24, NO. 3,2002
New Drugs Caspofungin:
An Echinocandin Antifungal Agent
Elizabeth A. Stone, PharmD,I Horatio B. Fung, PhurmD, BCPS,2 and Harold L Kirschenbaum, MS, PharmD3 ‘Pharmacy Service, and 2Critical Care Center, VA Medical Center, Bronx, New York, and 3Division of Pharmacy Practice, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York
Background: The mainstays of treatment for nosocomial fungal infections have been amphotericin B and azole derivatives. Caspofungin acetate is a new echinocandin antifungal agent with a mechanism of action that targets a structural component of the fungal cell wall. Objective: This article describes the pharmacologic properties and potential clinical usefulness of caspofungin. Methods: Relevant information was identified through searches of MEDLINE (1966September 2001), Iowa Drug Information Service (1966September 2001), and International Pharmaceutical Abstracts (1970September 2001), as well as meeting abstracts of the Infectious Diseases Society of America and the Interscience Conference on Antimicrobial Agents and Chemotherapy (19962001), using the terms caspofungin, MK-0991, pneumocandin, echinocandin, candin, and P(1,3)-glucan inhibitor. Results: In vitro, caspofungin exhibits antifungal activity against an array of clinically important yeasts and molds, including Candida and Aspergillus spp. The proposed susceptibility breakpoint for caspofungin against Candida spp, the most common cause of nosocomial fungal infections, is a minimum inhibitory concentration of I1 pg/mL. In humans, caspofungin has a volume of distribution of 9.67 L, is extensively bound to albumin (97%), has a plasma elimination half-life of 9 to 11 hours, and is metabolized to inactive metabolites in the liver. Dose adjustment based on age, sex, race, or renal function does not appear to be necessary, although patients with moderate hepatic insufficiency (Child-Pugh score 7-9) should receive a lower maintenance dose. The results of clinical trials, although somewhat preliminary, suggest that caspofungin is effective in the treatment of esophageal and oropharyngeal candidiasis and invasive aspergillosis. When comAccepted for publication January 4,2002. Printed in the USA. Reproduction in whole or part is not permitted.
bined with other antifungal agents, caspofungin produces a synergistic or additive effect against a variety of clinically important fungi. The most commonly reported adverse events with caspofungin have included fever, infusion-related reactions, headache, nausea, elevations in liver transaminase levels, and histamine-type reactions. The recommended dosage in adults is 70 mg IV on day 1 followed by 50 mg/d, with the duration of treatment depending on the severity of the patient’s underlying condition and the clinical response. Conclusion: Although additional studies are needed, caspofungin appears to be a promising agent for the treatment of patients with difficult-to-treat or lifethreatening fungal infections. Key words: caspofungin, MK-0991, pneumocandin, echinocandin, candin, B-(1,3)-glucan inhibitor, fungal infections. (Clin Thel: 2002;24:351-377) INTRODUCTION The past 2 decades have witnessed a steady increase in the incidence of nosocomial fungal infections. Based on a review of 30,447 patients with nosocomial fungal infections, the infection rate has risen from 0.20% in 1980 to 0.66% in 1990.’ More recent surveillance of nosocomial infections at 49 US hospitals over a 3year period (1995-1998) found that 8% of bloodstream infections were caused by fungi.* According to an analysis of data collected through the National Nosocomial Infections Surveillance System between 1992 and 1995, 12% of all bloodstream infections in medical intensive care units in the United States were caused by fungi.3 This increase in the incidence of fungal infections may be attributed primarily to increased numbers of critically 352
ill and immunocompromised patients, including those with AIDS, cancer patients undergoing chemotherapy, and organ transplant recipients taking immunosuppressive therapy. Other possible reasons for the increased incidence of fungal infections include the growing numbers of patients undergoing invasive medical procedures, receiving broad-spectrum antibiotics or long-term corticosteroid therapy, and receiving parenteral nutrition or hemodialysis.4 Candida is responsible for -80% of nosocomial fungal infections.’ According to data from the 1997 SENTRY Antimicrobial Surveillance Program, Candida albicans was the predominant Candida pathogen, accounting for 56% of clinical isolates, followed by Candida glabrata (19%), Candida parapsilosis (9%), Candida tropicalis (7%), Candida krusei (2%), Candida guilliermondii (l%), and other Candida spp (6%).5 Aspergillus spp
are less common, causing -4% to 5% of all nosocomial fungal infections.6 Despite this relatively low percentage, invasive aspergillosis in immunocompromised patients is associated with an extremely high mortality rate, approaching 85% even with aggressive antifungal therapy.6 The number of available antifungal agents suitable for treating systemic fungal infections is limited. For the past 2 decades, the primary mainstays of antifungal therapy have been agents that target the integrity of the fungal cell membrane: polyenes such as amphotericin B and nystatin, and azole derivatives such as fluconazole and itraconazole (Figure l).“,’ Amphotericin B binds preferentially to ergosterol, a structural component of the fungal cell membrane, thereby disrupting its integrity and causing it to “leak” electrolytes. Amphotericin B is a potent, broad-
E.A. STONE ET AL.
Lanosterol Lanosterol 1Calpha demethylase
1 l&alpha-demethyl I
Azoles: Clotrimazole Fluconazole ltraconazole Ketoconazole Miconazole
Zymosterol 1 Fecosterol
1. Fungal ergosterol fungal agents.4t7
spectrum fungicidal agent and has been the preferred choice for the treatment of severe systemic fungal infections.4*8 Its use, however, is associated with significant adverse effects (AEs), including nephrotoxicity and infusion-related events such as fever and chills. Newer lipid formulations of amphotericin B may produce fewer AEs, but their acquisition cost is -40 to 50 times higher than that of the older formulations. Azoles inhibit the enzyme lanosterol demethylase by blocking the biosynthesis of ergosterol.8 They have improved tolerability profiles compared with amphotericin B, but their cytocidal activity may be organism and concentration depen-
showing the targets for various types of anti-
dent.&-lo Their extensive use has led to the emergence of resistance among susceptible species, including C albicans, C tmpicalis, and Cparapsilosi~.~ C glabrata often develops acquired resistance to the azoles, and C krusei is innately resistant to these agents5 According to results from the SENTRY Antimicrobial Surveillance Program for 1997, only 87.2% and 67.0% of Candida spp isolated from bloodstream infections in the United States were susceptible to fluconazole and itraconazole, respectively.5 In addition, many strains are cross-resistant to all azoles.8 Thus, despite the introduction of lipid formulations of amphotericin B and development of potentially more effective
investigational azoles such as voriconazole and posaconazole, newer antifungal agents are needed, preferably with a different mechanism of action.11*12In the past few years, research has been focused on developing antifungal agents that target a different structural component of the fungus. l3 The fungal cell wall presents an attractive target: it is essential to the fungus, performing vital functions that include physical protection against cell lysis by other microorganisms and host phagocytes, and maintenance of the osmotic stability of the protoplast. The fungal cell wall also regulates cell shape and mediates cell-to-cell communication and a number of essential enzymatic reactions.14 More important, the cell walls of the fungi responsible for most disease in humans possess unique components that are absent from mammalian hosts.4,15 Most information about the fungal cell wall comes from studies involving yeasts, primarily C albicans and Saccharomyces cerevisiae. The cell wall of yeast consists of an outer layer of mannoproteins and an inner layer of p-( 1,3)-glucan/chitin mesh with some entrapped mannoproteins. The p-(1,3)-glucan is responsible for the structural integrity of the cell wall. Crosslinkages of glucan and chitin provide additional rigidity. l5 Therefore, the mannoproteins, glucan, and chitin of the fungal cell wall provide new drug targets.16 It is hoped that antifungal agents that target components of the fungal cell wall will have a deleterious effect on fungi similar to that of the beta-lactam antimicrobial agents on bacteria. Figure 2 illustrates the structure of the cell wall of S cerevisiae and antifungal agents that target different components of the cell wa11.4 Among the antifungal agents being developed are the echinocandins, a chemi354
tally distinct class of antimicrobial agents that inhibit the enzyme p-( 1,3)-glucan synthase, resulting in disruption of cellwall glucan formation.8 Cilofungin was the first echinocandin to reach Phase II clinical development for its activity against Candida spp. Its further development was suspended, however, when nephrotoxicity and metabolic acidosis related to the intravenous vehicle polyethylene glycol were noted.16g17 Another echinocandin, caspofungin acetate* (MK-0991, L-743,872), has been studied in humans and is the first to receive marketing approval from the US Food and Drug Administration (FDA). It is a water-soluble, semisynthetic derivative of pneumocandin B,, a fermentation product isolated from the fungus Glarea Zozoyensis.12 Other echinocandins that have advanced to clinical trials include LY303366 (Eli Lilly and Company, Indianapolis, Ind) and FK463 (Fujisawa Healthcare, Inc, Deerfield, I11).8 Caspofungin is indicated for the treatment of invasive aspergillosis in patients who fail to respond to or are unable to tolerate other therapies.18 It is an azasubstituted, diamino analogue of the natural product pneumocandin B,.19 It is a l-[(4R,5S)-5-[(2-aminoethyl)amino]-N2(10,12-dimethyl1-oxotetradecyl)-4hydroxy-t_-ornithinel-5[(3R)-3-hydroxyL-ornithine] diacetate salt of pneumocandin B, with the molecular formula C,,H,,N,,,0,,2C,H,O, and a molecular weight of 1213.42 d (Figure 3).18 This review summarizes available information on the pharmacologic properties and clinical usefulness of caspofungin. To identify appropriate publications *Trademark [email protected]
(Merck & Co, Inc, Whitehouse Station, New Jersey).
