Antifungal Pharmacokinetics and Pharmacodynamics .Antifungal Pharmacokinetics and Pharmacodynamics

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  • published online November 10, 2014Cold Spring Harb Perspect Med Alexander J. Lepak and David R. Andes Antifungal Pharmacokinetics and Pharmacodynamics

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    http://perspectivesinmedicine.cshlp.org/cgi/collection/ For additional articles in this collection, see

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  • Antifungal Pharmacokineticsand Pharmacodynamics

    Alexander J. Lepak and David R. Andes

    University of Wisconsin, Madison, Wisconsin 53705

    Correspondence: dra@medicine.wisc.edu

    Successful treatment of infectious diseases requires choice of the most suitable antimicrobialagent, comprising consideration of drug pharmacokinetics (PK), including penetration intoinfection site, pathogen susceptibility, optimal route of drug administration, drug dose, fre-quency of administration, duration of therapy, and drug toxicity. Antimicrobial pharmacoki-netic/pharmacodynamic (PK/PD) studies consider these variables and have been useful indrug development, optimizing dosing regimens, determining susceptibility breakpoints, andlimiting toxicity of antifungal therapy. Here the concepts of antifungal PK/PD studies arereviewed, with emphasis on methodology and application. The initial sections of this reviewfocus on principles and methodology. Then the pharmacodynamics of each major antifungaldrug class (polyenes, flucytosine, azoles, and echinocandins) is discussed. Finally, thereview discusses novel areas of pharmacodynamic investigation in the study and applicationof combination therapy.

    PHARMACOKINETICS

    Pharmacokinetic (PK) studies describe thehost exposure and elimination of a drug.Common PK measures include absorption, ac-cumulation in various tissues or compartments,metabolism, and elimination. From a pharma-codynamic (PD) perspective, PK measures rep-resent drug exposure with respect to the host,for example, translating a dose (i.e., mg/kg) toa drug exposure (e.g., area under the concentra-tion curve, or AUC) (Drusano 2004). Tradition-al PK measures considered in PD analyses in-clude the maximal concentration (Cmax), thetotal exposure or AUC, and assessment of con-centration over time by use of the elimination

    half-life. The most common site of PK assess-ment is the serum. However, other PK tissue sitesof suggested clinical relevance include the cere-brospinal fluid, ocularcompartments, the urine,and the epithelial lining fluid (ELF) compart-ment of the lung. Most fungal infections occurin the extracellular fluid compartment, and,therefore, serum or plasma drug concentrationscorrelate quite well with drug concentrations atthe site of infection (Mukherjee et al. 2006). Thishas been shown to be true for candidiasis, in-cluding mucocutaneous and invasive/dissemi-nated disease (Andes 2004; Mukherjee et al.2006). However, a subset of fungal infectionsinvolves primarily pulmonary parenchymal dis-ease, for example, aspergillosis and zygomy-

    Editors: Arturo Casadevall, Aaron P. Mitchell, Judith Berman, Kyung J. Kwon-Chung, John R. Perfect, and Joseph Heitman

    Additional Perspectives on Human Fungal Pathogens available at www.perspectivesinmedicine.org

    Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reservedAdvanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a019653

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  • cetes. The relevance of drug concentration with-in the ELF of the lung has been investigated, butthe evidence that ELF concentrations are morepredictive of serum or plasma concentrations islacking. This is likely because of the fact thatthese disease syndromes are invasive in nature,with significant tissue involvement. However,ELF concentrations may be more relevant forprophylaxis as the organism must first colonizeand infect the alveolar space, and prophylaxisstudies in animal models using ELF concentra-tions are an emerging area of study (Rodvoldet al. 2011). Infection of the central nervoussystem (CNS), eye, and lower urinary tract areexamples in which drug penetration and PKmeasurement at the site of infection has beenshown to be relevant (Perfect et al. 1986; Savaniet al. 1987; Groll et al. 2000; Gauthieret al. 2005).For example, only flucytosine and fluconazoleachieve reliably therapeutic urine concentra-tions for treatment of lower urinary tract infec-tions (Fisher et al. 2011). For intraocular andCNS infections fluconazole, voriconazole, flu-cytosine, and liposomal amphotericin B wouldbe optimal from the PK standpoint (Utz 1975;Brammer et al. 1990; Purkins et al. 2002; Sunet al. 2009; Riddell et al. 2011; Schwartz et al.2011).

    An additional PK measurement that war-rants consideration is binding of drug to serumalbumin (Kunin et al. 1973; Craig and Kunin1976; Craig and Ebert 1989). A relatively largenumber of antimicrobial treatment studies haveshown that only free, non-protein-bound drugis pharmacologically active (Craig and Welling1977; Zeitlinger et al. 2011). This can be a resultof limited penetration of protein-bound drugto the site of infection as well as limited abilityof protein-bound drug to bind at the site ofactivity. In the context of antifungal drugs, therelevance of protein binding has been shownfor both triazoles and echinocandins and willbe elucidated in the following sections (Andes2003a; Andes et al. 2010).

    In Vitro Drug Potency

    A unique factor in antimicrobial PD studiesis ability to consider PK relative to a measure

    of drug potency, specifically the in vitro suscep-tibility test most commonly expressed as theminimum inhibitory concentration (MIC). Avarietyof antifungal susceptibility testing proto-cols have been standardized using broth micro-dilution, disk-diffusion, and antifungal gradientstrip (Etest) methodologies (Wanger et al. 1995;CLSI 2004, 2008a,b,c; EUCAST 2008, 2012). Ineach, the goal is to define the minimum concen-tration of drug that inhibits some degree of or-ganism growth MIC. MIC end points and timeat which they are read can differ from drug todrug and between standardized methodologies(Chryssanthou and Cuenca-Estrella 2006; Pfal-ler and Diekema 2012).

    In Vitro PK/PD Models

    In vitro PK/PD studies are often the first todefine the PD characteristics. The majority ofin vitro PK/PD studies use a nutrient broth sys-tem of variable complexity ranging from a singlestatic environment to multiple chambers to al-low the investigator to closely mimic human PKprofiles. The advantages of in vitro systems in-clude the ability to frequently assess microbio-logic effect and closely parallel PK in patients.The disadvantages of in vitro approaches in-clude the lack of the clinical infection site, whichdoes not account for the host immune systemand tissue PK, including protein binding. Ad-ditionally, in vitro models do not always accountfor variability in organism fitness that is oftenobserved in vivo. However, the models providean opportunity to accurately assess PD charac-teristics, such as the impact of concentrationand can also be useful for estimating the PK/PD target (Lewis et al. 1998, 2000; Ernst et al.1999; Te Dorsthorst et al. 2013). More recently,investigators have modified in vitro systems tomore closely mimic the host and infection site.For example, a human cell culture with a bilayerof alveolar epithelial cells and pulmonary arteryendothelial cells has been shown to be particu-larly useful to examine the pharmacology of in-vasive pulmonary aspergillosis treatment (Hopeet al. 2007a; Gregson et al. 2012; Jeans et al.2012a,b). This model has also been val