Phase II dose escalation study of caspofungin for invasive Aspergillosis.
ABSTRACT Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the same non-hematological treatment-related adverse event of grade ≥ 4 in 2 of 8 patients or ≥ 3 in 4 of 8 patients in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies) received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5 days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution. Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500 mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response rates were similar to those previously reported for voriconazole and liposomal amphotericin.
- [Show abstract] [Hide abstract]
ABSTRACT: Invasive fungal disease (IFD) remains life threatening in premature infants and immunocompromised children despite the recent development of new antifungal agents. Optimal dosing of antifungals is one of the few factors clinicians can control to improve outcomes of IFD. However, dosing in children cannot be extrapolated from adult data because IFD pathophysiology, immune response, and drug disposition differ from adults. We critically examined the literature on pharmacokinetics (PK) and pharmacodynamics (PD) of antifungal agents and highlight recent developments in treating pediatric IFD. To match adult exposure in pediatric patients, dosing adjustment is necessary for almost all antifungals. In young infants, the maturation of renal and metabolic functions occurs rapidly and can significantly influence drug exposure. Fluconazole clearance doubles from birth to 28 days of life and, beyond the neonatal period, agents such as fluconazole, voriconazole, and micafungin require higher dosing than in adults because of faster clearance in children. As a result, dosing recommendations are specific to bracketed ranges of age. PD principles of antifungals mostly rely on in vitro and in vivo models but very few PD studies specifically address IFD in children. The exposure-response relationship may differ in younger children compared with adults, especially in infants with invasive candidiasis who are at higher risk of disseminated disease and meningoencephalitis, and by extension severe neurodevelopmental impairment. Micafungin is the only antifungal agent for which a specific target of exposure was proposed based on a neonatal hematogenous Candida meningoencephalitis animal model. In this review, we found that pediatric data on drug disposition of newer triazoles and echinocandins are lacking, dosing of older antifungals such as fluconazole and amphotericin B products still need optimization in young infants, and that target PK/PD indices need to be clinically validated for almost all antifungals in children. A better understanding of age-specific PK and PD of new antifungals in infants and children will help improve clinical outcomes of IFD by informing dosing and identifying future research areas.Drugs. 05/2014;
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ABSTRACT: Killing rates (K) of 1-32 mg ml-1 caspofungin was determined in RPMI-1640 and in 50% serum using time-kill methodology against three C. krusei (MIC of all three isolates 0.25 mg ml-1 in RPMI-1640 and 2 mg ml-1 in serum) and three C. inconspicua clinical isolates (MIC ranges 0.06-0.12 mg ml-1 in RPMI-1640 and 0.25-0.5 mg ml-1 in serum), against C. krusei ATCC 6258 and against one C. krusei isolate resistant to echinocandins (MIC 8 mg ml-1 in RPMI-1640 and 32 mg ml-1 in serum). In RPMI-1640, the highest mean K values were observed at 4 (-1.05 h-1) and 16 (-0.27 h-1) mg ml-1 caspofungin for C. krusei and C. inconspicua clinical isolates, respectively. In 50% serum, mean K value ranges at 1-32 and 4-32 mg ml-1 concentrations for C. inconspicua and C. krusei were -1.12 to -1.44 h-1 and -0.42 to -0.57, respectively. While K values against C. krusei in RPMI-1640 and 50% serum were comparable, serum significantly increased the killing rate against C. inconspicua (P<0.0003 for all tested concentrations). In a neutropenic murine model daily 1, 2, 3, 5 and 15 mg/kg caspofungin significantly decreased the fungal tissue burden of C. inconspicua in the kidneys (P<0.05-0.001). Against C. krusei, doses 3, 5 and 15 mg/kg were effective (P<0.05-0.01). All effective doses were comparably efficacious for both species. Fifteen mg/kg caspofungin was effective even against the echinocandin resistant C. krusei isolate. In 50% serum, killing was concentration independent at effective concentrations (≥4 mg ml-1 and ≥1 mg ml-1 for C. krusei and C. inconspicua, respectively), suggesting that the efficacy of dose escalation is questionable. These in vitro results were also supported by the murine model.Journal of Medical Microbiology 11/2013; · 2.30 Impact Factor
