University of Groningen
Clinical pharmacology and therapeutic drug monitoring of voriconazole
Veringa, Anette
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Fungi are ubiquitous; there are about five million different species of fungi worldwide. Most of these fungi are innocuous for healthy individuals. However, some are opportunistic and can cause invasive infections especially in immuno- compromised patients [1]. In comparison with bac-
terial infections, these fungal infections are generally underestimated. However, the number of immunocompromised patients is increasing, predominantly by advances in medical treat- ment and more aggressive chemotherapy. Therefore, fungal infections have become an in- creasing threat for these patients.
01
Introduction
1.1 Invasive fungal infections
Both yeasts and filamentous moulds can cause invasive fungal infections. Among invasive fungal infections, invasive candi-diasis (for yeasts) and invasive aspergillosis (for moulds) are most common [2]. Other less
commonly isolated fungi include
Crypto-coccus, Fusarium, Scedosporium and Rhizopus
species [3, 4].
Candida species are part of the normal
human microbiome, present on skin and mucosal surfaces. In immunocompromised patients, as well as in surgical patients, colonisation of Candida species can result in candidemia, the most common form of invasive candidiasis [5, 6]. Risk factors for
invasive candidiasis include indwelling vascular catheters, recent surgery, and the treatment with broad-spectrum anti- biotics. Furthermore, the incidence of invasive candidiasis is high in patients in intensive care units. Despite improve-ment of treatimprove-ment in invasive candidiasis mortality remains high, up to 40-50% [6, 7].
Aspergillus species are wide-spread and can
be found throughout the entire environ-ment. They easily spread by air via sporu-lation [8,9]. In healthy individuals, inhalation
of these airborne conidia is harmless. How-ever, in immunocompromised patients the conidia can germinate and hyphae can be formed, which results in invasive asper-gillosis [10]. Especially patients with
pro-longed neutropenia, allogeneic stem cell recipients, or patients who received a solid organ transplantation and are treated with immunosuppressive drugs are at risk for invasive aspergillosis [11]. Although
anti-fungal prophylaxis is used to prevent inva-sive aspergillosis and despite improved and less toxic treatment of invasive aspergi
l-losis with newer antifungal drugs, morbidity and mortality remains significant [12].
1.2 Treatment of invasive fungal infections
For the treatment of invasive fungal infec-tions, currently three classes of antifungal agents are available, including polyenes, azoles, and echinocandines. For optimal antifungal treatment it is crucial to select the right antifungal agent, since the anti- fungal spectrum differs between anti- fungals [13-15]. In Table 1 the antifungal
spec-trum is shown for multiple antifungal agents against several invasive fungal pathogens that are commonly observed in clinical practice [13-15].
For optimal
antifungal
treatment, it is
crucial to select
the right
anti-fungal agent.
9
Table 1. Antifungal spectrum of activity for several antifungal agents against commonly observed
invasive fungal pathogens in clinical practice (data merged from: Andes, 2013 [13]; Nett, 2016 [14]; Carmona, 2017 [15]).
Plus sign (+): good activity against the specified organism; plus/minus sign (±): moderate activity against the specified organism (resistance noted); minus sign (−): little or no activity against the specified organism.
aIncludes amphotericin B deoxycholate and lipid amphotericin B formulations. bLimited clinical data.
1.3 Clinical pharmacology and therapeutic drug monitoring
Another important factor for treatment optimisation is understanding a drug’s pharmacokinetic and pharmacodynamic properties. In pharmacokinetics the absorp- tion, distribution, metabolism and excre-tion of a drug is described. The area un-der the concentration-time curve (AUC) over 24 hours (AUC0-24h) is most often used to determine the exposure to a drug. Pharmacodynamics describes the pharma-cological effect of the drug on the micro- organism and in the human body, inclu-ding both efficacy and toxicity. Here, the minimum inhibitory concentration (MIC) is used to describe the potency of an antifun-gal agent against a funantifun-gal isolate. By com-
bining the pharmacokinetic and pharmaco- dynamic properties of a drug, the pharmaco- logical profile for the drug is described [16, 17].
The pharmacokinetic/pharmacodynamic (PK/PD) indices that are commonly used to determine optimal antifungal treatment are the ratio of AUC to the MIC (AUC/MIC), the percentage of time that drug concentrations exceed the MIC (T>MIC) and the ratio of peak serum concentrations to MIC (peak/MIC) [17].
For several antifungal agents the clinical effect and occurrence of adverse events is associated with its serum concentration [13, 18].
However, the pharmacokinetics of some antifungals, for instance voriconazole, can be highly variable in patients [19]. For
drugs with such variable pharmacokinetics,
10
serum concentrations can be measured for treatment optimisation, also known as the-rapeutic drug monitoring (TDM). In general, TDM should be considered for drugs with variable pharmacokinetics, provided that efficacy and/or safety are associated with serum concentrations, and the response to treatment cannot be measured in a faster or more direct way [16].
Drug resistance to antifungals is increas- ingly recognised as an emerging global problem [20]. For instance, resistance in
A. fumigates isolates has already been de-
tected in all continents of the world [21].
As a result the PK/PD target cannot be achieved. Here, higher drug exposure is necessary to increase the chance of treat-
ment success, while the risk of toxicity is increased. Therefore, TDM should be considered whenever drug resistance might play a role.
1.4 Aim of this thesis
Better understanding of the pharmaco- kinetic and pharmacodynamic variability of voriconazole, will help to improve the treat- ment with this drug. The aim of this thesis is to gain insight in the pharmacokinetic variability of voriconazole and find out the optimum dosing approach for this drug. Furthermore, we address the potential additional value of performing TDM for voriconazole in clinical practice.
1.5 Outline of this thesis
In Chapter 2, a general overview will be given for monitoring of anti-infective drugs by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). PK/PD rela- tionships of anti-infective drugs will be discussed as well as the role of TDM for anti-infective drugs. Subsequently we will discuss the use of LC-MS/MS as a fast and accurate technique to help optimise treatment. Lastly, we explore alternative matrices, as well as the added value of a proficiency testing programme.
In this thesis we focus on voriconazole, a second-generation triazole with broad- spectrum antifungal activity. It is con- sidered as first-line treatment of invasive aspergillosis in adults [11, 22]. The mechanism
of action of this antifungal agent is based on inhibition of cytochrome P450-dependant 14α-lanosterol demethylation, which results in interruption of the ergosterol synthesis. Although voriconazole shows fungicidal activity against some filamentous fungi, it is fungistatic for yeasts [23]. 11
Voriconazole is available in both oral and intravenous formulation. After oral admini- stration it is rapidly absorbed and bioavail- ability seems high in healthy volunteers (> 90%) [24]. Several studies suggest that
the bioavailability is significantly reduced in patients [25, 26]. However, other factors
than bioavailability may have influenced the results of these studies. Therefore, in Chapter 4 we study the effect of switching the route of administration on voriconazole serum concentrations in hospitalised patients using retrospective data and strict inclusion criteria.
The main route of elimination for vori- conazole is via the liver, less than 2% is ex- creted unchanged in urine. After hepatic metabolism by several cytochrome P450 iso-enzymes, including CYP2C19, CYP2C9 and CYP3A4, the main metabolite vori- conazole-N-oxide is formed [24]. In chapter
3a we discuss the additional value of the measurement of voriconazole-N-oxide concentrations. In the second part of this chapter (3b) we describe a method to analyse voriconazole and voriconazole- N-oxide concentrations using LC-MS/MS.
Voriconazole shows non-linear pharmaco- kinetics, probably caused by saturation of its metabolism. As a result, an increase in the administered dose is not linearly related to an increase in drug exposure [24].
Several studies have shown that the efficacy and safety of voriconazole are associated with its serum concentration [27]. However,
the serum concentration is highly varia-ble in clinical practice. This variability is not only seen between patients, but also within patients over time [28, 29]. Several fac-
tors are known to influence voriconazole serum concetrations, including age, CYP2C19
genotype, concomitant use of CYP450 inhi- bitors or inducers, and liver function [24, 30-32].
We hypothesise that voriconazole serum concentrations can also be influenced by severe inflammation, since several drug-metabolising enzymes are down- regulated in the liver during inflamma- tion [33]. In Chapter 5 we prospectively
study the effect of inflammation on vori- conazole metabolism by measuring con- secutive voriconazole and voriconazole- N-oxide concentrations. We additionally examine the effect of voriconazole meta- bolism for several different cytochrome P450 2C19 genotypes.
Voriconazole is also recommended as treatment of invasive aspergillosis in pae- diatric patients [34]. However, the pharmaco-
kinetics of voriconazole in children dif-fers from adults. In children < 12 years of age, the pharmacokinetics of vori- conazole appears to be near linear, while in children ≥ 12 years of age vori- conazole pharmacokinetics seems non- linear. Though, with higher voriconazole doses, non-linear pharmacokinetics can also be observed in children < 12 years of age [35]. As in adults, the voriconazole
concentration is also very variable in paediatric patients and it remains diffi-cult to understand this high inter- and intra-individual variability and to opti-mise voriconazole treatment in these patients [36]. In Chapter 6a we present a
study that investigates whether inflam- mation could contribute to the variable voriconazole concentrations observed in children. In the second part of this Chapter (6b) we present a linked PK/PD mathematical model for true individual- ised treatment with voriconazole in children.
12
Since voriconazole shows variable pharmacokinetics and the serum concen- tration is associated with efficacy and safety, TDM of voriconazole has been suggested to improve treatment out- come and to avoid toxicity. In a recent meta-analysis a therapeutic range bet- ween 1.0-6.0 mg/L was proposed [37].
However, it is currently uncertain whether personalised voriconazole treatment by using TDM for all adult patients re- ceiving this drug is superior to the standard voriconazole dosing regimen. Furthermore, the evidence to support the benefit of TDM is limited to a few studies, most of them uncontrolled. Therefore, in Chapter 7a multicentre, prospective, cluster randomised cross-over clinical trial is presented to test if individualised treatment of voriconazole by using TDM in adult patients is superior compared with patients who receive the standard voriconazole dose without performing TDM.
In Chapter 8 the outcomes of the research in this thesis will be discussed and future perspectives are provided.
An important factor
for treatment optimisation
is understanding a drug’s
pharmacokinetic and
pharmacodynamic properties.
13References
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