Pharmacokinetics and Metabolism
Administration of single dosages of 5–100 mg of caspofungin to healthy volunteers demonstrated linear pharmacokinetics with a beta half-life of 9–10 h and an average plasma clear- ance of 10–12 mL/min (Table 4). At higher dosages, an addi- tional, longer gamma half-life of 40–50 h was evident.
Multiple dose studies at dosages of 15, 35, and 70 mg daily for 2 or 3 weeks revealed dose-dependent accumulation of drug in plasma of up to 50%. A loading dose of 70 mg, followed by 50 mg daily, maintained plasma concentrations above 1 mg/mL from day 1 onward; this is above the reported MIC values for most susceptible fungi [117]. Investigation of higher dosages revealed constant pharmacokinetics after single doses of 150 and 210 mg and following 14-days of 100 mg, respectively [25].
Tissue distribution, particularly to the liver through specific uptake transporters, is the predominant mechanism influencing clearance of caspofungin: Mass balance studies demonstrate that approximately 92% of the administered radioactivity distributes to tissues at 36–48 h [6, 48, 118, 119]. Tissue distribution studies in mice revealed preferen- tial exposure of liver, kidney, and large intestine, whereas exposure for small intestine, lung and spleen was equivalent to that for plasma. Organs with a lower level of exposure included the heart, thigh, and brain [120]. Excretion of caspofungin in humans is slow, with 41% and 35% of the dosed radioactivity being recovered in urine and feces, respectively, over 27 days. Caspofungin is slowly metabo- lized by peptide hydrolysis and N-acetylation; only a small fraction of caspofungin (~1.4% of dose) is excreted unchanged in urine [6, 7, 118–120].
Dosage adjustment is not necessary for patients with impaired renal function and end-stage renal insufficiency.
While patients with mild hepatic insufficiency do not require a dosage adjustment, a dosage of 35 mg daily after the initial 70 mg loading dose is recommended for patients with mod- erate hepatic insufficiency (Child-Pugh score 7–9) due to an average increase of 76% in AUC. No clinical experience exists in patients with severe hepatic insufficiency (Child- Pugh score >9). Dosage adjustment based on weight, age, gender, serum albumin concentration or on the basis of race is not required [21, 25, 121].
Table 4 Single-dose caspofungin pharmacokinetics in pediatric and adult patients
Dosage
Premature neonates
Infants and toddlers (3–24 months)
Children (2–11 years)
Adolescents
(12–17 years) Adults
25 mg/m2 50 mg/m2 50 mg/m2 50 mg/m2 50 mg
AUC 0–24 h (mg·h/mL) n/a 120 96.4 77.6 70.6
C1 (mg/mL) 10.2 17.46 13.9 8.95 7.67
C24 (ug/mL) 2.3 1.34 1.09 1.26 1.35
T ½ beta (h) n/a 7.79 7.6 10.51 11.7
CL (mL/min/m2) n/a 6.05 7.78 6.3 6.07
Least square means are reported for AUC, C1 (Cmax), and C24 (Cmin), and harmonic means for t ½ beta. Data were obtained in groups of 6–10 pediatric patients and compared to those obtained in 32 adult patients with mucosal candidiasis
Compiled from Refs. [8, 114–116]
n/a, data not available from the publication
102 A.H. Groll et al.
In pediatric patients 2–17 years old, 50 mg/m2/day provided similar or slightly higher exposure relative to adults dosed with 50 mg daily [8] and was selected for further study.
While this dosage was also found to be appropriate in infants 3 months to 2 years of age [114], limited data indicate that a dosage of 25 mg/m2 daily is indicated to achieve comparable exposures in premature neonates (Table 4) [115].
Clinical Efficacy
The clinical efficacy of caspofungin has been investigated for oropharyngeal and esophageal candidiasis, invasive can- didiasis, invasive aspergillosis, and for empiric treatment of persistently febrile neutropenic patients. In a multicenter, randomized, double blind study comparing caspofungin (50 mg daily) and fluconazole (200 mg daily) for treatment of esophageal candidiasis in 177 mostly HIV-infected patients, response rates as assessed by the combined response of symptom resolution and significant endoscopic improve- ment 5–7 days after discontinuation of treatment were simi- lar for both cohorts (81% vs 85%) [116]. These favorable data were supported by two further, randomized, double- blind, multicenter trials that compared caspofungin with conventional amphotericin B (0.5 mg/kg/day) [122, 123] and a retrospective case series of patients with esophageal can- didiasis resistant to fluconazole [124].
The efficacy of caspofungin as primary treatment of invasive Candida infections has been investigated in a multicenter, randomized, double-blind phase III clinical trial comparing caspofungin, 50 mg daily after a loading dose of 70 mg, to amphotericin B deoxycholate,0.6–1 mg/kg daily. Patients were treated for 14 days after the last posi- tive culture, but could be switched to fluconazole after 10 days of intravenous therapy. Success required both symptom resolution and microbiological clearance. At study entry, 13% of patients were neutropenic; the majority had candidemia (83%). The predominant organism was C. albicans (45%). Among patients receiving at least one dose of study drug, 73% (80/109) of the caspofungin cohort and 61.7% (71/115) of the amphotericin B cohort were classified as therapeutic success at the end of intravenous therapy. There was no difference in relapse or survival at 6–8 weeks follow up [125].
