This is the peer reviewed version of the following article: Antifungal therapeutic drug monitoring: focus on drugs without a clear recommendation A Gómez-López Clin Microbiol Infect. 2020 Jun 11;S1198-743X(20)30335-9. which has been published in final form at https://doi.org/10.1016/j.cmi.2020.05.037 1 Antifungal therapeutic drug monitoring: focus on drugs without a clear 1 recommendation 2 3 Running title: Antifungal exposure 4 5 Alicia Gómez-López* 6 Mycology Reference and Research Laboratory, 7 Centro Nacional de Microbiología, Instituto de Salud Carlos III (CNM-ISCIII) 8 Majadahonda, 28220 Madrid, Spain. 9 10 Carretera Majadahonda-Pozuelo Km 2. 28220 Majadahonda (Madrid), Spain. 11 Phone: + 34-91-8223661. E-mail: aliciagl@isciii.es 12 13 (*) Corresponding author. e-mail: aliciagl@isciii.es 14 15 Keywords 16 Antifungal exposure; azoles, polyenes, echinocandins, therapeutic drug monitoring, 17 pharmacodynamics target 18 19 20 21 22 Código de campo cambiado 2 Abstract 23 Background. The goal of therapeutic drug monitoring is to determine the appropriate 24 exposure of difficult-to-manage medications to optimize the clinical outcomes in 25 patients under various clinical situations. Concerning antifungal treatment, and knowing 26 that this procedure is expensive and time consuming, it is particularly recommended for 27 certain systemic antifungals, i.e., agents with a well-defined exposure-response 28 relationship and unpredictable pharmacokinetic profile or narrow therapeutic index. 29 Little evidence supports the routine use of therapeutic drug monitoring for polyenes 30 (amphotericin B), echinocandins, fluconazole or new azoles such as isavuconazole, 31 despite the fact that a better understanding of antifungal exposure may lead to a better 32 response. Objectives. The aim of this work is to review published 33 pharmacokinetic/pharmacodynamic data on systemically administered antifungals 34 focusing on those whose monitoring is not routinely recommended by experts. Sources. 35 A MEDLINE search of the literature in English was performed introducing the following 36 search terms “Amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, 37 triazoles, caspofungin, micafungin, anidulafungin, echinocandins, pharmacokinetics, 38 pharmacodynamics, and therapeutic drug monitoring. Review articles and guidelines 39 were also screened. Content. This article collects different pharmacokinetic/ 40 pharmacodynamics aspects of systemic antifungals and summarizes recent threshold 41 values for clinical outcomes and adverse events. Although for polyenes, echinocandins, 42 fluconazole and isavuconazole extensive clinical validation is still required for a clear 43 threshold and a routine monitoring recommendation, particular points such as liposome 44 structure or complex pathophysiological conditions, affecting final exposure, are 45 discussed. For the rest, their better-defined exposure-response/toxicity relationship 46 3 allow to have useful threshold values and to justify routine monitoring. Additionally, 47 clinical data are needed to better define thresholds that can minimise the development 48 of antifungal resistance. 49 Implications. General therapeutic drug monitoring for all systemic antifungals is not 50 recommended, however, this approach may help to stablish an adequate antifungal 51 exposure for a favourable response, prevention of toxicity or development of resistance 52 in special clinical circumstances. 53 54 Background 55 For therapeutic drug monitoring (TDM) to be reasonably useful, the following 56 characteristics should be met: availability of a validated assay, demonstrated variable 57 interindividual exposure (pharmacokinetic variability, PKv), high correlation between 58 blood concentration and efficacy/toxicity, and a narrow therapeutic index. Being an 59 intervention method, the main goal is to establish the appropriate exposure of difficult-60 to-manage medications to improve patient responses to the drugs administered and to 61 avoid adverse drug reactions. 62 In clinical practice, drug exposure is monitored through measurement of blood trough 63 concentrations (Cmin), a more reliable index of drug exposure than dosage, which also 64 serve as surrogate markers of area under the curve (AUC). 