Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Pharmacotherapeutic group: antimycotics for systemic use
ATC Code: J02AX04
Caspofungin acetate is a semi-synthetic lipopeptide (echinocandin) compound synthesised from a fermentation product of Glarea lozoyensis. Caspofungin acetate inhibits the synthesis of beta (1,3)-D-glucan, an essential component of the cell wall of many filamentous fungi and yeast. Beta (1,3)-D-glucan is not present in mammalian cells.
Fungicidal activity with caspofungin has been demonstrated against Candida yeasts. Studies in vitro and in vivo demonstrate that exposure of Aspergillus to caspofungin results in lysis and death of hyphal apical tips and branch points where cell growth and division occur.
Caspofungin has in vitro activity against Aspergillus species (Aspergillus fumigatus [N=75], Aspergillus flavus [N=111], Aspergillus niger [N=31], Aspergillus nidulans [N=8], Aspergillus terreus [N=52], and Aspergillus candidus [N=3]). Caspofungin also has in vitro activity against Candida species (Candida albicans [N=1,032], Candida dubliniensis [N=100], Candida glabrata [N=151], Candida guilliermondii [N=67], Candida kefyr [N=62], Candida krusei [N=147], Candida lipolytica [N=20], Candida lusitaniae [N=80], Candidaparapsilosis [N=215], Candida rugosa [N=1], and Candida tropicalis [N=258]), including isolates with multiple resistance transport mutations and those with acquired or intrinsic resistance to fluconazole, amphotericin B, and 5-flucytosine. Susceptibility testing was performed according to a modification of both the Clinical and Laboratory Standards Institute (CLSI, formerly known as the National Committee for Clinical Laboratory Standards [NCCLS]) method M38-A2 (for Aspergillus species) and method M27-A3 (for Candida species).
Standardised techniques for susceptibility testing have been established for yeasts by EUCAST. EUCAST breakpoints have not yet been established for caspofungin, due to significant inter-laboratory variation in MIC ranges for caspofungin. In lieu of breakpoints, Candida isolates that are susceptible to anidulafungin as well as micafungin should be considered susceptible to caspofungin. Similarly, C. parapsilosis isolates intermediate to anidulafungin and micafungin can be regarded intermediate to caspofungin.
Isolates of Candida with reduced susceptibility to caspofungin have been identified in a small number of patients during treatment (MICs for caspofungin >2 mg/L (4- to 30-fold MIC increases) have been reported using standardized MIC testing techniques approved by the CLSI). The mechanism of resistance identified is FKS1 and/or FKS2 (for C. glabrata) gene mutations. These cases have been associated with poor clinical outcomes.
Development of in vitro resistance to caspofungin by Aspergillus species has been identified. In limited clinical experience, resistance to caspofungin in patients with invasive aspergillosis has been observed. The mechanism of resistance has not been established. The incidence of resistance to caspofungin by various clinical isolates of Aspergillus is rare. Caspofungin resistance in Candida has been observed but the incidence may differ by species or region.
Invasive Candidiasis in Adult Patients: Two hundred thirty-nine patients were enrolled in an initial study to compare caspofungin and amphotericin B for the treatment of invasive candidiasis. Twenty- four patients had neutropaenia. The most frequent diagnoses were bloodstream infections (candidaemia) (77%, N=186) and Candida peritonitis (8%, N=19); patients with Candida endocarditis, osteomyelitis, or meningitis were excluded from this study. Caspofungin 50 mg once daily was administered following a 70 mg loading dose, while amphotericin B was administered at 0.6 to 0.7 mg/kg/day to non-neutropaenic patients or 0.7 to 1.0 mg/kg/day to neutropaenic patients. The mean duration of intravenous therapy was 11.9 days, with a range of 1 to 28 days. A favourable response required both symptom resolution and microbiological clearance of the Candida infection. Two hundred twenty-four patients were included in the primary efficacy analysis (MITT analysis) of response at the end of IV study therapy; favourable response rates for the treatment of invasive candidiasis were comparable for caspofungin (73% [80/109]) and amphotericin B (62% [71/115]) [% difference 12.7 (95.6% CI -0.7, 26.0)]. Among patients with candidaemia, favourable response rates at the end of IV study therapy were comparable for caspofungin (72% [66/92]) and amphotericin B (63% [59/94]) in the primary efficacy analysis (MITT analysis) [% difference 10.0 (95.0% CI -4.5, 24.5)]. Data in patients with non-blood sites of infection were more limited. Favourable response rates in neutropaenic patients were 7/14 (50%) in the caspofungin group and 4/10 (40%) in the amphotericin B group. These limited data are supported by the outcome of the empirical therapy study.