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ABSTRACT: Apparently immunocompetent critically ill patients represent an increasing population at risk for invasive pulmonary aspergillosis (IPA). The current review gives an update on the epidemiology, diagnosis, and management of IPA in the ICU. Patients without apparent severe immunosuppression (e.g. chronic obstructive pulmonary disease, decompensated liver disease, etc.) represent the majority of ICU IPA cases. IPA diagnosis is problematic and the true incidence of IPA is difficult to be estimated because of the nonspecific clinical presentation. A user-friendly clinical diagnostic algorithm for IPA is valuable, particularly through a high negative predictive value. IPA carries a poor prognosis and has an important impact on hospital costs. Timely diagnosis and prompt administration of appropriate treatment may improve the outcomes. Intravenous voriconazole is the recommended primary IPA treatment, but liposomal amphotericin B also has clinical utility. Voriconazole presents bioavailability and toxicity issues, and drug level monitoring is advocated. Caspofungin or antifungal combinations are recommended as salvage therapy. A high level of suspicion in critically ill patients presenting with Aspergillus-positive respiratory tract cultures or nonresolving pulmonary infection may lead to earlier IPA diagnosis. Dosage individualization may decrease treatment discontinuation and improve clinical efficacy.Current Opinion in Infectious Diseases 02/2014; · 4.87 Impact Factor
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Dec. 2011, p. 5798–5803
Copyright © 2011, American Society for Microbiology. All Rights Reserved.
Vol. 55, No. 12
Phase II Dose Escalation Study of Caspofungin for Invasive Aspergillosis?§
O. A. Cornely,1,2,3,4†* J. J. Vehreschild,1†* M. J. G. T. Vehreschild,1G. Wu ¨rthwein,5D. Arenz,2
S. Schwartz,6C. P. Heussel,7G. Silling,8M. Mahne,2J. Franklin,9U. Harnischmacher,2
A. Wilkens,1F. Farowski,1M. Karthaus,10T. Lehrnbecher,11
A. J. Ullmann,12M. Hallek,1,3and A. H. Groll13
Department I of Internal Medicine, University of Cologne, Cologne, Germany1; Clinical Trials Center Cologne, ZKS Ko ¨ln, BMBF
01KN0706, University of Cologne, Cologne, Germany2; Center for Integrated Oncology CIO Ko ¨lnBonn, Cologne, Germany3;
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne,
Cologne, Germany4; Centre for Clinical Trials Muenster (BMBF 01KN0705), University Hospital Muenster, Muenster,
Germany5; Medizinische Klinik III, Charite ´ Campus Benjamin Franklin, Berlin, Germany6; Diagnostic and
Interventional Radiology, Chest Clinic at University Hospital Heidelberg, Heidelberg, Germany7;
Department A of Internal Medicine, University of Muenster, Muenster, Germany8; Institute of
Medical Statistics, Informatics and Epidemiology (IMSIE), University of Cologne, Cologne,
Germany9; Cancer Center Munich South, Klinikum Neuperlach, Munich, Germany10;
Pediatric Hematology and Oncology, University of Frankfurt, Frankfurt, Germany11;
Department of Hematology, Oncology and Pneumology, Johannes Gutenberg University,
Mainz, Germany12; and Infectious Disease Research Program, Department of
Pediatric Hematology/Oncology, University Children’s Hospital, Muenster, Germany13
Received 4 July 2011/Returned for modification 4 August 2011/Accepted 27 August 2011
Our objective was to evaluate the maximum tolerated dose of caspofungin for invasive aspergillosis (IA). The
safety and pharmacokinetics of escalating dosages of caspofungin were investigated in IA. Eight patients each
received caspofungin 70, 100, 150, or 200 mg once a day (QD). Dose-limiting toxicity (DLT) was defined as the
same non-hematological treatment-related adverse event of grade >4 in 2 of 8 patients or >3 in 4 of 8 patients
in a cohort. A total of 46 patients (median age, 61 years; 21 female; 89% with hematological malignancies)
received caspofungin (9, 8, 9, and 20 patients in the 70-, 100-, 150-, and 200-mg cohorts) for a median of 24.5
days. Plasma pharmacokinetics were linear across the investigated dosages and followed a two-compartment
model, with weight as the covariate on clearance and sex as the covariate on central volume of distribution.