65 Systemic antifungal agents for the management of invasive fungal infections (IFIs) 66 include polyenes (amphotericin B), triazoles (fluconazole, itraconazole, voriconazole, 67 posaconazole and isavuconazole), echinocandins (caspofungin, micafungin, and 68 anidulafungin), and flucytosine. For most of them, the PKv is a common issue. An in-69 4 depth understanding of the relationship between antifungal exposure and response is 70 required to establish clinically useful threshold values for clinical outcomes and adverse 71 events, and thus for TDM usefulness. However, the resources used in antifungal TDM, 72 i.e. economical costs, are not always backed by positive results. In most cases, studies 73 analysing the impact of antifungal TDM on efficacy and safety are observational or 74 include a low number of patients. However, most of them have found TDM to be 75 beneficial, particularly with certain types of triazole drugs and flucytosine, due to their 76 large inter- and intra-individual PKv and their high tendency for drug-drug interactions 77 or their toxicity [1]. Furthermore, there is scarce evidence to support the routine use of 78 TDM for polyenes, echinocandins, fluconazole or the new triazole isavuconazole, 79 although a better understanding of antifungal exposure may lead to better response. 80 TDM may be useful in certain circumstances, e.g., when dosing children, adolescents, 81 and critical or older patients, due to scarce exposure information. Conditions that affect 82 absorption of oral formulations (mucositis or vomiting) or distribution (inflammation 83 that leads to increased body fluids) may affect final exposure. Here, data on systemic 84 antifungal TDM are reviewed, focusing on those for which there are not clear expert 85 recommendations. Tables 1 and 2 summarize these data, including a list of available 86 studies and the main pharmacokinetic (PK) and pharmacodynamic (PD) characteristics 87 for each of them. 88 89 Antifungals with no routine recommendations for TDM monitoring 90 Polyenes 91 Amphotericin B (AmB) is the most commonly used polyene antifungal agent with a 92 broad spectrum of action against yeasts, moulds, and certain protozoa. It remains one 93 5 of the most prescribed antifungals for critically ill patients. The initial formulation was 94 amphotericin B deoxycholate (DAmB) and for many decades, it was the only polyene 95 agent available for the treatment of invasive fungal diseases. However, the major dose-96 limiting toxicity of DAmB (most notably nephrotoxicity and infusion-related reactions) 97 promoted the development of novel less toxic formulations. Different lipid-based 98 formulations have been developed: liposomal, lipid complex and colloidal dispersion [2]. 99 AMB lipid complex (ABLC, the largest of the lipid preparations) is available in the market 100 in few countries, whereas the production of AMB colloidal dispersion, a cholesteryl 101 sulphate complex of AMB, has stopped [3]. Liposomal amphotericin B (AmBisome®; 102 LAmB) is the most frequently used lipid formulation for nearly 30 years to treat a wide 103 range of fungal infections due to its antifungal activity, tolerability and efficacy. AmB 104 retains the antifungal activity after its incorporation into a liposome bilayer and its 105 toxicity is significantly reduced [4]. Studies in animals and humans have shown that 106 LAmB produces higher exposure in blood and tissues than other formulations (LAmB 107 maximum concentration in serum, Cmax, 22.9 ± 10 μg/ml vs DAmB Cmax, 1.4 ± 0.2 μg/ml), 108 with clear differences in PK behaviour between these two formulations [5]. Although 109 standard doses of lipid formulations are around five-time higher than those of 110 conventional DAmB (which can explain the high blood levels) it is suspected that, 111 because the structure of the liposome stabilized AmB in blood, the extravascular 112 liberation of AmB from liposomes might be limited. This would explain the high blood 113 levels and reduced distribution in normal organs, including kidneys, helping to increase 114 the safety of liposomal formulations. However, in infected tissues, a gap is formed 115 between vascular endothelial cells due to inflammation and tissues cells affected by 116 fungal invasion. This enhances the permeability of the capillary vascular wall and blood-117 6 tissue barrier [6] leading to higher distribution into the infected organs and increased 118 efficacy with some degree of selectivity. A study showed that in a patient with 119 pulmonary aspergillosis treated with LAmB, drug levels in the infected areas were 120 approximately 3-fold higher in comparison to non-infected areas, confirming that LAmB 121 is more likely to accumulate around infected lesions [7]. Demartini et al. also described 122 lower AmB concentrations in plasma than in tissues in 18 patients with lung cancer [8]. 