The clinical usefulness of caspofungin for treatment of patients with invasive candidiasis is further corroborated by a randomized, double-blind phase III trial comparing mica- fungin 100 mg daily and micafungin 150 mg daily with the standard dosage of caspofungin, 50 mg daily, in a total of 595 adults. This study showed similar success rates at the end of therapy (76%, 71%, and 72%, respectively) and no signifi- cant differences in time to culture negativity, mortality, relapses
and emerging infections [126]. In a more recent randomized phase III trial, high-dose caspofungin, 150 mg daily, was compared to treatment with the standard dose of 50 mg daily in a total of 204 patients. No safety concerns were found for the higher dose of caspofungin; however, no significant ben- efit in regards to clinical response or mortality was found [127]. Among 48 patients with non-fungemic invasive can- didiasis and chronic disseminated candidiasis who received caspofungin primary or salvage monotherapy at the standard dosage had an overall success rate at the end of therapy of 81% [128]. A review of 27 neutropenic patients showed a favorable response in 17 of 27 patients (63%) [129].
The clinical efficacy of caspofungin, 50 mg daily after a loading dose of 70 mg, against invasive aspergillosis has been studied in a multicenter, open-label, noncomparative phase II trial in patients with definite or probable invasive aspergillosis refractory to or intolerant of standard therapies [130]. A total of 83 patients received caspofungin for a mean duration of 28 days (range, 1–162 days). The majority had hematological malignancies or had undergone bone marrow transplantation, and most had refractory Aspergillus infec- tions. Complete or partial responses at end of therapy were achieved in 44.6% of patients receiving at least one dose of caspofungin; in patients receiving the drug for ³7 days, a favorable response was seen in 56%.
Caspofungin has also been explored as first line treatment of invasive aspergillosis in two phase II pilot trials initiated by the EORTC Infectious Diseases Group. In 61 mostly neutropenic patients with hematological malignancies or undergoing autolo- gous stem cell transplantation, 20 (31%) patients had a com- plete and partial response at end of treatment, and 9 (15%) achieved stabilization. The 12-week survival rate was 53%
(32/60) [131]. Among 24 eligible allogeneic stem cell transplant recipients, of whom 12 were neutropenic at baseline, 10 (44%) had a complete or partial response at end of treatment, and one (4%) had stable disease. Survival at day 84 was 48% [132].
Retrospective series suggest a potential usefulness of com- bination therapies of caspofungin with either voriconazole [133] or amphotericin B [134]. In a multicenter, prospective noncomparative study of caspofungin combined with other antifungal agents, including 53 adults with invasive aspergil- losis refractory or intolerant to prior therapy, the overall success rate at end of therapy was 55%. Success in patients with >7 days of combination therapy was 66% (27/41) [135].
In a prospective, randomized open pilot study in 30 patients with proven or probable invasive aspergillosis, combination of liposomal amphotericin B 3 mg/kg daily and caspofungin was tested against monotherapy with high-dose amphotericin B 10 mg/kg daily; while complete or partial response rates were higher in the combination group, survival rates at 12 weeks after inclusion were 100% and 80%, respectively [136].
Finally, in a single center retrospective observational study including 41 patients with biopsy-proven rhino-orbital-cerebral
103 Echinocandins
mucormycosis identified over 12 years, treatment with polyene-caspofungin therapy had superior success compared with patients treated with polyene monotherapy. In multi- variate analysis, only receipt of combination therapy was significantly associated with improved outcomes [137].
In a randomized, double-blind, multinational trial of empir- ical antifungal therapy in febrile neutropenic patients, the overall success rate of caspofungin treatment was non-inferior to that with liposomal amphotericin B 3 mg/kg daily [138].
However, among patients with baseline fungal infections, a higher proportion of those treated with caspofungin had a suc- cessful outcome (51.9% vs 25.9%, P = 0.04). Similarly, the proportion of patients who survived at least 7 days after ther- apy was greater in the caspofungin group (92.6% vs 89.2%, P = 0.05) and premature study discontinuation occurred less often in the caspofungin group (10.3% vs 14.5%, P = 0.03).
Randomized data also indicate that caspofungin may provide similar protection as itraconazole against invasive fungal infections when given as prophylaxis in patients undergoing remission induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome [139].
For children, efficacy data have been collected for caspo- fungin, 50 mg/m2 daily adfter a loading dose of 70 mg/m2,, in the setting of fever and neutropenia and in patients with doc- umented infections. As compared to liposomal amphotericin B, 3 mg/kg daily, caspofungin was equaly effective as empirical therapy but better tolerated [140]. Among 48 pediatric patients with proven or probable invasive fungal infections, success at end of therapy was achieved in 5 of 10 patients with invasive aspergillosis, and 30 of 37 with invasive can- didiasis [141]. Limited data support the use of caspofungin for treatment of neonatal candidemia [142–144]. Among 36 neonates, most of whom were premature, with candidemia refractory to therapy with amphotericin B, treatment with caspofungin at 2 mg/kg daily (mean: 23 mg/m2), 35 (97%) had a successful outcome [144].
