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Clinical Therapeutics

Pharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction: Differential Impact of Plasma Albumin and Bilirubin Levels

S. Kurland, M. Furebring, E. Löwdin, E. Eliasson, E. I. Nielsen, J. Sjölin
S. Kurland
aSection of Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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M. Furebring
aSection of Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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E. Löwdin
aSection of Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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E. Eliasson
bKarolinska Institutet, Department of Laboratory Medicine, Clinical Pharmacology, Karolinska University Hospital, Stockholm, Sweden
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E. I. Nielsen
cDepartment of Pharmaceutical Biosciences, Uppsala University, Sweden
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J. Sjölin
aSection of Infectious Diseases, Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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DOI: 10.1128/AAC.02466-18
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  • FIG 1
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    FIG 1

    Caspofungin plasma concentration-time curves on day 5 in patients receiving the 50-mg maintenance dose (A) and the 70-mg maintenance dose (B).

  • FIG 2
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    FIG 2

    Elimination rate constants, k10, on day 5 at different C-P levels (n = 37). Horizontal bars demonstrate median values.

  • FIG 3
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    FIG 3

    Correlation plot between AUC0–24 and albumin levels on day 5 (n = 37). The two patients with low AUC0–24 despite the highest albumin levels were the two classified as C-P class A with a score of 5 and associated with high elimination rates, as demonstrated in Fig. 4. Correlation analysis restricted to patients with C-P class B resulted in an r value of 0.51 (P = 0.002; n = 35).

  • FIG 4
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    FIG 4

    Proportion of patients on day 5 reaching target concentrations for Candida albicans (A) and C. glabrata (B) with different MICs. The distribution of the MIC values for C. albicans and C. glabrata are included at the top. Similar results were found on days 2 and 10. AUC/MIC ratios for C. albicans and C. glabrata of 865 and 450, respectively, were used in the calculations and refer to Andes et al. (32). The MIC distributions were obtained from Pfaller et al. (21).

  • FIG 5
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    FIG 5

    Pharmacokinetic two-compartment model. The central compartment (V1) represents blood and well-perfused organs, and the peripheral compartment (V2) represents more poorly perfused tissues. k12 and k21 are rate constants between V1 and V2, and k10 is the elimination rate constant from V1. k10 represents the fraction of caspofungin eliminated per hour from V1 at equilibrium between V1 and V2.

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  • TABLE 1

    Demographic and other characteristics of included patientsc

    ParameterValue(s)
    Demographics
        No. male/no. female (%)35/11 (76/24)
        Age [yr; median (range)]64 (19–89)
        Weight [kg; median (range)]80 (50–114)
        No. with weight of ≤80 kg23
        No. with weight of >80 kg23
        BMI [kg/m²; median (range)]25.1 (16.0-43.5)
    ICU, n
        Surgical and medical24
        Cardiothoracic19
        Burn3
    Primary diagnosis at admission to ICU, n
        Cardiac arrest3
        Cardiothoracic surgery8
        Pulmonary disease8
        Aortic surgery5
        Abdominal surgery or pancreatitis4
        Kidney transplantation1
        Hematological malignancies3
        Burn injury4
        Primary infection10
    APACHE II score, n (range)19 (3–40)
    Indication for treatment,a n (%)
        Candidemia3 (7)
        Abdominal candidiasis5 (11)
        Empirical37 (80)
        Prophylaxis1 (2)
    Species, nb
        C. albicans27
        C. glabrata1
        C. parapsilosis3
        Yeast; not specified1
        Mixed8
        C. albicans5
        C. glabrata4
        C. parapsilosis4
        C. tropicalis1
        C. lusitaniae1
        C. guilliermondii1
    • ↵a Indication as stated in the medical record.

    • ↵b Invasive isolates were C. albicans (5), C. glabrata (1), and C. parapsilosis (1).

    • ↵c Six patients had negative cultures.

  • TABLE 2

    Child-Pugh score, SOFA score, vital organ support, and parameters of hepatic and renal functiona