123 However, there are scarce data on the relationship between AmB exposure and clinical 124 outcome, which further complicates the identification of a target therapeutic range. 125 New data regarding a specific pharmacodynamic (PD) target recognize the maximum 126 concentration-to-MIC (Cmax/MIC) ratio of AmB as the index that best predicts clinical 127 response [9,10]. The Cmax/MIC ratio required for efficacy remains controversial ranging 128 from 3.8 to 40.2 in animal and human studies [11-14]. Although clinical verification is 129 still required, targeting a Cmax/MIC ratio 4.5 or higher may serve as an index for 130 predicting the clinical effects of LAmB in order to design treatment regimens. However, 131 little is known if this PD target should be established considering free or total AmB 132 (encapsulated and non-encapsulated in liposomes) [12]. In line with this, liposome 133 structure deserves special attention. As for other liposome formulations, drugs 134 sequestered within this particle cannot achieve diffusional equilibrium with the 135 extravascular compartment. Additionally, the AmB released from a liposome highly 136 binds to plasma protein (>90%, highly dependent on patient clinical status) and this 137 aspect may affect final AMB blood exposure. Thus, the total AmB measured in blood 138 after LAmB administration may not indicate the real exposure [12], and the clinical use 139 of monitoring AmB blood concentration may be questionable. Thus, until a clearer 140 relationship between total AmB exposure and efficacy is established, TDM may be 141 7 recommended for toxicity surveillance and treatment optimization but not in routine 142 clinical practice. 143 144 Azoles 145 Fluconazole (FLC) 146 Fluconazole is a common antifungal option for managing Candida infections. It is 147 available in oral and intravenous formulations. TDM is currently not recommended since 148 appropriate antifungal exposure has been correlated with favourable outcomes in 149 patients receiving this azole. However, in spite of its favourable PK behaviour, FLC 150 exposure and toxicity (hepatic) may be affected by complex pathophysiological 151 conditions, e.g. renal insufficiency, requiring dosage adjustment for better outcome. 152 Sinnollareddy et al described how fluconazole exposure was highly variable in critical 153 patients compared with healthy volunteers [15]. Thus, TDM‐guided dosing adaptation 154 may optimize drug exposure in selected patient populations (ie, pediatric patients or 155 those undergoing renal replacement therapies) [16]. The PD index that best relates to 156 the outcome is the AUC0_24/MIC (or dosage/MIC, as the AUC and the dosage are highly 157 correlated). PD values ranging between 50-100 were generally associated with 158 favourable clinical outcomes [16-18]. This target corresponded with a Cmin at around 10–159 15 mg/L [17]. In adult liver transplant recipients receiving FLC for invasive candidiasis, 160 TDM showed that a FLC Cmin > 11 mg/L significantly correlated with clinical success [18]. 161 However, several reports have shown that not many patients achieve the desired index 162 required for optimal outcome, which contributes to the emergence of FLC resistance. 163 Further data on exposure-resistance relationships may provide a role for FLC TDM for a 164 more rational use of this antifungal agent. 