E.A. STONE ET AL.
Mannoprotein complexing agents: Benanomicin Pradimicin
i3-(1,3)-glucan/ chitin mesh
i3-(1,3)-glucan synthesis inhibitors: Caspofungin FK463 LY303366
Fungal cell wall
Chitin synthesis inhibitors: Nikkomycin Polyoxin
_ Polyenes and triazoles: Amphotericin 6 _________.______________________________..................................... > Fluconazole Cytoplasm
Figure 2. Components of the cell wall of Succharomyces types of antifungal agenb4
cerevisiae as targets for various
Figure 3. Structural
formula of caspofungin.‘*
for review, the following databases were searched using the terms caspofungin,
p-( 1,3)-glucan synthesis is inhibited, ballooning out of the cellular contents from the weakened cell wall as a result of the high osmotic pressure of the protoplast results in cell lysis. 2o In a wide variety of fungi, p-( 1,3)-glucan synthase is composed of 2 subunits: a plasma membrane-bound catalytic subunit (FKS) and an activating subunit. The activating subunit, with guanosine triphosphatase activity, activates the catalytic subunit, which polymerizes UDP-glucose into fibrils of glucan and extrudes the polymer through the plasma membrane (Figure 4).4,20 There appear to be 2 glucan-synthesis systems, regulated by the genes FKSl and FKS2. Preliminary studies have shown that the FKSl gene is expressed during normal vegetative growth, whereas FKS2 is preferentially expressed during sporulation.*OBoth systems are inhibited by the echinocandins.4s20
MK-0991, pneumocandin, echinocandin, candin, and @(1,3)-glucan inhibitor:
MEDLINE (196~September 2001), Iowa Drug Information Service (196~September 2001), and International Pharmaceutical Abstracts (1970September 2001), as well as meeting abstracts of the Infectious Diseases Society of America and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1996-2001). MECHANISM OF ACTION Caspofungin is a noncompetitive inhibitor of the enzyme p-( 1,3)-glucan synthase, which catalyzes the polymerization of uridine diphosphate-glucose (UDP-glucose) into p-( 1,3)-glucan, a structural component of the fungal wall responsible for maintaining integrity and rigidity. l3 When
Glucan polymer 1 Fungal cell wall O-(1,3)-glucan synthase
and other inhibitors of l3-(1,3)-glucan synthesis
Figure 4. Fungal glucan synthesis, showing the target of action for caspofungin and other inhibitors of p-( 1,3)-glucan synthesis.4*20 356
E.A. STONE ET AL.
IN VITRO ANTIFUNGAL ACTIVITY
To date, there is no reliable standardized method of testing antifungal susceptibility. Minimum inhibitory concentration (MIC) values reported by clinical laboratories may vary greatly with the culture medium used, the incubation time, the assay methodology, and the defined end point of growth inhibition.*i The National Committee for Clinical Laboratory Standards (NCCLS) has published reference methods for susceptibility testing of Cundidu spp using broth-dilution techniques (document M27-A)** and has proposed guidelines for conidium-forming filamentous fungi (document M38-P).23 Currently, various experimental methods are being studied for determining the MIC for Aspergillus spp, including examination of morphologic changes of the hyphae, disk diffusion, and Epsilometer tests.24-26 Caspofungin has been tested in vitro against yeast, filamentous fungi, and dimorphic fungi, exhibiting antifungal activity against a wide variety of clinically important yeasts and molds, including Cundidu and Aspergillus spp.*’ It has limited activity against Cryptococcus neoformans (MIC required to inhibit 90% of organisms [MI&] >16 ug/mL), most likely because of differences in the configuration of glucan units in the fungal cell wa11.4,26 To date, there are no published susceptibility breakpoints for caspofungin. Based on 48-hour MIC values derived from a compilation of microdilution techniques (see Table I for MICs) and caspofungin concentrations achieved at therapeutic doses in pharmacokinetic studies (see Table III for serum concentrations), a tentative susceptibility breakpoint MIC of I1 pg/mL against Cundidu spp has been proposed.
Pfaller et aL5 Marco et a&t3 and Vazquez et a128evaluated the in vitro susceptibility of a total of 654 isolates of Cundidu spp. In these studies, RPMI-1640 medium was used, and the MIC was defined as the lowest concentration that completely inhibited growth of the organism. The 48-hour MIC ranged from 0.015 to 0.8 pg/rnL for C ulbicuns (346 isolates), 0.03 to 0.5 pg/ mL for C glubrutu (119). 0.03 to 2 pg/mL for C fropiculis (74), 0.03 to 8 pg/mL for C purupsilosis (83), 0.125 to 1 pg/rnL for C krusei (22), 0.4 to 0.8 pg/mL for Cundidu lusituniae (5), and 1.6 pg/mL for C guilliermondii (5). Similar findings were reported by Ernst et al,29~3oPfaller et aL31 and Barry et al. 32 The in vitro activity of caspofungin against Cundida spp at 48 hours is summarized in Table I. Nelson et al*l determined MIC values for 30 Cundidu isolates categorized as either amphotericin B resistant (7 isolates), amphotericin B and fluconazole resistant (l), fluconazole resistant (7), or amphotericin B and fluconazole susceptible ( 15). The range of 24-hour MICs of the susceptible isolates was the same as that of the resistant isolates (<0.0625-l &nL).21 The susceptibility of Cundidu spp with resistance to fluconazole or amphotericin B was evaluated in 3 additional studies,28,30,33 in which the MIC values of resistant strains were similar to those of susceptible strains. Bachmann et aP4 studied the in vitro activity of caspofungin against 19 clinical isolates of C ulbicuns with documented overexpression and/or point mutation in the ERG11 gene (encoding lanosterol demethylase), leading to azole resistance, and overexpression in the MDR and CDR genes (encoding the multidmg efflux pumps). Caspofungin demonstrated activity against
Table I. In vitro activity of caspofungin
Species Candida Candida Candida Candida Candidu Candida
Combined No. of Isolates Tested
MIC,* [email protected]
MIC,,’ u.g/mL (Range)
71 131 97 156 76
0.03-l 0.008-0.5 0.125-l 0.03-8 0.03-2
albicans dubliniensis glabrata krusei parapsilosis tropicalis
MIC = minimum *MIC determined
against Candida spp.
5, 13,28-30 31 5, 13,28, 29
13,32 5, 13,32 5, 13,28, 29
inhibitory concentration; ME, = MIC required to inhibit 90% of organisms. by broth microdilution with RPMI-1640 medium and incubation for 48 hours.
all isolates, with 48-hour MICs ranging from medium.34 One hundred fifty-two clinical isolates of less frequently seen Candida spp that are often refractory to antifungal therapy were tested against caspofungin in antibiotic medium 3 without 2% glucose.35 Species included C lusitaniae (58 isolates), C krusei (27), Candida kefyr (22), Candiah dubliniensis (29), and Candida lipolytica (16). At 48 hours, the geometric mean MIC for all isolates was CO.07 pg/mL. Thus, caspofungin appears to have activity against susceptible Candida spp independent of their resistance pattern to other antifungal agents.
0.25 to 2 pg/mL in RPMI-1640
Aspergillus Sutton et al35 determined the MIC for caspofungin against 61 isolates of Aspergillus nigel; 50 of Aspergillus terreus, and 35 of Aspergillus nidulans using antibiotic medium 3 without 2% glucose. The 48-hour geometric mean MIC and MIC,, were 0.07 and 0.25 pg/mL, respectively, for A niger, 17.89 and 32 pg/mL for A terreus, and 1.64 and 16 pg/mL for A nidulans. 358
Similar results were reported by Arikan et al36 and Flattery et al.37 The latter investigators evaluated 71 isolates of Aspergillus fumigatus, 9 of Aspergillus flaws, 3 of A niger, and 3 of A terreus in RPMI- 1640 medium. The MIC end points used were 100% and 80% inhibition (MIC,,) compared with the growth of control. The geometric mean MIC,, at 24 and 48 hours was 0.19 and 50.6 pg/mL, respectively, for Afumigatus, 0.68 and >64 yg/mL for A flavus, 0.04 and 0.04 &mL for A nigel; and 0.2 and 20.2 &mL for A terreus. In this study, caspofungin had in vitro activity with a geometric mean MIC,,
Table 11. In vitro activity of caspofungin
Geometric Mean MIC,* ~g/rnI. (Range)
MK’ @nL (Range)
8, 27, 36, 37
8,27, 36, 37
Combined No. of Isolates Tested
Species Aspergillus Aspergillus Aspergillus Aspergillus
against Aspergillus spp.
ji’avus fumigatus niger terreus
MIC = minimum inhibitory concentration. *Visual MIC (prominent growth inhibition) incubation for 24 hours.
produces profound morphologic damage to hyphae that is observable by microscopy. 3g A more reliable, reproducible, and clinically relevant method of antifungal susceptibility testing is needed, particularly for molds such as Aspergillus spp.
