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).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). Current 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 outcomes 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 favorable 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 clinical 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 improved tolerability (26). Two recently published trials investigated 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

Dose escalation studies with caspofungin against Candida glabrata

“…In accordance with other authors (Andes et al, 2010;Fernández-Silva et al, 2014;Lepak et al, 2012;Spreghini et al, 2012;Wiederhold et al, 2007), WT C. glabrata clinical isolates were highly susceptible in vivo to caspofungin even at 1 mg kg 21 in mice (corresponding to a 35 mg daily dose in humans) (Cornely et al, 2011;Flattery et al, 2011;Migoya et al, 2011). Moreover, as observed previously with Candida albicans, Candida krusei and Candida inconspicua, increasing the drug dose further did not yield better efficacy (Berényi et al, 2014;Kovács et al, 2014a), i.e.…”

“…to allow the fungi to establish tissue infection (Berényi et al, 2014;Földi et al, 2012b;Kovács et al, 2014a, Spreghini et al, 2012Wiederhold et al, 2007). This dosing strategy was based on previous pharmacokinetic studies (Andes et al, 2010;Cornely et al, 2011;Flattery et al, 2011;Migoya et al, 2011;Stone et al, 2002), on previous results from our study group (Berényi et al, 2014;Földi et al, 2012b;Kovács et al, 2014a) and on the findings of Howard et al (2011) At the beginning of therapy (day 1), the fungal kidney burden was determined after dissection of four untreated mice for each isolate (day 1 control burden) (Berényi et al, 2014). On day 6 p.i., all mice were sacrificed; both kidneys were removed, weighed and homogenized aseptically.…”

Population Pharmacokinetics of Escalating Doses of Caspofungin in a Phase II Study of Patients with Invasive Aspergillosis

“…The safety and tolerability of CAS as primary endpoints as well as descriptive pharmacokinetics and efficacy as secondary endpoints of the study were published by Cornely et al (11). Here we report the determination of PopPK parameters and the explorative analysis of trough levels at four escalating doses as further secondary endpoints.…”

“…The study was designed as a formal phase II doseescalation study in patients with invasive aspergillosis to define the maximum tolerated dose of CAS in this setting and to determine the pharmacokinetic properties of CAS given over a dosage range of 70 to 200 mg QD. The complete results of this trial have been published previously in this journal (11).…”

“…In order to explore the feasibility of administering higher doses of CAS in this setting, the safety, tolerability, and PKs of doses of CAS of up to 200 mg QD were investigated in a dose-escalation study in adult patients with proven or probable invasive aspergillosis (11). Here we report the detailed population pharmacokinetic (PopPK) analysis of CAS in patients enrolled in this clinical trial.…”