Simulated peak plasma concentrations at steady state ranged from 14.2 to 40.6 mg/liter (28%), trough
concentrations from 4.1 to 11.8 mg/liter (58%), and area under the concentration-time curve from 175 to 500
mg/liter/h (32%) (geometric mean, geometric coefficient of variation). Treatment was well tolerated without
dose-limiting toxicity. The rate of complete or partial responses was 54.3%, and the overall mortality at 12-week
follow-up was 28.3%. In first-line treatment of invasive aspergillosis, daily doses of up to 200 mg caspofungin
were well tolerated and the maximum tolerated dose was not reached. Pharmacokinetics was linear. Response
rates were similar to those previously reported for voriconazole and liposomal amphotericin.
Invasive aspergillosis (IA) remains an important cause of
infectious morbidity and mortality in immunocompromised
patients. It is the most common invasive fungal disease
(IFD) in patients with hematological malignancies (5). Cur-
rent first-line therapies with liposomal amphotericin B and
voriconazole fail in approximately 50% of patients. With
12-week mortality rates as high as 28%, new approaches are
urgently needed (7, 12).
High-dose liposomal amphotericin B (i.e., 10 mg/kg per day
for the first 2 weeks of treatment) did not yield better out-
comes than a standard dose of 3 mg/kg per day but resulted in
higher rates of renal adverse events (AEs) (7). Dose escalation
of voriconazole is not pursued due to the nonlinear disposition
of the compound and a narrow therapeutic window. Antifungal
combination therapy is another attractive strategy, but it has
yet to be proven superior to monotherapy (22).
Caspofungin is generally well tolerated and exhibits favor-
able pharmacokinetic properties (21). Unlike the triazoles, it is
not metabolized through the cytochrome P450 enzyme system
(11). The drug had excellent efficacy and safety results in clin-
ical trials of candidiasis (1, 17, 23, 24) and was effective as
salvage therapy for IA after amphotericin B or itraconazole
proved ineffective or toxic (15), and a large-scale study in
neutropenic patients with persistent fever demonstrated an
efficacy similar to that of liposomal amphotericin B but im-
proved tolerability (26). Two recently published trials investi-
gated the caspofungin standard maintenance doses of 50 mg
once a day (QD) for first-line treatment of IA and yielded
response rates of 33 and 42% (13, 25). While these response
rates were below the expected outcomes (7, 12), they have
been attributed to the severely ill patient groups enrolled in
these trials and the rigorous enforcement of the EORTC/MSG
* Corresponding author. Mailing address: University Hospital of
Cologne, 1st Department of Internal Medicine, Kerpener Str. 62,
50937 Cologne, Germany. Phone for O. A. Cornely: 49-221-478-6494.
Fax: 49-221-478-3611. E-mail: email@example.com. Phone for J. J.
Vehreschild: 49-221-478-6494. Fax: 49-221-478-3611. E-mail: janne
† These authors contributed equally to the work.
§ Supplemental material for this article may be found at http://aac
?Published ahead of print on 12 September 2011.
consensus criteria (8), which may result in a delayed treatment
trigger (6, 10).
Preclinical and limited clinical data support the concept of
dose-dependent antifungal efficacy of caspofungin (1, 19, 23).
Data from healthy volunteers demonstrate that caspofungin
can be safely given at doses of up to 210 mg/day (19). In
patients with candidemia and invasive candidiasis, the safety
and tolerability of caspofungin 150 mg once daily were com-
parable to those of the 50-mg standard dose (2, 20).
Dose escalation of caspofungin for treatment of invasive
aspergillosis has not been formally studied. We therefore in-
vestigated the safety, tolerability, and pharmacokinetics of
higher doses of caspofungin, up to 200 mg QD, in a dose
escalation study in adult patients with proven or probable
MATERIALS AND METHODS
This was a formal phase II dose escalation study in patients with invasive
aspergillosis pursuing the definition of the maximum tolerated dose (MTD)
of caspofungin in this setting and determining the pharmacokinetic properties
of caspofungin given at dosages ranging from 70 to 200 mg QD. The study was
registered with the European Union Drug Regulating Authorities Clinical
Trials website (EudraCT2006-001936-30)
Study endpoints. The primary endpoints of the study were the safety and
tolerability of caspofungin. Endpoints of safety and tolerability were the numbers
of toxicity-related study therapy discontinuations and predefined grade ?3 clin-
ical and laboratory events, as evaluated on the basis of current NCI criteria (18).
