Dosing of caspofungin based on a pharmacokinetic/pharmacodynamic index for the treatment of invasive fungal infections in critically ill patients on continuous venovenous haemodiafiltration

Highlights

• A population PK model was developed for caspofungin in ICU patients.

• Simulations of different dosage regimens were performed.

• Suboptimal concentrations are achieved with licensed regimen in ICU patients.

• Probabilities of target attainment with increasing doses were estimated.

Abstract

Introduction

The study objective was to evaluate the efficacy of different dosages of caspofungin in the treatment of invasive candidiasis and aspergillosis, in relation to the probability of pharmacokinetic/pharmacodynamic (PK/PD) target attainment, using modelling and Monte Carlo simulations in critically ill adult patients on continuous haemodiafiltration.

Methods

Critically ill adult patients on continuous venovenous haemodiafiltration treated with caspofungin were analysed. A population PK model was developed. Four caspofungin dosing regimens were simulated: the licensed regimen, 70 mg/day, 100 mg/day or 200 mg/day. A PK/PD target was defined as the ratio between the area under the caspofungin concentration-time curve over 24 hours and the minimal inhibitory concentration (AUC/MIC) for candidiasis or the minimal effective concentrations (AUC/MEC) for Aspergillus spp. Target attainment based on preclinical target for Candida and Aspergillus was assessed for different MIC or MEC, respectively.

Results

Concentration-time data were described by a two-compartment model. Body–weight and protein concentration were the only covariates identified by the model. Goodness-of-fit plots and bootstrap analysis proved the model had a satisfactory performance. As expected, a higher maintenance dose resulted in a higher exposure. Target attainment was >90% for candidiasis (MIC≤0.06 mg/L) and aspergillosis (MEC≤0.5 mg/L), irrespective of the dosing regimen, but not for C. parapsilosis. Standard regimen was insufficient to reach the target for C. albicans and C. parapsilosis with MIC≥0.1 mg/L.

Conclusion

The licensed regimen of caspofungin is insufficient to achieve the PK/PD targets in critically ill patients on haemodiafiltration. The determination of MICs will enable dose scheme selection.

Introduction

Caspofungin is an echinocandin licensed for both invasive candidiasis and aspergillosis treatment in adult and paediatric patients who are refractory or intolerant to amphotericin B, lipid formulations of amphotericin B or itraconazole, and as empirical therapy of presumed fungal infections in febrile, neutropenic patients. In the critical care setting, current guidelines recommend all three echinocandins (anidulafungin, caspofungin and micafungin) as first–line treatment of invasive candidiasis [1], [2].

Dosing is based on body weight. A loading dose of 70 mg followed by a daily maintenance dose of 50 mg or 70 mg is recommended in patients with body weight up to 80 kg, or greater than 80 kg, respectively. No dose adjustment is needed in case of renal impairment [3]. Adequate dosing in special populations, such as patients with co-morbidities or renal insufficiency or critically ill patients, is of crucial importance to prevent suboptimal outcomes and to avert the emergence of resistance [4], [5]. For these reasons, researchers have recently investigated the pharmacokinetics (PK) of echinocandins in these populations [6], [7]. Although echinocandins exhibit some similarities in their PK profiles, limited data have been published on caspofungin PK during continuous renal replacement therapy (CRRT) and regarding the impact of dosing schedule variations under these circumstances [8]. Drug removal in critically ill patients receiving CRRT is complex, with multiple variables affecting clearance. Weiler et al. investigated the influence of haemofiltration and haemodialysis on the PK of caspofungin in critically ill patients [9]. In this non-compartmental analysis, caspofungin exposure in patients on CRRT was comparable to exposure in control patients, and the standard dosage was concluded to be probably adequate for patients on CRRT [9]. Recently, Aguilar et al. reported similar findings in critically ill patients on haemodiafiltration [10].

Survival rates in patients with invasive aspergillosis treated with echinocandins ranged from 50% to 67% and in patients with invasive candidiasis ranged from 66% to 90% [11]. Preclinical and limited clinical data support the concept of escalating doses of caspofungin with preservation of its safety profile [12], [13]. Pharmacokinetic/pharmacodynamic (PK/PD) study results have demonstrated concentration-dependent killing of echinocandins [14]. Thus, antifungal dosage could be optimized based on PK/PD properties. A PK/PD target in humans has not yet been established, but, interestingly, caspofungin has been associated with a 1 log kill/24 h in a neutropenic mouse model of disseminated candidiasis, when the area under the caspofungin concentration-time curve over 24 hours-minimal inhibitory concentration ratio (AUC/MIC) was between 450 and 1185 [15]. On the other hand, caspofungin shows a fungistatic action against moulds and it is difficult to establish an MIC at which Aspergillus spp. is inhibited. Some authors indicated that the minimal effective concentration (MEC) rather than the MIC is a better indicator to determine the activity of caspofungin against moulds [16]. A maximum concentration-MEC (C_max/MEC) ratio of 10-20 has been proposed as a good predictor of caspofungin efficacy in invasive aspergillosis [14].

The objective of this study was to evaluate the efficacy of different dosages of caspofungin in the treatment of invasive candidiasis and aspergillosis, in relation to the probability of PK/PD target attainment, using modelling and Monte Carlo simulations in critically ill adult patients on continuous haemodiafiltration.