In a second study, patients with invasive candidiasis received daily doses of caspofungin at 50 mg/day (following a 70-mg loading dose on Day 1) or caspofungin at 150 mg/day (see section 4.8). In this study, the caspofungin dose was administered over 2 hours (instead of the routine 1-hour administration). The study excluded patients with suspected Candida endocarditis, meningitis, or osteomyelitis. As this was a primary therapy study, patients who were refractory to prior antifungal agents were also excluded. The number of neutropenic patients enrolled in this study was also limited (8.0%). Efficacy was a secondary endpoint in this study. Patients who met the entry criteria and received one or more doses of caspofungin study therapy were included in the efficacy analysis. The favourable overall response rates at the end of caspofungin therapy were similar in the 2 treatment groups: 72% (73/102) and 78% (74/95) for the caspofungin 50-mg and 150-mg treatment groups, respectively (difference 6.3% [95% CI -5.9, 18.4]).
Invasive Aspergillosis in Adult Patients: Sixty-nine adult patients (age 18-80) with invasive aspergillosis were enrolled in an open-label, non-comparative study to evaluate the safety, tolerability, and efficacy of caspofungin. Patients had to be either refractory to (disease progression or failure to improve with other antifungal therapies given for at least 7 days) (84% of the enrolled patients) or intolerant of (16% of enrolled patients) other standard antifungal therapies. Most patients had underlying conditions (haematologic malignancy [N=24], allogeneic bone marrow transplant or stem cell transplant [N=18], organ transplant [N=8], solid tumour [N=3], or other conditions [N=10]). Stringent definitions, modelled after the Mycoses Study Group Criteria, were used for diagnosis of invasive aspergillosis and for response to therapy (favourable response required clinically significant improvement in radiographs as well as in signs and symptoms). The mean duration of therapy was 33.7 days, with a range of 1 to 162 days. An independent expert panel determined that 41% (26/63) of patients receiving at least one dose of caspofungin had a favourable response. For those patients who received more than 7 days of therapy with caspofungin, 50% (26/52) had a favourable response. The favourable response rates for patients who were either refractory to or intolerant of previous therapies were 36% (19/53) and 70% (7/10), respectively. Although the doses of prior antifungal therapies in 5 patients enrolled as refractory were lower than those often administered for invasive aspergillosis, the favourable response rate during therapy with caspofungin was similar in these patients to that seen in the remaining refractory patients (2/5 versus 17/48, respectively). The response rates among patients with pulmonary disease and extrapulmonary disease were 47% (21/45) and 28% (5/18), respectively. Among patients with extrapulmonary disease, 2 of 8 patients who also had definite, probable, or possible CNS involvement had a favourable response.