PHARMACOKINETICS Preclinical animal studies have shown that caspofungin is minimally absorbed after oral administration, with an absolute bioavailability of 0.3% to 1% in mice and 9% in dogs.* When given intraperitoneally to mice, caspofungin is distributed into tissues (volume of distribution, 0.1 l-O.27 L/kg), with the highest drug concentrations in the liver. The following tissue:plasma ratios have been reported: 16 in the liver, 2.9 in the kidneys, 2.0 in the large intestine, 1.3 in the small intestine, 1.1 in the lungs, 1 .O in the spleen, 0.3 in the heart, 0.2 in the thigh, and 0.1 in the brain. In mouse serum, caspofungin is extensively (96%) bound to plasma protein.lg After intravenous administration to a variety of animals, including mice, rats, rhesus monkeys, and chimpanzees, caspo-
by broth microdilution
fungin had a clearance ranging from 0.24 to 0.5 1 mL/min per kg and an elimination half-life ranging from 5.6 to 7.6 hours. Less than 3% of the parent drug was recovered unchanged from the urine.1g There are few published pharmacokinetic studies of caspofungin in humans, and those that are available are mainly in abstract form. In a Phase I dose-ranging study in which 12 healthy men received single infusions of caspofungin 5 to 100 mg IV, plasma concentrations of caspofungin increased as the dose increased.40 In the same study, multiple dosing was associated with moderate accumulation (25%-50%) in healthy men (5 or 6 per group) who received caspofungin 15, 35, or 70 mg IV once daily for 2 weeks and in 10 healthy men who received caspofungin 70 mg IV once daily for 3 weeks. After a single 70-mg dose of intravenous caspofungin, the mean peak plasma concentration at 1 hour was 10.45 [email protected]
and the trough concentration at 24 hours was 1.19 I~,g/rnL.“~,~*Mean trough concentrations in 10 healthy men who received caspofungin 70 mg IV daily for 3 weeks were 1.34, 2.43, and 2.64 pg/mL
on days 1, 14, and 21 of the study, respectively.40 In a 1Cday Phase I study evaluating the effect of a loading dose in a multiple-dose regimen, 16 healthy subjects (8 men, 8 women) received a loading dose of caspofungin 70 mg IV on day 1 followed by 50 mgid on days 2 through 14, and 8 healthy men received caspofungin 50 mgld for 14 days without a loading dose.43 Mean trough concentrations of caspofungin were ~1 p,g/mL throughout the study in subjects who received the loading dose, whereas they were
over 27 days.45 Plasma caspofungin elimination is typically triphasic, with mean a, p, and y half-lives of 1 to 2, 9 to 11, and 40 to 50 hours, respectively.U Little caspofungin is excreted unchanged by the kidneys (1.44% of the dose), and the mean renal clearance is 0.15 mL/min.‘8 Findings of a radioactivity study suggest that there is a small amount (cl%) of biliary excretion as we11.44 The total clearance of caspofungin is 12 mL/min. 18,40 The pharmacokinetic parameters of caspofungin in adults are summarized in Table III. Special Populations The Elderly
An open-label study evaluated the effect of age on the single-dose pharmacokinetics of caspofungin in healthy volunteers.42 Six elderly men (age range, 68-77 years), 6 elderly women (67-77 years), and 6 young men (24-44 years) were administered a single dose of caspofungin 70 mg IV All the elderly subjects had a creatinine clearance of 260 mL/min. Compared with the young control subjects, the elderly subjects had higher mean caspofungin concentrations at 1 hour (11.32 vs 10.45 kg/n& respectively) and 24 hours
Table III. Pharmacokinetic parameters of caspofungin in healthy adults.18,4U5 Peak concentration* Trough concentration* Plasma elimination half-life Distribution Plasma protein binding Metabolism Clearance Renal clearance
10.45 pg/mL 1.19 pg/mL 9-11 hours Not widely distributed; volume of distribution, 9.67 L Extensively bound to albumin (97%) Metabolized in the liver, primarily by hydrolysis to inactive metabolites 12 mLlmin 0.15 mL/min
*After a single dose of 70 mg IV, peak at 1 hour after infusion, trough at 24 hours after infusion.
E.A. STONE ET AL.
(1.57 vs 1.19 pg/mL). Although specific values were not reported, the mean halflife was stated to be 26% longer in elderly subjects. The elderly subjects had a 28% mean increase in area under the concentration-time curve (AUC) compared with control subjects (90% CI, 8 to 50). Plasma concentrations of caspofungin were not significantly elevated in the elderly women, who had an AUC from 0 to 24 hours (AUC,,) that was -18% greater than that of their male counterparts (90% CI, -8 to 52). The investigators concluded that dose adjustment of caspofungin based on age was not necessary. Sex
In a 14-day, parallel-panel, Phase I study, Stone et al43 studied the effect of sex on the multiple-dose pharmacokinetits of caspofungin in healthy subjects. Eight men and 8 women received caspofungin 70 mg IV on the first day, followed by caspofungin 50 mg/d for the next 13 days. Plasma concentrations of caspofungin were similar in the men and women on day 1. Based on AUC,,, values on day 14, the women had a mean 22% more drug in their body (90% CI, 1 to 47). Other pharmacokinetic parameters such as elimination half-life and volume of distribution were not reported. The investigators concluded that dose adjustment based on sex was not warranted because of the small difference in caspofungin disposition between sexes. Nevertheless, it appears prudent to note these sex-related pharmacokinetic differences. Race Based on regression analyses, no clinically significant differences in the pharmacokinetic parameters of caspofungin have been noted between white, black, or
Hispanic patients. l* Therefore, no dose adjustment appears to be necessary on the basis of race. Renal Insu$iciency After administration of a single 70-mg IV dose of caspofungin, volunteers with moderate renal insufficiency (creatinine clearance 31-49 mL/min), severe renal insufficiency (5-30 mL/min), and endstage renal disease (~10 mL/min and dialysis dependent) had moderate increases in caspofungin plasma concentrations compared with control subjects.‘* The increase in AUC ranged from 30% to 49%. Statistical analyses of the results were not provided. No results of pharmacokinetic studies involving multiple doses of caspofungin in subjects with renal insufficiency have been published. Nevertheless, based on the fact that mild to severe renal impairment had no remarkable effect on trough concentrations in patients receiving multiple doses of caspofungin 50 mg/d in clinical trials, the manufacturer does not recommend dose adjustment in patients with renal insufficiency. I8 However, because AUC is increased, close monitoring for AEs in patients with renal insufficiency appears prudent. Caspofungin is not removed by hemodialysis, so supplemental doses are not required.‘* Hepatic [email protected]
The effect of hepatic insufficiency on caspofungin pharmacokinetics was evaluated in a Phase I pilot study.‘@ Eight subjects with mild hepatic insufficiency (Child-Pugh score 5-6) and 8 subjects with moderate hepatic insufficiency (Child-Pugh score 7-9) were administered a single dose of caspofungin 70 mg IV The extent of absorption of caspofungin
(denoted by AUC) increased by 55% (90% CI, 32 to 86) and 76% (90% CI, 51 to 106) in patients with mild and moderate hepatic insufficiency, respectively, compared with historical healthy control subjects (n = 24). Hence, it appears that dose adjustment of caspofungin is necessary in patients with hepatic insufficiency. In a lCday, multiple-dose study, Stone et a146 evaluated the pharmacokinetics of caspofungin in 8 subjects with mild hepatic insufficiency, 8 subjects with moderate hepatic insufficiency, and 16 healthy subjects matched by age, sex, and body weight. Control subjects and those with mild hepatic insufficiency received a 70-mg IV loading dose of caspofungin on day 1 followed by 50 mg IV daily for the remainder of the study. Subjects with moderate hepatic insufficiency received a 70-mg loading dose of caspofungin IV on day 1, followed by 35 mg IV daily on days 2 through 14. on day 14 increased by The AUC,,, 21% (90% CI, 4 to 39) and 7% (90% CI, -10 to 28) in subjects with mild and moderate hepatic insufficiency, respectively, compared with control subjects. On the basis of this preliminary study, the investigators did not recommend dose adjustment for patients with mild hepatic insufficiency. In patients with moderate hepatic insufficiency, however, they recommended that after the initial 70-mg loading dose, the maintenance dose be reduced to 35 mg/d. No pharmacokinetic data on caspofungin are available in patients with severe hepatic insufficiency (Child-Pugh score >9). ls
PHARMACODYNAMICS Growth-kinetic studies have demonstrated that caspofungin possesses a concentration-
dependent fungicidal or fungistatic effect that varies within and between Cundida spp, depending on the isolate tested.29 Ernst et al29 studied the in vitro pharmacodynamic activity of caspofungin against 2 strains each of C albicans, C glabrata, and C tropic&s using time-kill curve methods. Caspofungin showed concentrationdependent fungicidal activity against 1 strain of C albicans, 2 strains of C ghbruta, and 1 strain of C tropic& whereas fungistatic activity was observed against the other C albicans and C tropicalis strains. Therefore, it has been suggested that the dose of caspofungin may be increased to 70 mg/d in patients who tolerate caspofungin but are not responding clinically to the 50-mg/d regimen, although the clinical benefit of this higher maintenance dose is yet to be elucidated. 18,44 After exposure of C albicans strains to 1 hour of concentrations above the MIC, caspofungin displayed a postantifungal effect of >12 hours using time-kill methods. The duration of postantifungal effect was shown to decrease sharply to 0 to 2 hours after 1 hour of exposure to concentrations below the MIC, suggesting that this effect is also concentration dependent.30 In contrast, radiometric assays have shown caspofungin to have a relatively short postantifungal effect (cl hour) against A fumigatus.47 Reports on the effects of human sera on the antifungal activity of caspofungin against Candida and Aspergillus spp are conflicting. In an in vitro preclinical evaluation of caspofungin, Bartizal et a133 reported that the susceptibility of C albicans to caspofungin was not significantly reduced by the addition of human serum. With 50% mouse serum, these investigators reported an insignifi-
E.A. STONE ET AL.