Secondary endpoints included pharmacokinetic parameters for each dosage level
and efficacy of caspofungin at four escalating dosages. The primary variable of
antifungal efficacy was therapeutic success, defined as the complete or partial
response of initial proven or probable aspergillosis at the end of caspofungin
treatment. Other efficacy variables included assessments of relapse of IA at 4 and
12 weeks after the end of caspofungin study therapy (in those patients with
therapeutic success at the end of therapy), the absence of study drug discontinu-
ations due to toxicity or lack of efficacy, and survival.
Patient eligibility criteria. Adults 18 years or older were eligible if they had an
immunocompromising condition associated with invasive fungal disease and ev-
idence of proven or probable IA defined by modified EORTC criteria as de-
scribed previously (7). Briefly, patients were also included and considered a
probable IFD case with a chest computed tomography (CT) scan positive for a
halo or air crescent sign without microbiological evidence.
Female patients of childbearing age must have had a negative pregnancy test
at study entry and had to take adequate contraceptive measures throughout the
study. Exclusion criteria were pregnancy or breast-feeding, elevated liver func-
tion tests as defined in detail by the study protocol, clinical or laboratory evidence
of active veno-occlusive disease, hemodynamic instability or an expected survival
time of ?5 days, previous enrollment in this study, patients concurrently receiv-
ing efavirenz, nevirapine, rifampin, systemic dexamethasone, phenytoin, carba-
mazepine, phenobarbital, or cyclosporine, a documented history of intolerance
to echinocandin antifungals, concomitant other systemic antifungal agents,
chronic invasive fungal disease, prior systemic therapy of ?4 days with any
polyene antifungal agent within 14 days of study enrollment, and prior systemic
therapy of ?4 days with nonpolyenes for the current, documented IFD. Before
enrollment, written informed consent was obtained from each patient or the
patient’s parent or legal guardian. The study was approved by the institutional
review board or ethics committee at each participating center.
Study drug treatment. Caspofungin was administered once daily as an intra-
venous infusion over 120 min of 70 mg, 100 mg, 150 mg, or 200 mg. In the
absence of dose-limiting toxicity (DLT), treatment with caspofungin was contin-
ued until at least a partial response was achieved or a switch to sequential oral
antifungal therapy was considered feasible. The maximum duration of treatment
with caspofungin study medication was limited to 28 days.
Assessments during study. All radiological assessments were performed as
clinically indicated. High-resolution or multislice CT scans of the chest were
recommended within 72 h of the start of study drug. Clinical and microbiological
assessments were done according to appropriate guidelines, including galacto-
mannan serum tests at least twice weekly (3, 4, 14). Safety monitoring included
daily physical examination and vital signs, as well as assessments of laboratory
values (complete blood count, alanine aminotransferase [ALT], aspartate
transaminase [AST], ?-glutamyl transferase [?GT], total bilirubin, alkaline phos-
phatase, serum creatinine, potassium) twice weekly.
Statistical design and stopping rules. The analysis was that of a formal dose
escalation study and based on a minimum group size of eight patients per dosage
group. Group size was calculated to detect a 40% toxicity rate at a 90% signif-
Clinical and laboratory safety data were analyzed using descriptive statistics.
Comparisons of continuous variables were performed by nonparametric variance
analysis, and comparisons between discrete variables were performed by ?2
analyses. All patients who had received at least one dose of study drug were
included in the analysis of safety and efficacy.
Responses to treatment at the end of study drug treatment and the assess-
ment of IA relapse at 4 and 12 weeks post-end of study treatment in patients
with therapeutic success were tabulated for each dosage group, and differ-
ences in responses between dose groups were evaluated by means of ?2
Patients not evaluable for toxicity or pharmacokinetic analysis were replaced.
Criteria for assessment of the maximum tolerated dose were as follows: if two
out of eight patients in the same dosage cohort developed the same grade ?4
nonhematological adverse event related to the study drug, or if four out of eight
patients in the same dosage cohort developed a grade ?3 nonhematological
adverse event related to the study drug, no further dose escalation was consid-
ered and enrollment in this cohort was terminated. If two patients in the same
dosage cohort developed the same grade 3 nonhematological adverse event
related to the study drug, a further four patients were to be enrolled in this
dosage cohort. If no further drug-related grade ?3 AE of the same type oc-
curred, the study was to be continued with enrollment in the next-higher dosage
cohort. If DLT was reached in a dosage cohort, the dosage of the next-lower
dosage cohort would have been defined as the maximum tolerated dose and an
additional 12 patients enrolled in that dosage cohort to collect further safety
data. Similarly, if no DLT was reached at the highest dosage level of 200 mg QD,
an additional 12 patients were to be enrolled in the 200-mg cohort.