Empirical Therapy in Febrile, Neutropaenic Adult Patients: A total of 1,111 patients with persistent fever and neutropaenia were enrolled in a clinical study and treated with either caspofungin 50 mg once daily following a 70 mg loading dose or liposomal amphotericin B 3.0 mg/kg/day. Eligible patients had received chemotherapy for malignancy or had undergone hematopoietic stem-cell transplantation, and presented with neutropaenia (<500 cells/mm³ for 96 hours) and fever (>38.0°C) not responding to >96 hours of parenteral antibacterial therapy. Patients were to be treated until up to 72 hours after resolution of neutropaenia, with a maximum duration of 28 days. However, patients found to have a documented fungal infection could be treated longer. If the drug was well tolerated but the patient’s fever persisted and clinical condition deteriorated after 5 days of therapy, the dosage of study drug could be increased to 70 mg/day of caspofungin (13.3% of patients treated) or to 5.0 mg/kg/day of liposomal amphotericin B (14.3% of patients treated). There were 1,095 patients included in the primary Modified Intention-To-Treat (MITT) efficacy analysis of overall favourable response; caspofungin (33.9%) was as effective as liposomal amphotericin B (33.7%) [% difference 0.2 (95.2% CI -5.6, 6.0)]. An overall favourable response required meeting each of 5 criteria: (1) successful treatment of any baseline fungal infection (caspofungin 51.9% [14/27], liposomal amphotericin B 25.9% [7/27]), (2) no breakthrough fungal infections during administration of study drug or within 7 days after completion of treatment (caspofungin 94.8% [527/556], liposomal amphotericin B 95.5% [515/539]), (3) survival for 7 days after completion of study therapy (caspofungin 92.6% [515/556], liposomal amphotericin B 89.2% [481/539]), (4) no discontinuation from the study drug because of drug-related toxicity or lack of efficacy (caspofungin 89.7% [499/556], liposomal amphotericin B 85.5% [461/539]), and (5) resolution of fever during the period of neutropaenia (caspofungin 41.2% [229/556], liposomal amphotericin B 41.4% [223/539]). Response rates to caspofungin and liposomal amphotericin B for baseline infections caused by Aspergillus species were, respectively, 41.7% (5/12) and 8.3% (1/12), and by Candida species were 66.7% (8/12) and 41.7% (5/12). Patients in the caspofungin group experienced breakthrough infections due to the following uncommon yeasts and moulds: Trichosporon species (1), Fusarium species (1), Mucor species (1), and Rhizopus species (1).
The safety and efficacy of caspofungin was evaluated in paediatric patients 3 months to 17 years of age in two prospective, multicentre clinical trials. The study design, diagnostic criteria, and criteria for efficacy assessment were similar to the corresponding studies in adult patients (see section 5.1).
The first study, which enrolled 82 patients between 2 to 17 years of age, was a randomized, double- blind study comparing caspofungin (50 mg/m² IV once daily following a 70-mg/m² loading dose on Day 1 [not to exceed 70 mg daily]) to liposomal amphotericin B (3 mg/kg IV daily) in a 2:1 treatment fashion (56 on caspofungin, 26 on liposomal amphotericin B) as empirical therapy in paediatric patients with persistent fever and neutropenia. The overall success rates in the MITT analysis results, adjusted by risk strata, were as follows: 46.6% (26/56) for caspofungin and 32.2% (8/25) for liposomal amphotericin B.
The second study was a prospective, open-label, non-comparative study estimating the safety and efficacy of caspofungin in paediatric patients (ages 6 months to 17 years) with invasive candidiasis, oesophageal candidiasis, and invasive aspergillosis (as salvage therapy). Forty-nine patients were enrolled and received caspofungin at 50 mg/m² IV once daily following a 70-mg/m² loading dose on Day 1 (not to exceed 70 mg daily), of whom 48 were included in the MITT analysis. Of these, 37 had invasive candidiasis, 10 had invasive aspergillosis, and 1 patient had esophageal candidiasis. The favourable response rate, by indication, at the end of caspofungin therapy was as follows in the MITT analysis: 81% (30/37) in invasive candidiasis, 50% (5/10) in invasive aspergillosis, and 100% (1/1) in oesophageal candidiasis.