Safety and Tolerance
Caspofungin is generally well tolerated: In the seven randomized, comparative clinical trials discussed in detail earlier, less than 5% of patients discontinued the drug prematurely due to drug-related clinical adverse experiences [116, 122–128, 138]. Exploration of higher dosages of up to 210 mg daily in healthy volunteers [25] and of up to 150 mg daily in patients with invasive candidiasis [127] revealed no new or increased rates of adverse events.
The most commonly reported drug-related clinical adverse experiences occurring in ³5% of 228 patients in 3 active control studies included fever, phlebitis, nausea, and head- ache [145, 146]. Symptoms such as rash, facial swelling,
pruritus, or sensation of warmth, potentially mediated through endogenous histamine release [147], have been reported in isolated cases [148]. Laboratory abnormalities occurring in ³5% of patients were increased liver enzymes, decreased serum potassium, decreased hemoglobin, and decreased white blood cell count [145, 146]. A similar inci- dence and pattern of adverse events has been observed larger surveys outside the setting of clinical trials [149, 150].
Caspofungin appears to be well-tolerated in pediatric patients: In a phase I/II dose-finding study in 39 children and adolescents, none of the patients developed a serious drug- related adverse event nor was therapy discontinued for toxicity [114]. A similarly favorable safety profile has also been reported in immunocompromised pediatric patients who received the compound within pharmacokinetic dose finding trials, as empirical therapy, or for treatment of invasive infec- tions [151] and in neonates with refractory invasive candidiasis [144]. As caspofungin solution contains sucrose, patients with rare hereditary problems of fructose intolerance or sucrase–
isomaltase insufficiency should not receive this agent.
Because of transient elevations of hepatic transaminases in single-dose interaction studies, the concomitant use of caspofungin with cyclosporine is not recommended by the manufacturer [145, 146]. However, retrospective analyses [152, 153] did not show evidence of a toxicodynamic inter- action of caspofungin and cyclosporine.
Drug Interactions
Caspofungin is not a substrate of P-glycoprotein and is a poor substrate of cytochrome P-450 enzymes and a weak cytochrome P-450 enzyme inhibitor [7]. No pharmacokinetic interactions were observed in healthy volunteers between caspofungin and itraconazole, amphotericin B deoxycholate, mycophenolate mofetil, and nelfinavir [21, 25, 154], and no clinically relevant interactions have been found between tac- rolimus or cyclosporine A and caspofungin. In vitro, caspo- fungin significantly inhibited the metabolism of cytarabine, a substrate of CYP3A4; no in vivo interaction studies have been conducted as to determine the clinical relevance of this finding [155].
Coadministration of inducers of drug clearance and/or mixed inducer/inhibitors, namely efavirenz, nevirapine, phenytoin, rifampin, dexamethasone, and carbamazepine with caspofungin may result in clinically meaningful reduc- tions in caspofungin concentrations. The manufacturer rec- ommends an increase in the dosage of caspofungin to 70 mg daily in patients on concurrent therapy with these drugs [21, 25, 145, 146].
Results from regression analyses indicate that pediatric patients will have similar reductions with inducers as seen in
104 A.H. Groll et al.
adults. If caspofungin is co-administered with the listed inducers of drug clearance, a dose of 70 mg/m2 daily (maxi- mum daily dose of 70 mg) should be considered [145, 146].
Approval Status and Dosing Recommendations
In USA, caspofungin is licensed in adults and pediatric patients 3 months and older for treatment of esophageal can- didiasis, candidemia, certain forms of invasive Candida infections, including intra-abdominal abscesses, peritonitis and pleural space infections. It is recommenrded as second line therapy of proven or probable invasive aspergillosis and for empirical antifungal therapy in granulocytopenic patients with persistent fever [145]. In Europe, the compound is approved in adult and pediatric patients of all ages for treat- ment of invasive candidiasis, second line treatment of inva- sive aspergillosis, and for empirical therapy for presumed fungal infections in neutropenic patients [146].
The recommended dose regimen for adults consists of a single 70-mg loading dose on day 1, followed by 50 mg daily thereafter, administered over 1 h. The regimen approved in pediatric patients 3 months to 17 years is 50 mg/m2 daily after a 70 mg/m2 loading dose (maximum daily dose 70 mg).
The preliminary dosage in infants < 3 months and in prema- ture neonates is 25 mg/m2 daily. No dosage adjustment is required in patients with renal insufficiency. In patients with mild hepatic insufficiency (Child-Pugh category A), no adjustments are needed; in patients with moderate hepatic insufficiency (Child-Pugh category B), decreasing the main- tenance dose to 35 mg/day is recommeded after the loading dose of 70 mg. No recommendations exist for patients with severe hepatic insufficiency (Child-Pugh category C).
Caspofungin has been shown to cross the placental barrier and to be embryotoxic in rats and rabbits. Adequate data in pregnant and lactating women do not exist, and the com- pound should only be used if the potential benefit justifies the risk to the fetus [145, 146].