The potential for interactions between caspofungin and nelfinavir or rifampin was evaluated in two parallelpanel studies. In study A, healthy subjects received a 14-day course of caspofungin alone (50 mg administered intravenously [IV] once daily) (n ؍ 10) or with nelfinavir (1,250 mg administered orally twice daily) (n ؍ 9) or rifampin (600 mg administered orally once daily) (n ؍ 10). In study B, 14 subjects received a 28-day course of rifampin (600 mg administered orally once daily), with caspofungin (50 mg administered IV once daily) coadministered on the last 14 days, and 12 subjects received a 14-day course of caspofungin alone (
MK-0524 ( Fig. 1) is a selective antagonist of prostaglandin D2 receptor 1 (DP1) (Sturino et al., 2007) that is undergoing preclinical and clinical development for the treatment of niacin-induced flushing. Niacin (nicotinic acid), a member of the vitamin B complex, has been used as a dietary supplement in milligram quantities and as a successful plasma lipid-modifying agent when administered in gram quantities. Niacin decreases plasma concentrations of cholesterol, free fatty acids, and triglycerides in humans, increases plasma high-density lipoprotein cholesterol (Shepherd et al., 1979), and decreases plasma very low-density lipoprotein and low-density lipoprotein cholesterol (Knopp, 1999). Furthermore, studies have shown that niacin can be effectively combined with statins to treat patients with low highdensity lipoprotein cholesterol (Rubenfire, 2004;Zhao et al., 2004). The major side effect with niacin therapy is the mild to severe cutaneous flushing experienced by patients that is mediated by vasodilation (Vogt et al., 2006). MK-0524, a potent DP1 antagonist, has an IC 50 value of 1.1 nM in a mouse DP1 functional assay (C. Sturino, G. The objective of the present study is to investigate the absorption, metabolism, and excretion of [ 14 C]MK-0524 in six male human volunteers. In preclinical species (rats and dogs), MK-0524 was eliminated primarily via glucuronidation, followed by excretion of the acyl glucuronic acid conjugate of the parent compound (M2) in bile . The in vitro metabolism of MK-0524 in nonclinical species and humans has been described elsewhere . The major metabolite in hepatocytes from all the species was M2, whereas phase I metabolites (hydroxylated and keto derivatives) collectively comprised a minor component of the metabolic profiles . Materials and Methods Chemicals
We describe the pharmacokinetics (PKs) of caspofungin, an echinocandin antifungal, administered once daily as a 1-hour intravenous infusion in children and adolescents (ages, 3 months to 17 years), based on pooled data from four prospective pediatric studies. Caspofungin dosing was body-surface-area (BSA) based (50 mg/m 2 daily after 70 mg/m 2 on day 1). The area under the concentration-time curve from time zero to 24 h (AUC 0-24 ), the concentration at the end of infusion (1 h after the start of infusion; C 1 ), and the trough concentration (24 h after the start of infusion; C 24 ) were obtained for 32 pediatric patients with invasive candidiasis, 10 with invasive aspergillosis, and 82 in the setting of empirical therapy with fever and neutropenia. Exposures were modestly higher (93 to 134% for C 1 , 45 to 78% for C 24 , ϳ40% for AUC 0-24 ) in pediatric patients than in adults receiving the standard 50-mg daily dose. The potential for covariates (age, gender, weight, race, renal status, serum albumin level, and disease state) to alter PKs was evaluated with a multiplelinear-regression model. Weight and disease state had statistically significant (P < 0.05) yet small effects on caspofungin PKs in pediatric patients. Concomitant use of dexamethasone (a cytochrome p450 inducer) was associated with a statistically significant reduction (44%) in C 24 in a limited number of patients (n ؍ 4). Odds ratios were estimated for the association between log-transformed PKs and treatment outcome or adverse events. No PK parameter or hybrid parameter (AUC/MIC, C 1 /MIC, and C 24 /MIC) was significantly correlated with treatment outcome or adverse events in the setting of similar response levels as adults, which suggests that the concentrations examined fall within the therapeutic window for caspofungin in pediatric patients. These results support a 50-mg/m 2 daily dosing regimen (after a 70-mg/m 2 loading dose) in children ages 3 months to 17 years.Caspofungin is an intravenous (i.v.) echinocandin antifungal agent that inhibits the synthesis of -(1,3)-D-glucan, an essential component of the cell wall of many pathogenic fungi, including Candida and Aspergillus species. In vitro and in vivo studies have demonstrated that caspofungin has fungicidal activity against Candida spp. and potent activity against various species of Aspergillus (9). Caspofungin has recently been approved by the FDA and other health authorities for use in pediatric patients (3 months of age and older) for the treatment of esophageal candidiasis, invasive candidiasis, and invasive aspergillosis or as empirical therapy for presumed fungal infections in patients with persistent fever and neutropenia (13).Candida and Aspergillus species are the fungi most frequently responsible for invasive infections in children. Mortality rates range from 19 to 31% in children with candidemia (17,18,32) and from 68 to 77% in those with invasive aspergillosis (10, 28). Even higher rates are observed in children with significant immune suppression, such as those receiving h...
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