cant increase in MIC (decreased susceptibility), although the specific values were not provided. These findings are expected, given that caspofungin is highly protein bound. Of interest, human serum may potentiate the antifungal activity of caspofungin against Aspergillus. Chiller et a139 assessed the influence of human sera on the in vitro activity of caspofungin against A fimigatus. The addition of 5% human serum to caspofungin at a concentration of 0.1 or 0.05 pg/mL significantly enhanced caspofungin’s inhibitory activity against A fimigatus (P c 0.01). Although the exact mechanism of this enhancement is unknown, it does not seem to be related to the presence of complement or formation of an Aspergillus antibody in human sera. 39The same investigators also examined the effect of human monocytes and macrophages on the antifungal activity of caspofungin against A fumigatus.48 Caspofungin cocultured with human monocytes for 24 hours had significantly greater inhibitory activity against Aspergillus hyphal growth compared with controls (P < 0.01). Similar results were observed for caspofnngin cocultured with human macrophages, but not with polymorphonuclear neutrophils. Hence, it is hypothesized that monocytes or macrophages damage the fungal hyphae, enhancing the delivery of caspofungin to the sites of action. On the basis of the preceding findings, it is possible that caspofungin may have better antifungal activity against A fumigatus in vivo than in vitro.
ined the effects of caspofungin on other opportunistic fungi, such as Pneumocystis carinii,56 Histoplasma capsulatum,‘7,57 Coccidioides immitis,16 and C neoformans.a Caspofungin has shown benefit against all fungi except C neoformans, probably due to the difference in configuration of glucan in the fungal cell ~a.ll.~ Candidiask To date, all in vivo studies of the efficacy of caspofnngin in candidiasis appear to have been performed in mice. In mouse models involving both competent and suppressed immune systems, caspofungin has been effective against disseminated candidiasis, with its 90% effective dose comparing favorably with that of antifungal agents such as amphotericin B, amphotericin B lipid complex, and fluconazole. 12,49-5 * In addition, caspofungin has been noted to decrease tissue-colony counts of C albicans, C krusei, and C glabrata in target organs.52s53In 1 study in mice, a single dose of caspofungin was more effective than amphotericin B at clearing C albicans from kidney tissue (P < 0.05).49 Aspergillosis In numerous animal models, the effectiveness of caspofungin in preventing and treating aspergillosis has been found to be similar to that of amphotericin B.12*49,51*54,55 Efficacy was observed consistently in both transient and chronic immune suppression.L2*55
ANIMAL STUDIES The efficacy of caspofungin has been demonstrated against Candida and Aspergillus ~pp.‘**~~~~Studies have exam-
Infection by Other Opportunistic Fungi P carinii exists in cyst and trophozoite forms, whereas B-( 1,3)-glucan is found 363
only in the cyst wall. Treatment with caspofungin was found to decrease the number of P carinii cysts by 90% in immunosuppressed rats.56 These results suggest a prophylactic role for caspofungin, since the trophozoite is more prevalent in acute disease and the cyst predominant in latent disease. The role of caspofungin has also been studied in the treatment of H capsulatum and C immitis infection. Caspofungin has shown variable in vitro activity against H capsulatum and appears to have a limited treatment role.17p57Caspofungin treatment has been effective in reducing tissue burdens of C immitis in mice.16 However, the published data are insufficient, and further in vivo investigation is needed before caspofungin can be recommended for treatment of these infections in humans. CLINICAL TRIALS Because of their weakened immune systems, immunocompromised patients are more susceptible to serious, life-threatening opportunistic fungal infections such as candidemia and aspergillosis.4 At the time of writing, 1 clinical study on caspofungin had been published in a peer-reviewed journal; other clinical studies were reported only in abstract form. Esophageal and Oropharyngeal Candidiasis In a randomized, double-blind, multicenter trial, Villanueva et a15*compared caspofungin with amphotericin B in the treatment of Candida esophagitis in adults. A total of 128 patients with endoscopyconfirmed Candida esophagitis were randomized to receive either caspofungin 50 mg IV (n = 46), caspofungin 70 mg IV (n = 364
28), or amphotericin B 0.5 mg/kg IV (n = 54) once daily for 14 days. Seventy-eight percent of patients in the combined caspofungin arms and 82% of patients in the amphotericin B arm were HIV positive. Forty-six percent of patients in the caspofungin arms and 41% of patients in the amphotericin B arm had a CD4 cell count of ~50 cells/pL. One hundred twenty-two patients completed the study. Based on a modified intent-to-treat analysis, a clinical response (resolution of symptoms) was seen in 73.9% (34/46) of patients receiving caspofungin 50 mg (95% CI, 59 to 86), 89.3% (25/28) of those receiving caspofungin 70 mg (95% CI, 72 to 98), and 63.0% (34/54) of those receiving amphotericin B (95% CI, 49 to 76). In general, caspofungin was well tolerated: 2 of 74 patients (2.7%) discontinued treatment due to an AE; however, only 1 event was deemed drug related-a generalized rash on day 10 of therapy. Caspofungin appeared to be as well tolerated and effective as amphotericin B in the treatment of esophageal candidiasis in this study. In a randomized, double-blind, multicenter trial, Arathoon et a159compared caspofungin with amphotericin B in the treatment of esophageal and oropharyngeal candidiasis. A total of 105 patients with esophagoscopy-proven esophageal candidiasis or oropharyngeal candidiasis were randomized to receive caspofungin 35 (n = 25), 50 (n = 26), or 70 mg (n = 29), or amphotericin B 0.5 mgkg (n = 25) once daily. The minimum duration of therapy was 10 days for esophageal candidiasis and 7 days for oropharyngeal candidiasis. The majority of patients were HIV positive, most with a CD4 cell count of ~50 cells/p,L. Ninety-five patients (60 with esophageal candidiasis, 35 with oropharyngeal candidiasis) were evaluable. In
E.A. STONE ET AL.