Role and composition of the DSMB. Escalation to the next-higher dosage level
was carried out only after the external data safety monitoring board (DSMB)
(M.K., T.L., and A.J.U.) and the trial committee (O.A.C., A.G.) agreed that the
aforementioned safety and tolerability criteria were met. Members of the DSMB
were both board-certified hematologists and infectious disease experts.
Pharmacokinetic sampling and analysis. Plasma sampling was performed on
day 1 and at peak and trough time points on days 4, 7, 14, and 28. Blood
specimens (5 ml) were collected in heparinized tubes and immediately centri-
fuged for 10 min at 1,500 ? g. Separated plasma was stored at ?80°C until assay.
Concentrations of caspofungin were measured by a liquid chromatography
tandem mass spectroscopy (LC-MS/MS) method as described in detail elsewhere
(9). Due to the expected high drug levels, the method was modified to allow
quantitation of caspofungin in the range from 84 ng/ml (lower limit of quanti-
tation) to 84,000 ng/ml. Accuracies were within ?11.9%, and intraday variability
(precision) was ?8.1%.
Concentration data were assessed by population pharmacokinetic analysis
using the NONMEM (version 6, level 1.0; GloboMax, ICON plc, Ellicott City,
MD) and Xpose (version 3.1; Andrew Hooker, Mats O. Karlsson and E. Niclas
Jonsson, Uppsala University, Uppsala, Sweden) programs. Secondary pharma-
cokinetic endpoints included the exposure and the dose linearity of caspofungin
across the investigated dosage range.
Definitions of clinical response. Responses to treatment and survival were
assessed at the end of therapy and at 4 and 12 weeks post-end of treatment.
Complete response was defined as resolution of all attributable symptoms, signs,
and radiographic or bronchoscopic abnormalities, and a partial response was
defined as a clinically meaningful improvement of attributable symptoms, signs,
and radiographic (?50% decrease) or bronchoscopic abnormalities, if present at
enrollment. Stable disease was no improvement of attributable symptoms, signs,
and radiographic (?50% decrease) or bronchoscopic abnormalities, if present at
enrollment. Failure was defined as deterioration of attributable clinical or ra-
diographic abnormalities necessitating alternative antifungal therapy or resulting
in death. A relapse was diagnosed upon reemergence of IA after discontinuation
of therapy following complete response, partial response, or stable disease or
early withdrawal. All computed tomography scans were reviewed by an expert
Role of the funding source. Merck & Co., Inc. (Whitehouse Station, NJ), was
the financial sponsor through a grant to the University of Cologne, Cologne,
Germany. The study was designed by academic authors (O.A.C., D.A., A.H.G.).
The legal sponsor was the University of Cologne, Cologne, Germany. Study
coordination was performed by the study sponsor, which included ensuring
VOL. 55, 2011CASPOFUNGIN FOR INVASIVE ASPERGILLOSIS5799
adherence to good clinical practice standards, training investigators, collecting
the data, monitoring and auditing clinical sites, managing the data, and perform-
ing the statistical analyses. The primary data and statistical analyses were made
available to all authors. All authors were granted full access to the complete data
set of the study, and the corresponding author had final responsibility for the
decision to submit for publication.
Patients. From September 2006 until July 2009, a total of 46
patients with proven or probable invasive aspergillosis were
enrolled at three German university hospitals. In the 70-mg
and the 150-mg cohorts, one patient each (2.2%) was replaced
because of incomplete pharmacokinetic sampling due to early
discontinuation after 3 and 4 days, respectively. Both replaced
patients were included in the pharmacokinetic and safety anal-
yses with the available data. Baseline characteristics of the 46
patients, including age, gender, weight, body mass index
(BMI), fever and/or neutropenia at baseline, underlying dis-
ease, and EORTC/MSG classification of invasive aspergil-
losis, were comparable between cohorts. Of the 46 patients,
21 were female, 27 had acute leukemia, and 31 were neu-
tropenic as a baseline. According to the modified EORTC/
MSG criteria used for the trial, one patient had proven
aspergillosis, 25 had probable aspergillosis with microbio-
logical evidence, and 20 had probable aspergillosis without
microbiological evidence. The complete details are available
in the supplemental files (see Table S1 in the supplemental
material). All patients had the lung as the only site of in-
fection. Demographic characteristics did not significantly
differ between dosage groups.
