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...

Tumor necrosis factor alpha (TNF-alpha) has been shown to be an important mediator of the lethal effects of endotoxin in several experimental models of septic shock. However, studies with a recombinant human interleukin-1 (IL-1) receptor antagonist protein (IL-1ra) suggest a role for IL-1 as a mediator of septic shock as well. In the present study, we show that mice treated in vivo with Corynebacterium parvum are primed for the production of interferon-gamma (IFN-gamma) and exhibit an enhanced capacity to produce serum IL-1 alpha, TNF-alpha, and IL-6 when challenged intravenously with lipopolysaccharide (LPS). The majority of C. parvum-treated mice die within 24 h of an LPS challenge. Pretreatment with a rat antimouse TNF-alpha monoclonal antibody (mAb) protected 90% of the animals against the lethal endotoxin challenge, while an anti-IFN-gamma mAb gave approximately 75% protection. The anti-IFN-gamma mAb also caused a reduction in LPS-induced serum TNF-alpha and IL-1 alpha. Anti-IL-1 alpha, anti-IL-1 beta, and anti-IL-6 neutralizing mAb did not protect against lethality when administered to mice prior to the LPS challenge. These results indicate that TNF-alpha and IFN-gamma are major mediators of endotoxin shock in C. parvum-treated mice. The results further suggest that the IFN-gamma produced by C. parvum-primed mice in response to an LPS challenge serves as a stimulus for enhanced production of TNF-alpha and IL-1 alpha. These findings are consistent with an increasing body of evidence suggesting a major role for IFN-gamma in lethal endotoxemia.

Recent studies have demonstrated that interleukin-10 (IL-10) has the capacity to protect mice from the lethal effects of endotoxin. In this investigation, we have examined the ability of IL-10 to protect both normal mice and Corynebacterium parvum-primed mice against endotoxin lethality. In the overwhelming majority of experiments, recombinant murine IL-10 (rMuIL-10) and recombinant human IL-10 (rHuIL-10) did not protect normal BALB/cJ mice from lipopolysaccharide (LPS)-induced lethality at doses up to 10 micrograms/mouse. Despite their inability to protect, both IL-10 preparations were highly effective in preventing the increase in serum tumor necrosis factor alpha (TNF-alpha) that occurred in response to the lethal dose of LPS. Moreover, a neutralizing antibody against TNF-alpha gave only partial protection when administered alone to BALB/cJ mice. Treatment with a combination of neutralizing antibodies against TNF-alpha and interferon-gamma (IFN-gamma) resulted in complete protection. In contrast to BALB/cJ mice, normal BDF1 mice were protected from lethal endotoxemia by treatment with both rMuIL-10 and rHuIL-10. However, IL-10 did not protect C. parvum-primed BDF1 against LPS lethality even though it caused a reduction in the LPS-induced serum TNF-alpha response in C. parvum-primed mice as well as in normal BDF1 mice. Neutralizing antibodies against TNF-alpha and IFN-gamma were protective when administered alone to normal BDF1 mice, as previously demonstrated in C. parvum-primed mice. These findings suggest that lethal endotoxemia is a result of the cooperative activities of TNF-alpha and IFN-gamma in normal mice of the BALB/cJ and BDF1 strains as well as in C. parvum-primed BDF1 mice. IL-10 appears to be less effective in protecting mice from lethal endotoxemia when cooperation between IFN-gamma and TNF-alpha is facilitated by high-level production of the cytokines as in C. parvum-primed mice or when there is evidence of strong synergy between them as in normal BALB/cJ mice.

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Clinical Pharmacology & Therapeutics (2003) 73, P67–P67; doi: