Determination of a cyclic hexapeptide (L-743 872), a novel pneumocandin antifungal agent in human plasma and urine by high-performance liquid chromatography with fluorescence detection

Schwartz, Michael S.; Kline, Walter F.; Matuszewski, B.K.

doi:10.1016/s0003-2670(97)00263-8

Cited by 58 publications

(54 citation statements)

References 4 publications

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“…All plasma and urine samples were stored at Ϫ70°C until they were analyzed. Plasma drug concentrations were determined by highpressure liquid chromatography (HPLC) with fluorescence detection as previously described (8). The limit of quantification was 10 ng/ml.…”

Section: Methodsmentioning

confidence: 99%

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Single- and Multiple-Dose Pharmacokinetics of Caspofungin in Healthy Men

Stone

Holland

Wickersham

et al. 2002

Antimicrob Agents Chemother

230

201

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Caspofungin, a glucan synthesis inhibitor, is being developed as a parenteral antifungal agent. The pharmacokinetics of caspofungin following 1-h intravenous infusions in healthy men was investigated in four phase I studies. In an alternating two-panel (six men each), rising-single-dose study, plasma drug concentrations increased proportionally with the dose following infusions of 5 to 100 mg. The ␤-phase half-life was 9 to 10 h. The plasma drug clearance rate averaged 10 to 12 ml/min. Renal clearance of unchanged drug was a minor pathway of elimination (ϳ2% of the dose). Multiple-dose pharmacokinetics were investigated in a 2-week, serial-panel (5 or 6 men per panel) study of doses of 15, 35, and 70 mg administered daily; a 3-week, single-panel (10 men) study of a dose of 70 mg administered daily; and a parallel panel study (8 men) of a dose of 50 mg administered daily with or without a 70-mg loading dose on day 1. Moderate accumulation was observed with daily dosing. The degree of drug accumulation and the time to steady state were somewhat dose dependent. Accumulation averaged 24% at 15 mg daily and ϳ50% at 50 and 70 mg daily. Mean plasma drug concentrations were maintained above 1.0 g/ml, a target selected to exceed the MIC at which 90% of the isolates of the most clinically relevant species of Candida were inhibited, throughout therapy with daily treatments of 70 or 50 mg plus the loading dose, while they fell below the target for the first 2 days of a daily treatment of 50 mg without the loading dose. Caspofungin infused intravenously as a single dose or as multiple doses was generally well tolerated. In conclusion, the pharmacokinetics of caspofungin supports the clinical evaluation of once-daily dosing regimens for efficacy against fungal infections.Caspofungin (Cancidas; MK-0991) is an echinocandin that was recently approved by the U.S. Food and Drug Administration for patients with invasive aspergillosis who are refractory to or intolerant of standard therapy. Caspofungin inhibits the synthesis of 1,3-␤-D-glucan, which forms a critical component of many fungal cell walls (3). It has been shown to have potent activity in vitro against many clinically important fungi, including Candida spp. and Aspergillus spp. (2, 7, 9; M. Del Poeta, W. A. Schell, and J. R. Perfect, Abstr. 36th Intersci. Conf. Antimicrob. Agents Chemother., abstr. F33, 1996). In in vivo studies with healthy and immunocompromised animals, prolonged survival in models of disseminated aspergillosis and candidiasis and clearance of Candida spp. from a target organ have been demonstrated with caspofungin treatment (1,5,6 , abstr. 1103, p. 371, 2000).Caspofungin has been developed as a parenteral agent due to its high molecular weight, unfavorable log P (partition coefficient), and extremely poor oral bioavailability in animals. In all the clinical studies, caspofungin has been administered as a constant-rate, 1-h intravenous (i.v.) infusion. This paper describes the results from four phase I studies conducted with healthy male subjects to ...