The median duration of study drug treatment was 24.5 days.
Details are provided in Table 1. Reasons for discontinuation of
study treatment were completion of the maximum 28 days on
study drug (n ? 15), treatment failure (n ? 10), sufficient
treatment response prior to day 28 (n ? 8), switch to oral
treatment (n ? 6), adverse events (n ? 5), and patients’ deci-
sion (n ? 2).
Safety and tolerance. Analysis of the cumulated reported
adverse events revealed that only one patient had an adverse
event which could potentially be rated as DLT criterion as
defined in the protocol. This event (elevated ?-glutamyl trans-
ferase, ?GT) occurred in the 200-mg group. Since no other
such adverse event occurred, DLT was not achieved.
Adverse events leading to discontinuation were suspected
drug fever (n ? 1), elevated liver function tests (n ? 1), patient
death (n ? 1), worsening of aspergillus pneumonia (SAE, n ?
1), and not reported (n ? 1). Table 2 gives an overview of
grade 3 to 5 adverse events by dose group. There was no clear
relationship between caspofungin dose and the incidence of
adverse events. Details on the frequency of adverse events of
various severity grades and serious adverse events reported for
the patients in each dose cohort are provided in the supple-
mental files (see Tables S2 and S3 in the supplemental mate-
rial). Only two events with a probable relationship to the study
drug were reported (100-mg group, grade 1 loss of appetite;
200-mg group, grade 3 ?-glutamyl transferase [?GT] eleva-
tion); no events were considered definitely related. The num-
ber of grade ?3 events with at least a possible relationship to
study drug was zero in all dose cohorts except the 200-mg
group, where six such events (all grade 3) occurred in six
patients: hyponatremia, elevated alkaline phosphatase (3
events), alanine transaminase, and ?GT.
A total of 42 serious adverse events (SAE) occurred in 26
patients, and none was related to study treatment. The mean
numbers of SAE per patient were 0.2, 1.0, 1.1, and 1.1 in the
70-, 100-, 150-, and 200-mg cohorts, respectively.
Pharmacokinetics. Dose-normalized trough concentrations
revealed dose linearity of caspofungin across the investigated dos-
age range. Based on population pharmacokinetic analysis, plasma
data were best described by a linear two-compartment phar-
macokinetic model with weight as covariate on clearance
(0.401 liter/h), sex as covariate on central volume of distri-
bution (male, 6.7 liters; female, 4.89 liters), an intercom-
partmental clearance of 0.815 liter/h, and a peripheral vol-
ume of distribution of 6.84 liters. Based on the final model,
simulated peak plasma concentrations at steady state ranged
from 14.2 to 40.6 mg/liter (28%), trough concentrations
from 4.1 to 11.8 mg/liter (58%), and area under the concen-
tration-time curve from 175 to 500 mg/liter/h (32%) for the
dosage range of 70 to 200 mg QD (geometric mean, geo-
metric coefficient of variation of variation) (Table 3).
Treatment success. The treatment outcome of the different
dose groups is shown in Table 1. Favorable responses at end of
treatment (EOT), 4 weeks follow-up, and 12 weeks follow-up,
defined as complete and partial responses, were observed in 25
the dosage groups, favorable outcomes in the 70-mg, 100-mg,
150-mg, and 200-mg groups at EOT were observed in 4 (44%), 3
(36%), 6 (67%), and 12 (60%) patients, respectively.
TABLE 1. Treatment allocation and outcomes
No. of patients
Days on study drug,
No. of patients per groupc
Response at EOTa
Favorable (CR/PR) Stable diseaseFailure 4 wk 12 wk
44 24.5 (3–29)
15 25% 28%
2 2/6 (33%)
aEOT, end of treatment; CR, complete response; PR, partial response.
bDenominator indicates no. of patients with CR or PR at EOT.
cAt EOT, 4-week follow-up, and 12-week follow-up, 2, 16, and 23 outcomes out of 46, respectively, were not recorded due to patient death, earlier relapse, or missing
CT diagnostics and thus were not available for analysis.