Caspofungin is extensively bound to albumin. The unbound fraction of caspofungin in plasma varies from 3.5% in healthy volunteers to 7.6% in patients with invasive candidiasis. Distribution plays the prominent role in caspofungin plasma pharmacokinetics and is the rate-controlling step in both the alpha- and beta-disposition phases. The distribution into tissues peaked at 1.5 to 2 days after dosing when 92% of the dose was distributed into tissues. It is likely that only a small fraction of the caspofungin taken up into tissues later returns to plasma as parent compound. Therefore, elimination occurs in the absence of a distribution equilibrium, and a true estimate of the volume of distribution of caspofungin is currently impossible to obtain.
Caspofungin undergoes spontaneous degradation to an open ring compound. Further metabolism involves peptide hydrolysis and N-acetylation. Two intermediate products, formed during the degradation of caspofungin to this open ring compound, form covalent adducts to plasma proteins resulting in a low-level, irreversible binding to plasma proteins.
In vitro studies show that caspofungin is not an inhibitor of cytochrome P450 enzymes 1A2, 2A6, 2C9, 2C19, 2D6 or 3A4. In clinical studies, caspofungin did not induce or inhibit the CYP3A4 metabolism of other medicinal products. Caspofungin is not a substrate for P-glycoprotein and is a poor substrate for cytochrome P450 enzymes.
The elimination of caspofungin from plasma is slow with a clearance of 10-12 ml/min. Plasma concentrations of caspofungin decline in a polyphasic manner following single 1-hour intravenous infusions. A short alpha-phase occurs immediately post-infusion, followed by a beta-phase with a half- life of 9 to 11 hours. An additional gamma-phase also occurs with a half-life of 45 hours. Distribution, rather than excretion or biotransformation, is the dominant mechanism influencing plasma clearance.
Approximately 75% of a radioactive dose was recovered during 27 days: 41% in urine and 34% in faeces. There is little excretion or biotransformation of caspofungin during the first 30 hours after administration. Excretion is slow and the terminal half-life of radioactivity was 12 to 15 days. A small amount of caspofungin is excreted unchanged in urine (approximately 1.4% of dose).
Caspofungin displays moderate non-linear pharmacokinetics with increased accumulation as the dose is increased, and a dose dependency in the time to reach steady state upon multiple-dose administration.
Increased caspofungin exposure was seen in adult patients with renal impairment and mild liver impairment, in female subjects, and in the elderly. Generally the increase was modest and not large enough to warrant dosage adjustment. In adult patients with moderate liver impairment or in higher weight patients, a dosage adjustment may be necessary (see below).
Weight was found to influence caspofungin pharmacokinetics in the population pharmacokinetic analysis in adult candidiasis patients. The plasma concentrations decrease with increasing weight. The average exposure in an adult patient weighing 80 kg was predicted to be about 23% lower than in an adult patient weighing 60 kg (see section 4.2).
In adult patients with mild and moderate hepatic impairment, the AUC is increased about 20 and 75%, respectively. There is no clinical experience in adult patients with severe hepatic impairment and in paediatric patients with any degree of hepatic impairment. In a multiple-dose study, a dose reduction of the daily dose to 35 mg in adult patients with moderate hepatic impairment has been shown to provide an AUC similar to that obtained in adult subjects with normal hepatic function receiving the standard regimen (see section 4.2).
In a clinical study of single 70 mg doses, caspofungin pharmacokinetics were similar in adult volunteers with mild renal impairment (creatinine clearance 50 to 80 ml/min) and control subjects. Moderate (creatinine clearance 31 to 49 ml/min), advanced (creatinine clearance 5 to 30 ml/min), and end-stage (creatinine clearance <10 ml/min and dialysis dependent) renal impairment moderately increased caspofungin plasma concentrations after single-dose administration (range: 30 to 49% for AUC). However, in adult patients with invasive candidiasis, oesophageal candidiasis, or invasive aspergillosis who received multiple daily doses of caspofungin 50 mg, there was no significant effect of mild to advanced renal impairment on caspofungin concentrations. No dosage adjustment is necessary for patients with renal impairment. Caspofungin is not dialysable, thus supplementary dosing is not required following haemodialysis.