evaluable patients with esophageal candidiasis, a clinical response (complete resolution of symptoms and reduction in disease grade to 0 or 0.5 on a scale from 0 to 4) was seen in 78.6% (1 l/14) of patients who received caspofungin 35 mg, 93.3% (14/15) of patients who received caspofungin 50 mg, 77.8% (14/l 8) of patients who received caspofungin 70 mg, and 69.2% (903) of patients who received amphotericin B . In evaluable patients with oropharyngeal candidiasis, clinical response rates (defined as for esophageal candidiasis) were 77.8% (7/9) in the caspofungin 35-mg group, 90.9% (10/l 1) in the caspofungin 50-mg group, 100% (9/9) in the caspofungin 70-mg group, and 83.3% (5/6) in the amphotericin B group. Higher doses of caspofungin appeared to be associated with higher response rates, but statistical analyses were not provided. Although the investigators indicated that caspofungin was well tolerated and associated with fewer AEs than amphotericin B, the exact incidence of AEs was not reported. Overall, caspofungin appeared to be effective in the treatment of both esophageal and oropharyngeal candidiasis. Caspofungin was compared with fluconazole in the treatment of Cundidu esophagitis in a multicenter, randomized, triple-blind, noninferiority trial.60 Adult patients with endoscopyand cultureconfirmed esophageal candidiasis or histopathologic evidence of Cundida from esophageal lesions were randomized to receive caspofungin 50 mg IV (n = 8 1) or fluconazole 200 mg IV (n = 94) once daily for 7 to 21 days. The majority of patients were men (71%) and nonneutropenic (98%). Coinfection with HIV was present in 87% of patients, with a median CD4 cell count of 30 cells/FL. The predominant isolate was C albicans. A favorable
response (resolution of symptoms and significant improvement on endoscopic examination 5 to 7 days after therapy) was seen in 81.5% (66/81) of patients in the caspofungin group (95% CI, 7 1 to 89) and 85.1% (80/94) of patients in the fluconazole group (95% CI, 76 to 92). The difference in response rates was not statistically significant. In 95% of patients in both groups, symptoms of esophageal candidiasis had resolved by the end of therapy, and the median time to resolution was c5 days. The incidence of AEs was similar in both groups: 54% in the caspofungin group and 5 1% in the fluconazole group. One patient in the fluconazole group discontinued therapy due to a drugrelated AE. The nature of the ABs was not described. In this study, caspofungin was as efficacious and well tolerated as fluconazole in patients with Candidu esophagitis, including those coinfected with HIV
Invasive Aspergillosis An open-label, noncomparative trial evaluated the safety, tolerability, and efftcacy of caspofungin in 69 patients with invasive aspergillosis.18~44~61Patients were aged between 18 and 80 years, met National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria for invasive aspergillosis,62 and had not responded to a minimum of 7 days of standard antifungal therapy or were unable to tolerate such therapy. Patients received a loading dose of caspofungin 70 mg IV, followed by a maintenance dose of 50 mg/d for 1 to 162 days, with a mean duration of treatment of 33.7 days. Of the 63 patients for whom outcome data were available, 45 (7 1.4%) had pulmonary disease and 18 (28.6%) had extrapulmonary
disease; 53 (84.1%) were refractory to treatment with amphotericin B, lipid formulations of amphotericin B, itraconazole, or an investigational azole with reported activity against Aspergillus; and 10 (15.9%) were unable to tolerate prescribed therapy. The predominant underlying condition was hematologic malignancy (24 patients), followed by allogeneic bone marrow transplantation or stem cell transplantation (18), and solid tumor (3). A favorable response (complete resolution or clinically meaningful improvement in signs and symptoms and radiographic findings, as determined by an independent expert panel) was seen in 41.3% (26/63) of patients who received 21 dose of caspofungin and in 50.0% (26/52) of patients who received >7 days of caspofungin. Response rates in patients with pulmonary and extrapulmonary disease were 46.7% (21/45) and 27.8% (5/18), respectively. Overall, the incidence of drugrelated clinical AEs with caspofungin was 13.8%. At least 2 patients discontinued caspofungin treatment due to a drugrelated AE. The specific types of AEs reported are discussed later in this article. Although the data are limited, caspofungin appears to be a promising option for the treatment of invasive aspergillosis in patients who do not respond to or are unable to tolerate standard antifungal therapy.
SYNERGY When combined with other antifungal agents against a variety of clinically important fungi, caspofungin produces a synergistic or additive effect both in vitro and in vivo, probably because of the different mechanisms of action of the agents. Perea et a163 evaluated the in vitro activity of caspofungin and voriconazole alone and
in combination against 48 clinical isolates of Aspergillus obtained from patients with invasive aspergillosis, using the checkerboard broth-microdilution method in accordance with NCCLS M38-P guidelines.23 The isolates included 4 Aspergillus spp: A jkmigatus (24 isolates), A terreus (lo), A flavus (9), and A niger (5). Synergy, additive action, and indifference were observed with a respective 45.8%, 41.6%, and 12.5% of the combinations of caspofungin and voriconazole. No antagonism was observed. Using the same methodology, Arikan et [email protected]
investigated the in vitro activity of caspofungin combined with amphotericin B against 14 clinical isolates of Aspergillus (A flavus , A fumigatus , A niger , A terreus ) and 6 clinical isolates of Fusarium (Fusarium solani , Fusarium oqsporum ). The combination of caspofungin and amphotericin B showed a synergistic or additive effect against more than half of the isolates of both Aspergillus and Fusarium, although the exact percentages were not reported. Again, no antagonism was observed. Similar results were reported for combinations of caspofungin with amphotericin B or itraconazole against A fumigatus,65 with amphotericin B or voriconazole against A &migutus,‘j6 with amphotericin B or fluconazole against C neoformans,” and with amphotericin B against C albicans, C neoformans, and A fumigatus. 31 Flattery et a168 evaluated the efficacy of caspofungin in combination with amphotericin B or fluconazole in mouse models of disseminated aspergillosis, candid&is, and cryptococcosis. Efficacy was assessed in terms of mortality prevention and reductions in fungal colony-forming units per gram of target organ tissue. Although synergy was ob-
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served only at certain concentrations in the candidiasis model, no evidence of antagonism between caspofungin and amphotericin B or fluconazole was noted. In a murine model of disseminated aspergillosis, Douglas et a169 used polymerase chain-reaction assays to assess the efficacy of caspofungin alone and in combination with amphotericin B in reducing fungal tissue burden. Combinations of caspofungin and amphotericin B reduced the kidney burden of A fumigatus to levels less than or equal to those seen with either agent alone in a respective 62.5% and 37.5% of cases. Based on the preceding findings, combinations of caspofungin with other antifungal agents having a different mechanism of action may improve patient outcomes in the setting of life-threatening invasive fungal infections, although clinical studies are needed to delineate the usefulness of such combinations.
RESISTANCE In nature, high-level resistance (>lO-fold increase in MIC) to caspofungin and other echinocandins or pneumocandins has been attributed primarily to mutations of the FKSI and FKS2 genes.*O Low-level resistance (
a l-fold increase in MIC (from 0.06 to 0.125 pg/mL) was noted. In addition, no apparent morphologic changes were observed microscopically. Development of in vitro resistance of Aspergillus to caspofungin has not been studied.44
Because caspofungin was only recently approved by the FDA, the nature and incidence of ABs associated with its use are still being described. In addition, any ABs associated with long-term use may take months or even years to develop. At least 1 case of an anaphylactic reaction characterized by dyspnea, stridor, and rash has been reported with caspofungin.‘* However, only a small number of patients have been treated with caspofungin in Phase II and Phase III clinical studies.‘*,““ Consequently, much of the available information on the tolerability profile of caspofungin has been compiled from this limited clinical experience and from healthy subjects enrolled in Phase I clinical pharmacology studies. A total of 274 healthy subjects participated in the clinical pharmacology studies. Subjects received various doses of caspofungin (~50 mg = 36 subjects, 50 mg = 81, ~50 mg = 157) for 1 to 21 days. The most frequently reported drug-related AEs were mild to moderate infusionrelated reactions and headache. Dermatologic effects (eg, flushing, erythema, wheals, or rash), facial edema, or respiratory symptoms (wheezing or bronchoconstriction) associated with histamine release were noted in 1.8% (5/274) of subjects. The most common laboratory Al? was elevated liver transaminase levels, which occurred in 14 (5.8%) of 243 subjects. These elevations were dose re-
lated, given that 13 of these 14 subjects were receiving the highest doses of caspofungin (>50 mg). The elevations in liver enzymes were generally reversible on cessation of caspofungin and did not exceed 4 times the upper limit of normal. A >1.5fold increase in serum creatinine levels from baseline was seen in 3.2% (5056) of subjects. The overall incidence of drugrelated AEs was 24.8% (68/274) in the clinical pharmacologic studies.44 In a multicenter, noncomparative study, caspofungin was generally well tolerated in 69 patients with invasive aspergillosis who received a loading dose of caspofungin 70 mg IV followed by a maintenance dose of 50 mg/d for 1 to 160 days.18*44,61 The most commonly reported drug-related AEs included dermatologic reactions (rash, erythema, and flushing [3 AEs]), nausea (2), fever (2), infusion-related reactions (2), and headache (1). Laboratory abnormalities related to caspofungin included proteinuria (3 abnormal results) and eosinophilia (2). Serious drug-related AEs leading to discontinuation of caspofungin included development of pulmonary infiltrates in a 38-year-old patient and hypercalcemia (12.8 mg/dL) in a 23year-old patient, both following allogeneic bone marrow transplantation. In general, AEs associated with caspofungin therapy appeared to be uncommon (~5%) and mild in patients with invasive aspergillosis. A total of 263 patients with Candida infection received caspofungin 35 mg (n = 34), 50 mg (n = 164), or 70 mg (n = 65) daily for 7 to 21 days in 3 multicenter, randomized, double-blind trials.44*58-60 Tolerability information was available only for patients who received caspofungin 50 or 70 mg/d. In pooled data from the 3 trials, the most frequently reported AEs were infusion-related phlebitis (17.5%;
40/229), fever (16.2%; 37/229), headache (8.3%; 19/229), nausea (3.9%; 9/229), pain (2.8%; 4/145), rash (2.8%; 4/145), chills (2.1%; 3/145), anemia (2.1%; 3/145), pruritus (2.1%; 3/145), paresthesia (2.1%; 3/145), vomiting (1.7%; 4/229), and erythema (1.4%; 2/145). Laboratory abnormalities (increase/decrease beyond upper/lower limit of normal for each test) included elevated alanine aminotransferase (ALT) levels in 10.5% (24/228) of patients, elevated aspartate aminotransferase levels in 12.3% (28/228), decreased hemoglobin count in 9.6% (22/228), decreased hematocrit in 8.3% (19/228), hypoalbuminemia in 7.5% (17/228), hypokalemia in 5.7% (13/228), decreased white blood cell count in 5.7% (13/228), thrombocytopenia in 3.1% (7/228), and eosinophilia in 3.1% (7/228). As expected, patients receiving caspofungin had fewer infusion-related AEs such as chills and fever compared with those receiving amphotericin B (2.1% and 16.1%, respectively, vs 75.3% and 69.7%), fewer increases in serum creatinine (0.4% vs 28.1%), and fewer decreases in hemoglobin count (13.5% vs 37.1%). Of interest, patients receiving caspofungin had a higher incidence of rash (6.9% vs 3.4%), eosinophilia (3.1% vs l.l%), and pruritus (2.1% vs 0.0%) compared with those receiving amphotericin B. Serious drugrelated AEs leading to discontinuation of caspofungin were infrequent (1.3%) and occurred at a rate similar to that seen with amphotericin B (2.2%). Data from 1 trial showed a similar incidence of clinical AEs with caspofungin and fluconazole.44,60 However, information on the occurrence of drug-related abnormalities in laboratory values such as liver enzymes and eosinophil count was not provided. Overall, AEs related to caspofungin were gener-
E.A. STONE ET AL.