5800CORNELY ET AL.ANTIMICROB. AGENTS CHEMOTHER.
Survival. The median observation time (ending with the end
of the follow-up or patient death) was 109 days. Thirteen of 46
patients (28.3%) died during the treatment or the 12-week
follow-up period. Causes of death were the underlying disease
in 5 patients, pneumonia in 3, sepsis or sepsis-related compli-
cations in 4, and pulmonary hemorrhage in 1. Twelve weeks
after EOT, the estimated overall survival was 73.9% (Kaplan-
Meier estimate; data not shown). At 100 days, the estimated
survival rate was 71% (95% confidence interval [CI], 57% to
84%). To allow better comparison with earlier trials, a post hoc
analysis of survival 12 weeks after starting treatment was per-
formed, showing a 76% overall survival probability.
The results of this dose escalation study evaluating caspo-
fungin as the first-line treatment of invasive aspergillosis
demonstrate acceptable safety and tolerance of daily doses
of caspofungin up to 200 mg over extended periods of time.
Dose-limiting toxicity was not observed, and thus, 200 mg/kg
may be defined as current MTD in this setting.
While no severe adverse events with a probable or definite
relationship to study treatment were observed at all dose
levels, there was a tendency toward higher rates of adverse
and serious adverse events in the higher-dose groups. How-
ever, we evaluated a severely ill patient population: most
individuals were still under treatment for their underlying
malignancy and were profoundly immunocompromised. Un-
der these conditions, substantial variance in the number of
adverse events is anticipated. Also, given the open-label
character of the study, investigators may have been inclined
to attribute events to study treatment in the higher dose
groups. It is still possible that a 200-mg dose of caspofungin
may be associated with a higher rate of adverse events.
Assessment of pharmacokinetic parameters revealed
dose-proportional increases in exposure without changes in
total clearance, consistent with linear pharmacokinetics
across the investigated dosage range of 70 to 200 mg QD.
Following administration of 100 mg QD, the steady-state
estimated mean area under the concentration-time curve
(AUC) values were slightly (15%) higher in the study pa-
tients relative to values following similar dosing schedules in
healthy volunteers (16). Changes in plasma composition,
saturation effects of OATP1B1-mediated hepatocellular up-
take, and the generally higher inter-individual variability in
drug disposition in critically ill patients all may account for
this likely not clinically relevant observation.
Invasive aspergillosis is a disease associated with a high
rate of treatment failure and a high mortality (7, 12). The
response and 12-week survival rates compare well to the
findings reported from large randomized trials of voricona-
zole and liposomal amphotericin B for first-line treatment of
IA (7, 12). Of note, recently published trials on caspofungin
monotherapy for IA reported low response and 12-week
survival in patients with hematological malignancies and
patients after allogeneic stem cell transplantation (13, 25).
The apparently better results from our trial may have been
achieved by the higher dose and the less rigid enrolment
criteria. In particular, waiving the necessity of microbiolog-
ical evidence in our trial may have allowed earlier treatment
of invasive aspergillosis, leading to better treatment results
TABLE 3. Estimated steady-state pharmacokinetic
Dose (mg QD)
Geometric mean (geometric coefficient of variation)a
aAUC, area under the concentration-time curve; CMAXand CMIN, peak and
trough plasma concentrations, respectively.
TABLE 2. Treatment-emergent adverse events of grades 3 to 5
Body systemAdverse event
No. of patients with event in
Total no. of
Increased liver function
Pain while breathing
Persistence or progression
of underlying disease
VOL. 55, 2011CASPOFUNGIN FOR INVASIVE ASPERGILLOSIS5801
(6, 10). However, our trial was not designed to determine
the efficacy of caspofungin in the treatment of IA, and
differences across trials must be rated with caution; the
observed effect may as well be random. Of note, we ob-
served a considerable number of late relapses after 12 weeks
follow-up. Most of the large randomized trials reported only
survival after 12 weeks and not the incidence of relapses (7,
12). Future research should try to highlight the actual num-
bers of relapses after successful primary treatment.
In summary, our trial demonstrates that early treatment
of IA with caspofungin is well tolerated in doses up to 200
mg and that dose linearity is maintained in this setting.
Response rates and survival were comparable to those
achieved with liposomal amphotericin and voriconazole.
