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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 6/2016

Open Access 01-06-2016 | Original Research Article

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

Authors: Lisa C. Martial, Roger J. M. Brüggemann, Jeroen A. Schouten, Henk J. van Leeuwen, Arthur R. van Zanten, Dylan W. de Lange, Eline W. Muilwijk, Paul E. Verweij, David M. Burger, Rob E. Aarnoutse, Peter Pickkers, Thomas P. C. Dorlo

Published in: Clinical Pharmacokinetics | Issue 6/2016

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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.
Literature
1.
Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA. 2009;302(21):2323–9.CrossRefPubMed
2.
Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(5):503–35.CrossRefPubMed
3.
Andes DR, Safdar N, Baddley JW, Playford G, Reboli AC, Rex JH, et al. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis. 2012;54(8):1110–22.CrossRefPubMed
4.
Pound MW, Townsend ML, Drew RH. Echinocandin pharmacodynamics: review and clinical implications. J Antimicrob Chemother. 2010;65(6):1108–18.CrossRefPubMed
5.
6.
7.
Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646–9.CrossRefPubMed
8.
Muilwijk EW, Schouten JA, van Leeuwen HJ, van Zanten AR, de Lange DW, Colbers A, et al. Pharmacokinetics of caspofungin in ICU patients. J Antimicrob Chemother. 2014;69(12):3294–9.CrossRefPubMed
9.
Andes DR, Diekema DJ, Pfaller MA, Marchillo K, Bohrmueller J. In vivo pharmacodynamic target investigation for micafungin against Candida albicans and C. glabrata in a neutropenic murine candidiasis model. Antimicrob Agents Chemother. 2008;52(10):3497–503.CrossRefPubMedPubMedCentral
10.
Louie A, Deziel M, Liu W, Drusano MF, Gumbo T, Drusano GL. Pharmacodynamics of caspofungin in a murine model of systemic candidiasis: importance of persistence of caspofungin in tissues to understanding drug activity. Antimicrob Agents Chemother. 2005;49(12):5058–68.CrossRefPubMedPubMedCentral
11.
Andes D, Diekema DJ, Pfaller MA, Bohrmuller J, Marchillo K, Lepak A. In vivo comparison of the pharmacodynamic targets for echinocandin drugs against Candida species. Antimicrob Agents Chemother. 2010;54(6):2497–506.CrossRefPubMedPubMedCentral
12.
Wiederhold NP, Kontoyiannis DP, Chi J, Prince RA, Tam VH, Lewis RE. Pharmacodynamics of caspofungin in a murine model of invasive pulmonary aspergillosis: evidence of concentration-dependent activity. J Infect Dis. 2004;190(8):1464–71.CrossRefPubMed
13.
Janmahasatian S, Duffull SB, Ash S, Ward LC, Byrne NM, Green B. Quantification of lean bodyweight. Clin Pharmacokinet. 2005;44(10):1051–65.CrossRefPubMed
14.
Lindbom L, Pihlgren P, Jonsson EN. PsN-Toolkit–a collection of computer intensive statistical methods for non-linear mixed effect modeling using NONMEM. Comput Methods Programs Biomed. 2005;79(3):241–57.CrossRefPubMed
15.
Hall RG, Swancutt MA, Gumbo T. Fractal geometry and the pharmacometrics of micafungin in overweight, obese, and extremely obese people. Antimicrob Agents Chemother. 2011;55(11):5107–12.CrossRefPubMedPubMedCentral
16.
Hall RG 2nd, Swancutt MA, Meek C, Leff R, Gumbo T. Weight drives caspofungin pharmacokinetic variability in overweight and obese people: fractal power signatures beyond two-thirds or three-fourths. Antimicrob Agents Chemother. 2013;57(5):2259–64.CrossRefPubMedPubMedCentral
17.
Hope WW, Seibel NL, Schwartz CL, Arrieta A, Flynn P, Shad A, et al. Population pharmacokinetics of micafungin in pediatric patients and implications for antifungal dosing. Antimicrob Agents Chemother. 2007;51(10):3714–9.CrossRefPubMedPubMedCentral
18.
Wurthwein G, Cornely OA, Trame MN, Vehreschild JJ, Vehreschild MJ, Farowski F, et al. Population pharmacokinetics of escalating doses of caspofungin in a phase II study of patients with invasive aspergillosis. Antimicrob Agents Chemother. 2013;57(4):1664–71.CrossRefPubMedPubMedCentral
19.
Beal SL, Sheiner LB, Boeckmann A. NONMEM user’s guides (1989–2006). Ellicott City: Icon Development Solutions; 2006.
20.
Jonsson EN, Karlsson MO. Xpose–an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed. 1999;58(1):51–64.CrossRefPubMed
21.
Keizer RJ, van Benten M, Beijnen JH, Schellens JH, Huitema AD. Pirana and PCluster: a modeling environment and cluster infrastructure for NONMEM. Comput Methods Programs Biomed. 2011;101(1):72–9.CrossRefPubMed