Caspofungin plasma concentrations were on average 17-38% higher in women than in men.
A modest increase in AUC (28%) and C24h (32%) was observed in elderly male subjects compared with young male subjects. In patients who were treated empirically or who had invasive candidiasis, a similar modest effect of age was seen in older patients relative to younger patients.
Patient pharmacokinetic data indicated that no clinically significant differences in the pharmacokinetics of caspofungin were seen among Caucasians, Blacks, Hispanics, and Mestizos.
In adolescents (ages 12 to 17 years) receiving caspofungin at 50 mg/m² daily (maximum 70 mg daily), the caspofungin plasma AUC0-24hr was generally comparable to that seen in adults receiving caspofungin at 50 mg daily. All adolescents received doses >50 mg daily, and, in fact, 6 of 8 received the maximum dose of 70 mg/day. The caspofungin plasma concentrations in these adolescents were reduced relative to adults receiving 70 mg daily, the dose most often administered to adolescents.
In children (ages 2 to 11 years) receiving caspofungin at 50 mg/m² daily (maximum 70 mg daily), the caspofungin plasma AUC0-24hr after multiple doses was comparable to that seen in adults receiving caspofungin at 50 mg/day.
In young children and toddlers (ages 12 to 23 months) receiving caspofungin at 50 mg/m² daily (maximum 70 mg daily), the caspofungin plasma AUC0-24hr after multiple doses was comparable to that seen in adults receiving caspofungin at 50 mg daily and to that in older children (2 to 11 years of age) receiving the 50 mg/m² daily dose.
Overall, the available pharmacokinetic, efficacy, and safety data are limited in patients 3 to 10 months of age. Pharmacokinetic data from one 10-month old child receiving the 50 mg/m² daily dose indicated an AUC0-24hr within the same range as that observed in older children and adults at the 50 mg/m² and the 50 mg dose, respectively, while in one 6-month old child receiving the 50 mg/m² dose, the AUC0-24hr was somewhat higher.
In neonates and infants (<3 months) receiving caspofungin at 25 mg/m² daily (corresponding mean daily dose of 2.1 mg/kg), caspofungin peak concentration (C1hr) and caspofungin trough concentration (C24hr) after multiple doses were comparable to that seen in adults receiving caspofungin at 50 mg daily. On Day 1, C1 hr was comparable and C24hr modestly elevated (36%) in these neonates and infants relative to adults. However, variability was seen in both C1hr (Day 4 geometric mean 11.73 μg/ml, range 2.63 to 22.05 μg/ml) and C24hr (Day 4 geometric mean 3.55 μg/ml, range 0.13 to 7.17 μg/ml). AUC0-24hr measurements were not performed in this study due to the sparse plasma sampling. Of note, the efficacy and safety of caspofungin have not been adequately studied in prospective clinical trials involving neonates and infants under 3 months of age.
Repeated dose toxicity studies in rats and monkeys using doses up to 7-8 mg/kg given intravenously showed injection site reactions in rats and monkeys, signs of histamine release in rats, and evidence of adverse effects directed at the liver in monkeys. Developmental toxicity studies in rats showed that caspofungin caused decreases in foetal body weights and an increase in the incidence of incomplete ossification of vertebra, sternebra, and skull bone at doses of 5 mg/kg that were coupled to adverse maternal effects such as signs of histamine release in pregnant rats. An increase in the incidence of cervical ribs was also noted. Caspofungin was negative in in vitro assays for potential genotoxicity as well as in the in vivo mouse bone marrow chromosomal test. No long-term studies in animals have been performed to evaluate the carcinogenic potential. For caspofungin, there were no effects on fertility in studies conducted in male and female rats up to 5 mg/kg/day.
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