    ParameterValue(s) on day:
    2 (n = 46)5 (n = 37)
    Child-Pugh, n (%)
        Score 52 (4)2 (5)
        Score 63 (7)0
        Score 725 (54)24 (65)
        Score 83 (7)6 (16)
        Score 912 (26)5 (14)
        Score 101 (2)0
        Class A5 (11)2 (5)
        Class B40 (87)35 (95)
        Class C1 (2)0
    SOFA score, median (range)9 (2–21)7 (2–17)
    Vital organ support, n (%)
        CRRT21 (45)15 (40)
        Ventilator41 (89)30 (81)
        ECMO9 (20)9 (20)
    Parameters of hepatic and
    renal function, median (range)
        P-bilirubin, μmol/liter24 (4–286)18 (4–296)
        P-albumin, g/liter18.5 (11–44)20 (12–39)
        P-INR1.2 (0.9–1.8)1.2 (1.0–1.7)
        P-ALT, μkat/liter0.64 (0.15–10.5)0.86 (0.15–8.0)
        P-ALP, μkat/liter1.7 (0.59–8.6)1.8 (0.9–8.0)
        P-creatinine, μmol/liter97 (29–550)96 (36–289)
        GFR, ml/min/1.73m²84b (23–116)89c (25–117)
    • ↵a Values are given in absolute numbers (percent) or median (range). SOFA score, sequential organ failure assessment score; CRRT, continuous renal replacement therapy mainly performed as continuous venovenous hemodialysis; ECMO, extracorporeal membrane oxygenation; P, plasma; INR, international normalized ratio; ALT, alanine aminotransferase; ALP, alkaline phosphatase; μkat/liter, microkatal/liter; GFR, glomerular filtration rate as estimated by the Modification of Diet in Renal Disease Study equation.

    • ↵b Twenty-five patients (patients with CRRT excluded).

    • ↵c Twenty-two patients (patients with CRRT excluded).

  • TABLE 3

    PK parameters estimated by using all data or specific data

    ParameteraPK values [median (range)] for:
    All data (n = 46)Day 2 (n = 46)Day 5 (n = 37)Day 10 (n = 21)
    Cmax (mg/liter)5.1 (1.1–8.8)5.6 (3.6–9.0)5.3 (3.6–9.4)
    Cmin (mg/liter)1.1 (0.5–2.3)1.2 (0.5–2.7)1.1 (0.5–2.6)
    AUC0-24 (mg·h/liter)59.6 (32.7–105)61.1 (32.8–108)57.8 (44.0–113)58.4 (37.2–105)
    CL (liters/h)0.87 (0.47–1.70)0.84 (0.46–1.78)0.88 (0.44–1.58)0.90 (0.47–1.88)
    V1 (liters)11.2 (6.7–26.4)11.2 (6.7–26.4)11.9 (7.5–20.1)11.2 (7.7–19.4)
    V2 (liters)6.9 (1.6–22)6.9 (2.6–13)5.3 (1.5–7.1)5.5 (3.3–6.6)
    k10 (/h)0.074 (0.047–0.11)0.072 (0.048–0.11)0.079 (0.054–0.12)0.077 (0.061–0.12)
    • ↵a Cmax, maximal concentration; Cmin, minimal concentration; AUC0–24, area under the concentration-time curve from 0 to 24 h; CL, clearance; V1, central volume of distribution; V2, peripheral volume of distribution; k10, elimination rate constant from V1 at equilibrium between V1 and V2. Shrinkage (%): all data, CL of 11.2, V1 of 9.3, and V2 of 33.7; day 2, CL of 2.6, V1 of 4.6, and V2 of 54.0; day 5, CL of 17.6, V1 of 28.9, and V2 of 63; day 10, CL of 11.5, V1 of 42.1, and V2 of 76.7.

  • TABLE 4

    Correlation coefficients between PK parameters and Child-Pugh score, plasma bilirubin, albumin, INR, and SOFA score on day 5a (n = 37)

    ParameterAUC0-24CLV1k10
    C-P score0.03−0.070.19−0.50**
    Bilirubin0.000.020.22−0.46**
    Albumin0.45**−0.31−0.15−0.34*
    INR−0.080.00−0.03−0.04
    SOFA score0.03−0.050.20−0.47**
    • ↵a C-P, Child-Pugh; INR, international normalized ratio; SOFA, sequential organ failure assessment; AUC0–24, area under the concentration-time curve from 0 to 24 h; V1, central volume of distribution; V2, peripheral volume of distribution; k10, the elimination rate constant from V1 at equilibrium between V1 and V2. *, P < 0.05. **, P < 0.01.

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Pharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction: Differential Impact of Plasma Albumin and Bilirubin Levels
S. Kurland, M. Furebring, E. Löwdin, E. Eliasson, E. I. Nielsen, J. Sjölin
Antimicrobial Agents and Chemotherapy May 2019, 63 (6) e02466-18; DOI: 10.1128/AAC.02466-18

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Pharmacokinetics of Caspofungin in Critically Ill Patients in Relation to Liver Dysfunction: Differential Impact of Plasma Albumin and Bilirubin Levels
S. Kurland, M. Furebring, E. Löwdin, E. Eliasson, E. I. Nielsen, J. Sjölin
Antimicrobial Agents and Chemotherapy May 2019, 63 (6) e02466-18; DOI: 10.1128/AAC.02466-18
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KEYWORDS

Child-Pugh score
caspofungin
critically ill
pharmacokinetics

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