22.
R Development Core Team. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2013.
23.
Pickkers P, de Keizer N, Dusseljee J, Weerheijm D, van der Hoeven JG, Peek N. Body mass index is associated with hospital mortality in critically ill patients: an observational cohort study. Crit Care Med. 2013;41(8):1878–83.CrossRefPubMed
24.
Bruggemann RJ, Van Der Velden WJ, Knibbe CA, Colbers A, Hol S, Burger DM, et al. A rationale for reduced-frequency dosing of anidulafungin for antifungal prophylaxis in immunocompromised patients. J Antimicrob Chemother. 2015;70(4):1166–74.PubMed
25.
Pfaller MA, Boyken L, Hollis RJ, Kroeger J, Messer SA, Tendolkar S, et al. Wild-type MIC distributions and epidemiological cutoff values for the echinocandins and Candida spp. J Clin Microbiol. 2010;48(1):52–6.CrossRefPubMedPubMedCentral
26.
Pfaller MA, Diekema DJ, Andes D, Arendrup MC, Brown SD, Lockhart SR, et al. Clinical breakpoints for the echinocandins and Candida revisited: integration of molecular, clinical, and microbiological data to arrive at species-specific interpretive criteria. Drug Resist Updat. 2011;14(3):164–76.CrossRefPubMed
27.
Wurthwein G, Young C, Lanvers-Kaminsky C, Hempel G, Trame MN, Schwerdtfeger R, et al. Population pharmacokinetics of liposomal amphotericin B and caspofungin in allogeneic hematopoietic stem cell recipients. Antimicrob Agents Chemother. 2012;56(1):536–43.CrossRefPubMedPubMedCentral
28.
Anderson BJ, Holford NH. Mechanistic basis of using body size and maturation to predict clearance in humans. Drug Metab Pharmacokinet. 2009;24(1):25–36.CrossRefPubMed
29.
Holford N, Heo YA, Anderson B. A pharmacokinetic standard for babies and adults. J Pharm Sci. 2013;102(9):2941–52.CrossRefPubMed
30.
West GB, Brown JH, Enquist BJ. A general model for the origin of allometric scaling laws in biology. Science. 1997;276(5309):122–6.CrossRefPubMed
31.
32.
Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient–concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev. 2014;20(77):3–11.CrossRef
33.
Mistry GC, Migoya E, Deutsch PJ, Winchell G, Hesney M, Li S, et al. Single- and multiple-dose administration of caspofungin in patients with hepatic insufficiency: implications for safety and dosing recommendations. J Clin Pharmacol. 2007;47(8):951–61.CrossRefPubMed
34.
Mora-Duarte J, Betts R, Rotstein C, Colombo AL, Thompson-Moya L, Smietana J, et al. Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med. 2002;347(25):2020–9.CrossRefPubMed
35.
Betts RF, Nucci M, Talwar D, Gareca M, Queiroz-Telles F, Bedimo RJ, et al. A Multicenter, double-blind trial of a high-dose caspofungin treatment regimen versus a standard caspofungin treatment regimen for adult patients with invasive candidiasis. Clin Infect Dis. 2009;48(12):1676–84.CrossRefPubMed
36.
Safdar A, Rodriguez G, Rolston KV, O’Brien S, Khouri IF, Shpall EJ, et al. High-dose caspofungin combination antifungal therapy in patients with hematologic malignancies and hematopoietic stem cell transplantation. Bone Marrow Transplant. 2007;39(3):157–64.CrossRefPubMed
37.
Cornely OA, Vehreschild JJ, Vehreschild MJ, Wurthwein G, Arenz D, Schwartz S, et al. Phase II dose escalation study of caspofungin for invasive Aspergillosis. Antimicrob Agents Chemother. 2011;55(12):5798–803.CrossRefPubMedPubMedCentral
38.
Radboud University. Pharmacokinetics of caspofungin (Cancidas®) given intravenously as therapy to patients with an invasive fungal infection in the intensive care unit—a search for co-variates (CASCADE) [ClinicalTrials.gov identifier NCT01533558]. US National Institutes of Health, ClinicalTrials.gov. https://​www.​clinicaltrials.​gov. Accessed 7 Nov 2015.
Metadata
Title
Dose Reduction of Caspofungin in Intensive Care Unit Patients with Child Pugh B Will Result in Suboptimal Exposure
Authors
Lisa C. Martial
Roger J. M. Brüggemann
Jeroen A. Schouten
Henk J. van Leeuwen
Arthur R. van Zanten
Dylan W. de Lange
Eline W. Muilwijk
Paul E. Verweij
David M. Burger
Rob E. Aarnoutse
Peter Pickkers
Thomas P. C. Dorlo
Publication date
01-06-2016
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 6/2016
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-015-0347-2

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