Dose Reduction of Caspofungin in Intensive Care Unit Patients with Child Pugh B Will Result in Suboptimal Exposure

Abstract

Background and objectives: Caspofungin is an echinocandin antifungal agent used as first-line therapy for the treatment of invasive candidiasis. The maintenance dose is adapted to body weight (BW) or liver function (Child-Pugh score B or C). We aimed to study the pharmacokinetics of caspofungin and assess pharmacokinetic target attainment for various dosing strategies.

Methods: Caspofungin pharmacokinetic data from 21 intensive care unit (ICU) patients was available. A population pharmacokinetic model was developed. Various dosing regimens (loading dose/maintenance dose) were simulated: licensed regimens (I) 70/50 mg (for BW <80 kg) or 70/70 mg (for BW >80 kg); and (II) 70/35 mg (for Child-Pugh score B); and adapted regimens (III) 100/50 mg (for Child-Pugh score B); (IV) 100/70 mg; and (V) 100/100 mg. Target attainment based on a preclinical pharmacokinetic target for Candida albicans was assessed for relevant minimal inhibitory concentrations (MICs).

Results: A two-compartment model best fitted the data. Clearance was 0.55 L/h and the apparent volumes of distribution in the central and peripheral compartments were 8.9 and 5.0 L, respectively. The median area under the plasma concentration-time curve from time zero to 24 h on day 14 for regimens I-V were 105, 65, 93, 130, and 186 mg·h/L, respectively. Pharmacokinetic target attainment was 100 % (MIC 0.03 µg/mL) irrespective of dosing regimen but decreased to (I) 47 %, (II) 14 %, (III) 36 %, (IV) 69 %, and (V) 94 % for MIC 0.125 µg/mL.

Conclusion: The caspofungin maintenance dose should not be reduced in non-cirrhotic ICU patients based on the Child-Pugh score if this classification is driven by hypoalbuminemia as it results in significantly lower exposure. A higher maintenance dose of 70 mg in ICU patients results in target attainment of >90 % of the ICU patients with species with an MIC of up to 0.125 µg/mL.

Fig. 1

Visual predictive check for the final pharmacokinetic model of caspofungin, based on n = 1000 simulations. Prediction-corrected simulated (shaded areas) and observed (circles and lines) caspofungin concentrations versus time after dose (h). The thick red line connects the observed median values per bin. The solid blue lines connect the 5th and 95th percentiles of the observations. The blue areas are the 95 % confidence interval of the 5th and 95th percentiles. The red area indicates the confidence interval of the median

Fig. 2

Goodness-of-fit plots for the final pharmacokinetic model of caspofungin. The solid black lines indicate the unit line or the line of identity. The thick lines (red or blue) are smooth lines showing the trend in the observations. CWRES conditional weighted residuals

Fig. 3

a AUC₂₄ on day 3 for the whole cohort, irrespective of body weight. b AUC₂₄ on day 14 for the whole cohort, irrespective of body weight. The horizontal line represents the AUC₂₄ for healthy volunteers. Regimens: (I) loading dose of 70 mg followed by 50 mg maintenance in patients with body weight ≤80 kg or by 70 mg maintenance in patients with body weight >80 kg; (II) 70 mg loading dose followed by 35 mg; (III) 100 mg loading dose followed by 50 mg maintenance; (IV) 100 mg loading dose followed by 70 mg maintenance; and (V) 100 mg loading dose followed by 100 mg maintenance. AUC area under the concentration–time curve, AUC ₂₄ AUC from time zero to 24 h

Fig. 4

Caspofungin concentration–time curve for a regimen I: a loading dose of 70 mg followed by 50 mg maintenance in patients with body weight ≤80 kg or by 70 mg maintenance in patients with body weight >80 kg; b regimen II: 70 mg loading dose followed by 35 mg as labeled for patients with moderate or severe hepatic dysfunction [2, 5, 6]; c regimen III: a 100 mg loading dose followed by 50 mg maintenance; d regimen IV: a 100 mg loading dose followed by 70 mg maintenance; and e regimen V: a 100 mg loading dose followed by 100 mg maintenance. The thick black lines are medians and the dotted lines are the 5 and 95 % percentiles. Conc concentration

Fig. 5

Target attainment versus MIC for all five simulated regimens based on a preclinical target AUC/MIC ratio of >865. Asterisk Indicates that the regimen is based on body weight: the maintenance dose was 50 mg for patients with body weight ≤80 kg and 70 mg for body weight >80 kg. AUC area under the concentration-time curve, MIC minimal inhibitory concentration