects on the steady-state pharmacokinetics of posaconazole in healthy adults; therefore, dosage adjustments based on these covariates are unnecessary.

We conducted a randomized, crossover study in healthy adults to examine the effects of a nutritional supplement (Boost Plus) on posaconazole pharmacokinetics. In this study, coadministration of posaconazole with Boost Plus increased the maximum concentration of posaconazole in serum and area under the concentration-time curve from 0 to 72 h values 3.4-and 2.6-fold, respectively, compared to those for the fasted state.Posaconazole is an orally bioavailable triazole antifungal agent currently in development for the treatment and prophylaxis of invasive fungal infections. It has potent in vitro activity against a wide array of pathogenic fungi (5-7, 10, 11), and clinical trial results have shown it to be well tolerated and effective against several mycoses, including aspergillosis, zygomycosis, coccidioidomycosis, and fusariosis (1).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/m 2 , 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 permi...