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Section: Methodsmentioning

confidence: 99%

“…Bovine serum albumin (2 ml of a 35% solution in saline per 200 ml of urine) was added to urine samples from the 70-mg group of study B to prevent adsorption of the drug. Urine samples from the 70-mg group were analyzed by HPLC with fluorescence detection as previously described (8). The limit of quantitation was 10 ng/ml.…”

Section: Methodsmentioning

confidence: 99%

Single- and Multiple-Dose Pharmacokinetics of Caspofungin in Healthy Men

Stone

Holland

Wickersham

et al. 2002

Antimicrob Agents Chemother

230

201

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“…In this open-label study, seven subjects (one white, two black, and four Hispanic; aged 21 to 40 years (average, 31 years); weighing 61 to 93 kg [average, 78 kg]) received the same dose, route of administration, and radiolabeled form of caspofungin as used in the preceding study. Plasma samples were collected at the same time points as in study A up to 72 h and then on days 5, 6, 7, 10, 14, 21, and 28 and at weeks 6,8,10,12,14,16,18,20,24, and 26 for assay of caspofungin and radioactivity. No urine or feces were collected in this study.…”

Section: Methodsmentioning

confidence: 99%

“…Plasma and urine samples were stored at Ϫ70°C, and feces were stored at Ϫ20°C until analysis. Plasma and urine concentrations of caspofungin were determined by high-pressure liquid chromatography with fluorescence detection as previously described (12). The plasma assay was modified slightly to allow for smaller sample volumes; 0.5 ml of plasma was used, with a resulting limit of quantitation (LOQ) of 25 ng/ml.…”

Section: Methodsmentioning

confidence: 99%

Disposition of Caspofungin: Role of Distribution in Determining Pharmacokinetics in Plasma

Stone

Winchell

et al. 2004

Antimicrob Agents Chemother

128

110

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The disposition of caspofungin, a parenteral antifungal drug, was investigated. Following a single, 1-h, intravenous infusion of 70 mg (200 Ci) of [ 3 H]caspofungin to healthy men, plasma, urine, and feces were collected over 27 days in study A (n ‫؍‬ 6) and plasma was collected over 26 weeks in study B (n ‫؍‬ 7). Supportive data were obtained from a single-dose [ 3 H]caspofungin tissue distribution study in rats (n ‫؍‬ 3 animals/time point). Over 27 days in humans, 75.4% of radioactivity was recovered in urine (40.7%) and feces (34.4%). A long terminal phase (t 1/2 ‫؍‬ 14.6 days) characterized much of the plasma drug profile of radioactivity, which remained quantifiable to 22.3 weeks. Mass balance calculations indicated that radioactivity in tissues peaked at 1.5 to 2 days at ϳ92% of the dose, and the rate of radioactivity excretion peaked at 6 to 7 days. Metabolism and excretion of caspofungin were very slow processes, and very little excretion or biotransformation occurred in the first 24 to 30 h postdose. Most of the area under the concentration-time curve of caspofungin was accounted for during this period, consistent with distribution-controlled clearance. The apparent distribution volume during this period indicated that this distribution process is uptake into tissue cells. Radioactivity was widely distributed in rats, with the highest concentrations in liver, kidney, lung, and spleen. Liver exhibited an extended uptake phase, peaking at 24 h with 35% of total dose in liver. The plasma profile of caspofungin is determined primarily by the rate of distribution of caspofungin from plasma into tissues.Caspofungin (CANCIDAS; MK-0991) is a parenteral antifungal agent that inhibits 1,3-␤-D-glucan synthesis, which forms a critical component of many fungal cell walls (4). Caspofungin is active against many clinically important fungal species, including Candida spp. and Aspergillus spp. (3,5,7,14), and in clinical trials it has been shown to be efficacious in the treatment of esophageal candidiasis (1, 15, 16), invasive candidiasis (9), and invasive aspergillosis (J. Maertens, I. Raad, G. Petrikkos, et al., Abstr. 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. M-868, 2002). This paper describes results from two studies conducted in healthy human subjects to investigate the disposition of caspofungin following intravenous (i.v.) infusion of radiolabeled caspofungin and supportive studies of [ 3 H]caspofungin tissue distribution in rats, in vitro metabolism, and in vitro binding and partitioning in human plasma and blood. The metabolites of caspofungin, a cyclic hexapeptide, in humans have been previously reported (2). Caspofungin is the major component of radioactivity in plasma and urine in the first 24 to 30 h postdose, with a ring-opened form of caspofungin, M0, comprising a minor component. At time points of Ն5 days, M0 was the major component in plasma, and urine radioactivity was largely comprised of the synthetic amino acid dihydoxyhomotyrosine (M1) and its N-acetyl derivative (M2). Caspofungin...

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“…CAS concentrations were determined by high-performance liquid chromatography (lowest sensitivity limit, 0.125 mg/liter) with a Perkin-Elmer Series 200 high-performance liquid chromatograph (9).…”

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confidence: 99%