The next step toward a more effective treatment than cur-
rent standard therapies could be a randomized comparison
of high-dose caspofungin versus voriconazole or liposomal
The individual contributions of the authors were as follows.
O.A.C. designed and wrote the protocol, conducted the trial, col-
lected, analyzed, and interpreted data, wrote the initial draft, re-
vised and edited the manuscript, and wrote, with contributions of all
authors, the final draft. J.J.V. conducted the trial, collected, ana-
lyzed, compiled, and interpreted data, wrote the initial draft, pre-
pared the data tables, and revised and edited the manuscript.
M.J.G.T.V. conducted the trial, collected and interpreted data, and
revised and edited the manuscript. G.W. performed pharmacoki-
netic analysis and revised and edited the manuscript. D.A. designed
and wrote the protocol, conducted the trial, and collected data. S.S.
conducted the trial, collected and interpreted data, and revised and
edited the manuscript. C.P.H. performed image data analysis. G.S.
conducted the trial, collected data, and revised and edited the
manuscript. M.M. performed database development, data manage-
ment, and monitoring. J.F. performed data analysis and figure de-
velopment. U.H. performed database development, data manage-
ment, and monitoring of the trial. A.W. generated, collected,
assembled, and analyzed the data. F.F. planned and conducted the
LC/MS-MS analysis and revised and edited the manuscript. M.K.
performed data analysis and served on the DSMB. T.L. performed
data analysis and served on the DSMB. A.J.U. performed data
analysis, served on the DSMB, and revised and edited the manu-
script. M.H. revised the manuscript and supervised the treatment of
patients. A.H.G. designed and wrote the protocol, conducted the
trial, collected, analyzed, and interpreted data, and revised and
edited the manuscript. All academic authors had access to the
primary data and to the results of their analyses, participated in the
preparation of the manuscript, and were given full independence in
decisions concerning the reporting of results and the content of the
The following potential conflicts of interest are noted. O.A.C. is
supported by the German Federal Ministry of Research and Edu-
cation (BMBF grant 01KN0706) and has received research grants
from, is an advisor to, or received lecture honoraria from Actelion,
Astellas, Basilea, Bayer, Biocryst, Celgene, F2G, Genzyme, Gilead,
Merck/Schering, Miltenyi, Mo ¨lnlycke, Optimer, Pfizer, Quintiles,
and Viropharma. J.J.V. is supported by the German Federal Min-
istry of Research and Education (BMBF grant 01KI0771) and has
received research grants from or has been a speaker for Astellas,
Merck, Pfizer, and Schering-Plough. G.W. has no conflicts of inter-
est to declare. M.J.G.T.V. has received lecture honoraria from
Astellas Pharma, Merck/MSD, Pfizer, and Gilead Sciences. D.A.
has received research grants from Merck. S.S. has received travel
grants and speaker honoraria from Astellas, Enzon, and Pfizer.
C.P.H. has stock ownership in medical industry GSK and Stada, has
received consultation or other fees from Astellas, AstraZeneca,
Basilea, Boehringer Ingelheim, Gilead, GSK, Lilly, MSD/ Schering-
Plough, Novartis, Pfizer, and Roche, and has received research
funding from Novartis. G.S. has been a speaker for Merck and
Pfizer. M.M. has no conflicts of interest to declare. J.F. has no
conflicts of interest to declare. U.H. has no conflicts of interest to
declare. A.W. has no conflicts of interest to declare. F.F. has re-
ceived research grants from MSD. M.K. is an advisory board mem-
ber for MSD. T.L. is a consultant to Astellas, Gilead, and MSD/
Merck, has received research grants from Gilead, and has served on
the speakers’ bureau for Astellas, Gilead, MSD/Merck, and Pfizer.
A.J.U. has served as a consultant for Astellas Pharma, Basilea,
Gilead, MSD, Pfizer, and the former Schering-Plough and has par-
ticipated in speakers’ bureaus for Astellas Pharma, Gilead, MSD,
Pfizer, and the former Schering-Plough. M.H. has no conflicts of
interest to declare. A.H.G. has served on the speaker’s bureau and
as a consultant to Astellas Pharma, Cephalon, Gilead Sciences,
Merck & Co., Pfizer, Schering-Plough, and Vicuron Pharmaceuti-
cals and has received research grants from Gilead Sciences and
Merck & Co.
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