ally mild and did not require hospitalization or discontinuation of therapy in patients with Can&da [email protected]
*58a AE data from the 3 clinical trials of caspofungin in candidiasis are summarized in Table IV. Elevations in liver enzymes were noted in 2 clinical studies involving healthy subjects who received caspofungin and cyclosporine. In 1 of these studies, in which subjects were administered 2 doses of cyclosporine 3 mg/kg 12 hours apart on day 10, transient elevations in ALT levels to 2 to 3 times the upper limit of normal were seen in 3 of 4 subjects who received caspofungin 70 mgld on days 1 through 10 and in 2 of 8 subjects who received caspofungin 35 mg/d on days 1 through 10. In the other study, transient increases in ALT levels of ~2 times the upper limit of normal were seen in 2 of 8 subjects who re-
ceived caspofungin 70 mgld on days 3 through 13 and cyclosporine 4 mg/kg on days 1 and 12. In both studies, cyclosporine increased the AUC of caspofungin by -35%. Despite the fact that the dose of caspofungin was 70 rather than 50 mgld, concurrent use of caspofungin and cyclosporine is not recommended.18 There are limited safety and tolerability data on the use of caspofungin for >2 weeks. Nevertheless, data from 68 patients who received caspofungin for 15 to 60 days and 12 patients who received caspofungin for 61 to 162 days suggest that caspofungin may be well tolerated over the longer terrn.18 Studies in pregnant women are not available. Caspofungin has been shown to be embryotoxic in animal studies, producing incomplete ossification of the skull and torso and an increased incidence of cervi-
Table IV. Incidence of most commonly reported (>l%) clinical adverse events in comparative trials of caspofungin in the treatment of Candida [email protected]
,5M* Combined Phase II Trials,58*59% of Events Caspofungin Adverse Event Fever Phlebitis, infusion related Headache Nausea Chills Pain Rash Paresthesia Vomiting Erythema Tachypnea
50 mg (n = 80)
70 mg (n = 65)
Amphotericin B 0.5 mg/kg (n = 89)
21.3 11.3 11.3 2.5 2.5 1.3 1.3 1.3 1.3 1.3 1.3
26.2 13.8 7.7 3.1 1.5 4.6 4.6 3.1 3.1 1.5 0.0
69.7 22.5 19.1 21.3 75.3 5.6 3.4 1.1 13.5 7.9 4.5
Phase III Trial,6o % of Events Caspofungin 50 mg (n = 83) 3.6 15.7 6.0 6.0 <2 <2 <2 <2 <2 <2 <2
Fluconazole 200 mg (n = 93) <2 17.2 <2 6.5 <2 <2 <2 <2 3.2 <2 <2
‘Statistical analysis of these data were not provided.
cal ribs. Consequently, caspofungin is designated a Pregnancy Category C drug (animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans). Although the distribution of caspofungin and its metabolites in human milk is not known, the drug is excreted in the milk of animals at concentrations similar to those in maternal plasma.‘* The use of caspofungin in pregnant women and nursing mothers should be avoided when clinically possible.
DRUG INTERACTIONS Studies have shown that caspofungin is slowly metabolized by hydrolysis and N-acetylation in the liver.44945In vitro and in vivo, caspofungin may affect hepatic cytochrome P450 (CYP450) activities, but not to a meaningful degree.18y43 Caspofungin is a poor substrate for CYP450 enzymes and is not a substrate for P-glycoprotein, which mediates drug efflux from a variety of cells.‘* Thus, it is unlikely that caspofungin would interact with other drugs through induction or inhibition of P-glycoprotein activities. In a lCday, randomized, Phase I study, Stone et al43 studied the potential for interaction between caspofungin and itraconazole, a strong inhibitor of the CYP3A4 isozyme. Twenty-four healthy men were randomized to receive oral itraconazole 200 mg/d (n = 8), caspofungin 70 mg IV on day 1 followed by 50 mg/d (n = 8), or oral itraconazole 200 mg/d plus caspofungin 70 mg IV followed by 50 mg/d (n = 8) for a total of 14 days. Concentrations of caspofungin and itraconazole were not significantly altered by coadministration, with a 3% increase in concentration for caspofungin (90% CI, -15 to 25) and a 3% reduction for itraconazole (90% CI,
-24 to 24), compared with controls (90% CIs not provided). Caspofungin does not appear to be subject to drug interactions as a result of inhibition of CYP3A4. Druginteraction studies of the coadministration of caspofungin and amphotericin B or mycophenolate in healthy subjects produced similar findings.‘* Seventeen healthy subjects participated in a 2-phase, randomized, placebocontrolled evaluation of the potential for interaction between caspofungin and tacrolimus.71 In the control phase of the study, subjects were randomized to receive 2 oral doses of tacrolimus 0.1 mg/kg (n = 12) or placebo (n = 5) 12 hours apart. In the drug-interaction phase, subjects received the same treatment after 10 days of daily administration of caspofungin 70 mg IV Based on analyses of pharmacokinetic data obtained on days 9 and 10, concentrations of caspofungin were not altered by the presence of tacrolimus (90% CI, -4 to 4). In contrast, concentrations of tacrolimus were reduced by 20% (90% CI, -28 to -11). Thus, tacrolimus concentrations should be closely monitored and the dose adjusted when caspofungin is given to a patient who has been receiving a stable dose of tacrolimus. Caspofungin may affect the CYP450 system. In 2 studies, cyclosporine increased the AUC of caspofungin by -35%.‘* The high incidence of elevations in transaminase levels precludes concurrent administration of cyclosporine and caspofungin. Results of regression analyses of pharmacokinetic data from an unspecified small number of patients suggest that concentrations of caspofungin may be reduced by coadministration of such inducers or mixed inducer/inhibitors of CYP450 isozymes as efavirenz, nelfinavir, nevirapine, phenytoin, rifampin, dex-
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amethasone, and carbamazepine. l8 Monitoring of caspofungin levels or a dose increase should be considered in patients who are not responding clinically while receiving these medications concomitantly. DOSAGE AND ADMINISTRATION In the United States, caspofungin is available in 50- and 70-mg vials. The recommended adult dosage is 70 mg IV on day 1 followed by 50 mg/d thereafter. The duration of treatment depends on the severity of underlying disease, recovery from immunosuppression, and clinical response. l8 Dose adjustment is not deemed necessary in patients with renal insufficiency or mild hepatic dysfunction.‘8*46In patients with moderate hepatic insuffciency, however, the maintenance dose should be reduced to 35 mg/d after a 70mg loading dose on the first day.46 No pharmacokinetic data or clinical experience is available in patients with severe hepatic insufficiency. Use of caspofungin in such patients is, therefore, not recommended.18 No adjustment of caspofungin dose is necessary based on age, sex, or race. 18*42*43 Caspofungin should be infused slowly over 1 hour and is not compatible with any diluent that contains dextrose.18 PHARMACOECONOMIC CONSIDERATIONS A review of the published literature identified no cost-effectiveness studies of caspofungin. Nevertheless, the average wholesale price (AWP) of a 50-mg vial of caspofungin is $360.00, and the AWP of a 70-mg vial is $463.75. In comparison, the AWP for a 50-mg vial of standard amphotericin B marketed as Fungizone (Bristol-Myers Squibb Company, Prince-
ton, NJ) is $17.84 (acquisition cost of 1.4 vials [dosage of 1 mg/kg in a patient weighing 70 kg], $24.98/d), and the AWP for a 50-mg vial of standard amphotericin B marketed as Amphocin (Pharmacia Corporation, Peapack, NJ) is $36.26 ($50.76/d). The AWP for a 50-mg vial of amphotericin B lipid complex (Abelcet, The Liposome Company, Inc, Princeton, NJ) is $134.66 (acquisition cost of 7 vials [dosage of 5 mg/kg in a patient weighing 70 kg], $942.62/d). The AWP for a 50-mg vial of the liposomal form of amphotericin B marketed as AmBisome for Injection (Fujisawa Healthcare Inc, Deerfield, Ill) is $188.40 (acquisition cost of 7 vials [dosage of 5 mg/kg], $1318.80/d).72 Therefore, based on acquisition cost alone, it appears that when clinically appropriate, treatment with standard amphotericin B is more cost-effective than treatment with caspofungin. The other formulations of amphotericin B, however, appear to be more costly. Nevertheless, pharmacoeconomic studies are needed that look at factors other than acquisition cost, including the cost of laboratory tests, IV bags and tubing, AEs, professional costs involved in administering the medication, and cost savings involved in curing a patient who might otherwise not be cured. CONCLUSIONS Limited data on caspofungin have been published in peer-reviewed journals. Much of the available information on the efficacy and tolerability of caspofungin appears only in abstracts, which often lack details of inclusion and exclusion criteria or statistical analyses of the results. Nevertheless, the available data suggest that caspofungin is generally well tolerated and efficacious in the treatment of inva371
sive aspergillosis and candidiasis. Because
of caspofungin’s unique mechanism of action-it targets p-( 1,3)-glucan, a structural component of the fungal cell wallit is hoped that the drug will have the same deleterious effect on fungi as the penicillins do on bacteria.14 In addition, because of this unique mechanism of action, cross-resistance with other currently available antifungal agents is unlikely to occur. When caspofungin is combined with other antifungal agents such as fluconazole or amphotericin B, synergistic or additive effects against a variety of clinically important fungi have been demonstrated in vitro and in vivo. The usefulness of combining caspofungin with other antifungal agents in clinical practice is yet to be evaluated. With the increasing incidence of difficult-to-treat and lifethreatening fungal infections such as invasive aspergillosis, caspofungin promises to be a useful addition to the antifungal armamentarium. REFERENCES Henderson VJ, Hirvela ER. Emerging and reemerging microbial threats. Nosocomial fungal infections. Arch Surg. 1996;131: 330-337.
4. Georgopapadakou NH, Tkacz JS. The fungal cell wall as a drug target. Trends Microbiol. 1995;3:98-104. 5. Pfaller MA, Jones RN, Doem GV, et al,
for the SENTRY Participant Group (Europe). International surveillance of blood stream infections due to Cundida species in the European SENTRY Program: Species distribution and antifungal susceptibility including the investigational triazole and echinocandin agents. Diagn Microbial Infect Dis. 1999;35:19-25. 6. Kontoyiannis DP A clinical perspective for
the management of invasive fungal infections: Focus on IDSA guidelines. Infectious Diseases Society of America. Pharmacotherupy. 2001;21(Suppl):175S-187s. 7. Barrett-Bee
K, Dixon G. Ergosterol biosynthesis inhibition: A target for antifungal agents. Acta Biochim Pol. 1995;42: 465-479.
8. Onishi J, Meinz M, Thompson J, et al.
Discovery of novel antifungal (1,3)-p-~glucan synthase inhibitors. Anrimicrob Agents Chemothel: 2000;44:368-377. 9. Manavathu
EK, Alangaden GJ, Chandrasekar PH. In-vitro isolation and antifungal susceptibility of amphotericin B-resistant mutants of Aspergillus fumigatus. J Antimicrob 615-619.
Edmond MB, Wallace SE, McClish DK, et al. Nosocomial bloodstream infections in United States hospitals: A three-year analysis. Clin Infect Dis. 1999;29:239-244.
10. Manavathu EK, Cutright JL, Chandrasekar PH. Organism-dependent fungicidal activities of azoles. Anrimicrob Agents Chemorhel: 1998;42:3018-3021.
11. Ernst EJ. Investigational antifungal agents. Richards MJ, Edwards JR, Culver DH, Gaynes RP. Nosocomial infections in medical intensive care units in the United States. National Nosocomial Infections Surveillance System. Crit Cure Med. 1999; 27:887-892.
12. Abruzzo GK, Gill CJ, Flattery AM, et al. Efficacy of the echinocandin caspofungin against disseminated aspergillosis and
E.A. STONE ET AL.
candidiasis in cyclophosphamide-induced immunosuppressed mice. Antimicrob Agents Chemother 2000;44:23 10-23 18. 13. Marco F, Pfaller MA, Messer SA, Jones RN. Activity of MK-0991 (L-743,872), a new echinocandin, compared with those of LY303366 and four other antifungal agents tested against blood stream isolates of Candida spp. Diagn Microbial Infect Dis. 1998;32:33-37.
14. Current WL. Fungal cell wall biosynthesis: Penicillins for fungi. In: Program and abstracts of the 35th Annual Meeting of the Infectious Diseases Society of America; September 13-16, 1997; San Francisco, Calif.
21 Nelson PW, Lozano-Chiu M, Rex JH. In vitro growth-inhibitory activity of pneumocandins L-733,560 and L-743,872 against putatively amphotericin B- and fluconazole-resistant Candida isolates: Influence of assay conditions. J Med Vet Mycol. 1997;35:285-287.
22. National Committee for Clinical Laboratory Standards. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: Approved Standard (M27-A). Wayne, Pa: NCCLS; 1997.
23. National Committee for Clinical Laboratory Standards. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Conidium-Forming Filamentous Fungi: Proposed Standard (M38-P).
Wayne, Pa: NCCLS; 1998. 15. Hector RF. Compounds active against cell walls of medically important fungi. Clin Microbial Rev. 1993;6: l-21.
16. Gonzalez GM, Tijerina R, Najvar LK, et al. Correlation between antifungal susceptibilities of Coccidioides immitis in vitro and antifungal treatment with caspofungin in a mouse model. Antimicrob Agents Chemother
17. Graybill JR, Najvar LK, Montalbo EM, et al. Treatment of histoplasmosis with MK-991 (L-743,872). Antimicrob Agents Chemother
18. [email protected]
[package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2001. 19. Hajdu R, Thompson R, Sundelof JG, et al. Preliminary animal pharmacokinetics of the parenteral antifungal agent MK-0991 (L-743,872). Antimictob Agents Chemothe,: 1997;41:2339-2344.
20. Kurtz MB, Douglas CM. Lipopeptide inhibitors of fungal glucan synthase. J Med Vet Mycol. 1997;35:79-86.
24. Lozano-Chiu M, Nelson PW, Paetznick VL, Rex JH. Disk diffusion method for determining susceptibilities of Candida spp. to MK-099 1. J Clin Microbial. 1999; 37:1625-1627.
25. Espinel-Ingroff A. E-test for testing the susceptibilities of Aspergillus species to caspofungin: A comparison with NCCLS M38-P and other testing parameters. In: Program and abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2001; Chicago, Ill. Abstract 580. 26. Brummer E, Chauhan SD, Stevens DA. Collaboration of human phagocytes with LY 303366 for antifungal activity against Aspergillusfumigatus. JAntimictob ther 1999;43:491-496.
27. Espinel-Ingroff A. Comparison of in vitro activities of the new triazole SCH56592 and the echinocandins MK-0991 (L743,872) and LY303366 against opportunistic filamentous and dimorphic fungi and yeasts. J Clin Microbial. 1998;36: 2950-2956.
28. Vazquez JA, Lynch M, Boikov D, Sobel JD. In vitro activity of a new pneumocandin antifungal, L-743,872, against azolesusceptible and -resistant Cundidu species. Antimicrob Agents Chemothel: 1997;41: 1612-1614. 29. Ernst EJ, Klepser ME, Ernst ME, et al. In vitro pharmacodynamic properties of MK-099 1 determined by time-kill methods. Diagn Micmbiol Infect Dis. 1999;33:75-80. 30. Ernst EJ, Klepser ME, Pfaller MA. Postantifungal effects of echinocandin, azole, and polyene antifungal agents against Candida albicans and Cryptococcus neofor-mans. Antimicrob Agents Chemother. 2000;44:1108-1111. 31 Pfaller MA, Messer SA, Gee S, et al. In vitro susceptibilities of Candida dubliniensis isolates tested against the new triazole and echinocandin antifungal agents. J Clin Microbial. 1999;37:870-872. 32. Barry AL, Pfaller MA, Brown SD, et al. Quality control limits for broth microdilution susceptibility tests of ten antifungal agents. J Clin Microbial, 2000;38:34573459. 33. Bartizal K, Gill CJ, Abruzzo GK, et al. In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872). Antimicmb Agents Chemother 1997;41:2326-2332.
fungin (MK-0991) against refractory clinical isolates of Candida and Aspergillus species. In: Program and abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2001; Chicago, Ill. Abstract 113. 36. Arikan S, Lozano-Chiu M, Paetznick V, Rex JH. In vitro susceptibility testing methods for caspofungin against Aspergillus and Fusarium isolates. Antimicrab Agents Chemother: 2001;45:327-330. 37. Flattery AM, Hicks PS, Wilcox A, Rosen H. In vitro susceptibility of clinical trial isolates of Aspergillus spp. to the echinocandin antifungal caspofungin (CancidasTU, MK-0991). In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto, Ont, Canada. Abstract 936. 38. Del Poeta M, Schell WA, Perfect JR. In vitro antifungal activity of pneumocandin L-743,872 against a variety of clinically important molds. Antimicrob Agents Chemother 1997;41:1835-1836. 39. Chiller T, Farrokhshad K, Brummer E, Stevens DA. Influence of human sera on the in vitro activity of the echinocandin caspofungin (MK-0991) against Aspergillus fumigatus. Antimicrob Agents Chemother 2000;44:3302-3305.
34. Bachmann SP, Perea S, Kirkpatrick ER, et al. In vitro activity of Cancidas (MK-099 1) against Cundida albicnns clinical isolates displaying different mechanisms of azole resistance. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto, Ont, Canada. Abstract 196.
40. Stone JA, Holland SD, Ju WD, et al. Single- and multiple-dose pharmacokinetics of the antifungal agent MK-0991 in man. In: Program and abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 24-27, 1998; San Diego, Calif. Abstract A-l 17.
35. Sutton DA, Rinaldi MG, Fothergill AW. In vitro activity of the echinocandin caspo-
41. Keating GM, Jarvis B. Caspofungin. Drugs. 2001;61:1121-1129.
E.A. STONE ET AL.
42. Stone JA, Ballow CH, Holland SD, et al. Single dose caspoftmgin pharmacokinetits in healthy elderly subjects. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto, Gnt, Canada. Abstract 853. 43. Stone JA, McCrea JB, Wickersham PJ, et al. A phase I study of caspofungin evaluating the potential for drug interactions with itraconazole, the effect of gender and the use of a loading dose regimen. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto, Ont, Canada. Abstract 854.
Chemotherapy; December 16-19, 2001; Chicago, Ill. Abstract 105. 48. Chiller T, Farrokhshad
K, Brummer E, Stevens DA. The interaction of human monocytes, monocyte-derived macrophages, and polymorphonuclear neutrophils with caspofungin (MK-0991), an echinocandin, for antifungal activity against Aspergillus fumigatus. Diagn Microbiol Infect Dis. 2001;39:99-103.
49. Abruzzo GK, Flattery AM, Gill CJ, et al.
Evaluation of the echinocandin antifungal MK-0991 (L-743,792): Efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis. Antimicrob Agents Chemothet 1997;41:2333-2338.
44 US Food and Drug Administration. Cancidas7M(caspofungin acetate for intravenous injection), Merck Corporation, NDA 21-227. Background document for Antiviral Drug Products Advisory Committee Meeting, January 10, 2001. Available at: http://www.fda.govlohrms/dockets/ ac/cderOl .htm. Accessed May 10, 2001.
50. Bartizal K, Smith JG, Gill CJ, et al. Pre-
45. Balani SK, Xu X, Arison BH, et al. Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine. Drug Metab Dispos. 2000;28:
51. Smith JG, Abruzzo GK, Gill CJ, et al. Evaluation of pneumocandin L-743872 in neutropenic mouse models of disseminated candidiasis and aspergillosis. In: Program and abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 15-18, 1996; New Orleans, La. Abstract F-041.
46. Stone JA, Holland S, Li S, et al. Effect of hepatic insufficiency on the pharmacokinetics of caspofungin. In: Program and abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19,200l; Chicago, Ill. Abstract 14. 47. Ramesh MS, Baskaran I, Ganesan LT, et al. Postantifungal effect of older and newer antifungal agents on Aspergillus fumigatus and Candida albicans. In: Program and abstracts of the 41st Interscience Conference on Antimicrobial Agents and
clinical efficacy of MK-0991 in pancytopenic mouse models of disseminated candidiasis and aspergillosis. In: Program and abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 28-Gctober 1, 1997; Toronto, Ont, Canada. Abstract F-80.
JR, Najvar LK, Luther MF, Fothergill AW. Treatment of murine disseminated candidiasis with L-743,872.
Antimicrob Agents Chemother. 1997;41: 1775-1777. 53. Graybill
JR, Bocanegra R, Luther M, et al. Treatment of murine Candida krusei or Candida glabrata infection with L-743,872. Antimicrob Agents Chemothe,: 1997;41:1937-1939.
CLINICAL [email protected]
54. Bernard EM, Ishimaru T, Armstrong D. Low doses of the pneumocandin L-743,872 are effective for prevention and treatment in an animal model of pulmonary aspergillosis. In: Program and abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 15-18, 1996; New Orleans, La. Abstract F-039. 55. Douglas CM, Bowman JC, Abruzzo GK, et al. The glucan synthesis inhibitor caspofungin acetate (Cancidas”, MK-0991, L743,792) kills Aspergillus fumigatus hyphal tips in vitro and is efficacious against disseminated aspergillosis in cyclophosphamide-induced chronically leukopenic mice. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20,200O; Toronto, Ont, Canada. Abstract 1683. 56. Powles MA, Liberator P, Anderson J, et al. Efficacy of MK-991 (L-743,792), a semisynthetic pneumocandin, in murine models of Pneumocystis carinii. Antimicrob Agents Chemothel: 1998;42:1985-1989. 57. Kohler S, Wheat LJ, Connolly P, et al. Comparison of the echinocandin caspofungin with amphotericin B for treatment of histoplasmosis following pulmonary challenge in a murine model. Antimicrob Agents Chemothel: 2000;44: 1850-l 854. 58. Villanueva A, Arathoon EG, Gotuzzo E, et al. A randomized double-blind study of caspofungin versus amphotericin for the treatment of candidal esophagitis. Clin Infect Dis. 2001;33:1529-1535. 59. Arathoon E, Gotuzzo A, Noriega L, et al. A randomized double-blind multicenter trial of MK-0991, an echinocandin antifungal agent, vs amphotericin B for the treatment of oropharyngeal and esophageal candidiasis in adults. In: Program and
abstracts of the 36th Annual Meeting of the Infectious Diseases Society of America; November 12-15, 1998; Denver, Colo. Abstract 99. 60. Villanueva A, Gotuzzo E, Arathoon E, et al. The efficacy, safety and tolerability of caspofungin vs fluconazole in the treatment of esophageal candidiasis. In: Program and abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2001; Chicago, 111.Abstract 675. 61. Maertens J, Raad I, Sable CA, et al. Multicenter noncomparative study to evaluate safety and efficacy of caspofungin in adults with invasive aspergillosis refractory or intolerant to amphotericin B, amphotericin B lipid formulations or azoles. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000, Toronto, Ont, Canada. Abstract 1103. 62. Denning DW, Lee JY, Hostetler JS, et al. NIAID Mycoses Study Group multicenter trial of oral itraconazole therapy for invasive aspergillosis. Am J Med. 1994;97: 135-144. 63. Perea S, Gonzalez G, Fothergill AW, et al. In vitro interaction of Cancidas with voriconazole against clinical isolates of Aspergillus spp. In: Program and abstracts of the 1Olst General Meeting of the American Society for Microbiology; May 20-24, 2001; Orlando, Fla. 64. Arikan S, Lozano-Chiu M, Paetznick V, Rex JH. In vitro synergy studies with caspofungin and amphotericin B against Aspergillus and Fusarium. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto, Ont, Canada. Abstract 932.
E.A. STONE ET AL.
65. Manavathu EK, Krishnan S, Cutright JL, Chandrasekar PH. A comparative study of the in vitro susceptibility of Aspergillus fumigatus to antifungal agents individually and in combinations by the fractional inhibitory concentration index, tetrazolium reduction, and radiometric assays. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto, Ont, Canada. Abstract 93 1. 66. Manavathu EK, Ganesan LT, Cutright JL, Chandrasekar PH. In vitro antifungal activity of voriconazole in two-drug combination with micafungin, caspofungin and amphotericin B. In: Program and abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2001; Chicago, Ill. Abstract 125. 67. Franzot SP, Casadevall A. Pneumocandin L-743,872 enhances the activities of amphotericin B and fluconazole against Cryptococcus neoformans in vitro. Antimicrob Agents Chemothe,: 1997;41:331-336.
68. Flattery AM, Bartizal K, Gill CJ, et al. Preclinical efficacy of MK-0991 in combination with amphotericin B or fluconazole in mouse models of disseminated aspergillosis candidiasis and cryptococcosis. In: Program and abstracts of the 38th Interscience
Conference on Antimicrobial Agents and Chemotherapy; September 24-27, 1998; San Diego, Calif. Abstract J-61. 69. Douglas CM, Bowman JC, Bartizal KF, et al. Use of a novel real time PCR assay to demonstrate efficacy of caspofungin alone and in combination with amphotericin B in reducing Aspergillus fumigatus tissue burden in chronically immunosuppressed mice with disseminated infection. In: Program and abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 200 1; Chicago, Ill. Abstract 1836. 70. Osherov N, May GS, Albert A, Kontoyiannis DP. Overexpression of Sbe2p, a Golgi protein involved in cell wall formation, confers resistance to caspofungin in Saccharomyces cerevisiae. In: Program and abstracts of the 4 1st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2001; Chicago, Ill. Abstract 1843. 71. Stone J, Holland S, Wickersham P, et al. Drug interaction between caspofungin and tacrolimus. In: Program and abstracts of the 4 1st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2001; Chicago, Ill. Abstract 13. 72. Drug pricing. Available at: http://www. physician.pdr.net/physician/static/htm? path=controlled/searchredbook.htm. Accessed September 11, 2001.
Address correspondence to: Horatio B. Fung, PharmD, BCPS, Critical Care Center, VA Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468. E-mail: [email protected]