165 8 Isavuconazole (ISZ): Isavuconazonium sulfate is the most recently approved triazole for 166 the treatment of adults with invasive aspergillosis and invasive mucormycosis [19]. It is 167 a water-soluble prodrug that is rapidly hydrolysed by esterases to the active moiety, ISZ. 168 Data from healthy volunteers and animal models allow concluding that ISZ PK is linear 169 and dose-proportional with dosages up to 600 mg/day, which is useful for predicting 170 blood concentrations in humans. Although the clinical experience with ISZ is limited in 171 comparison to other triazoles, the IDSA and ECIL-6 guidelines recognize lower rates of 172 adverse effects (photosensitivity, skin disorders, hepatobiliary or visual disorders) and a 173 better safety profile compared with other triazoles [20,21]. Additionally, ISZ has a lower 174 predisposition for drug-drug interactions mediated by cytochrome P450 in comparison 175 to VRC [22]. A relevant covariate that affects ISZ exposure is ethnicity [23]. Although 176 animal studies show a very strong relationship between the AUC0_24/MIC ratio and 177 treatment outcome, there is little evidence in humans regarding concentration-178 dependent efficacy or failure to establish a true PD target. No exposure-response 179 relationship was found in the SECURE study, suggesting that the achieved ISZ exposures 180 by clinical dosage regimens were near maximal and enough for treating the infecting 181 organisms [23], concluding that routine ISZ TDM is not recommended. However, ISZ is a 182 relatively new antifungal, and clinical evidences are still needed in selected patient 183 populations. Subjects with critical illness, sepsis, low or high body weight, polypharmacy, 184 hepatic impairment, renal replacement therapy or other extracorporeal devices, long-185 term administration (which is usually required in proven invasive fungal disease), and 186 on oral treatment may benefit from ISZ exposure monitoring. Data from real-world 187 experiences and clinical trials revealed a low percentage of patients (˂10%) showing 188 exposures <1 mg/L, which represents the highest value for a recently established clinical 189 9 breakpoint for this compound. Newly reported mean values for ISZ blood concentrations 190 range between 2.98 and 3.30 mg/L [24]. 191 192 Echinocandins 193 Echinocandins ( caspofungin, micafungin and anidulafungin) are valued antifungals due 194 to their potent activity and lower rates of toxic events in comparison to azoles and 195 polyenes [25]. They act as fungicidal drugs to Candida spp., including triazole-resistant 196 isolates, showing a fungistatic activity against Aspergillus [26]. Current guidelines 197 recommend echinocandins as first-line therapies for most types of invasive candidiasis 198 [27], although microbiologic resistance to this class of antifungal agents has emerged 199 and can result in clinical failure [28]. Echinocandins display a relevant post-antifungal 200 effect and therefore a concentration-dependent activity. Cmax/MIC and AUC0_24/MIC 201 (measured as total drug concentrations) ratios are considered relevant PD indices for 202 these drugs [29]. A trough concentration of at least 1 mg/L has been proposed as the 203 target concentration in invasive infections (derived from in vitro susceptibility testing of 204 Candida spp.), since a robust PD target is yet to be identified via clinical studies (most 205 data from animal studies were found to be highly variable). This value is described as 206 safeguard of efficacy for the management of Candida spp infections. These levels exceed 207 by far the MIC90 for the usual strains of Candida spp; although they would be insufficient 208 for the management of C. parapsilosis [30]. It is worth mentioning the considerable 209 interindividual variability observed in a series of cases including critically ill patients 210 described by Sinnollareddy et al. [15]. Other factors such as obesity, age and clinical 211 status may affect exposure, and contribute to substantial PK differences between them. 212 Variability has been established as a source of underexposure and development of 213 10 resistance. A recent study modelling Candida glabrata gastrointestinal colonization and 214 dissemination in mice, suggests that echinocandin-resistant isolates recovered from 215 blood or other internal organs may have originated in the gut where sub-therapeutic 216 drug concentrations might have led to the development of resistant organisms [31]. 217 Most experts consider that the data regarding the relationship between blood 218 echinocandin concentrations and therapeutic outcome is insufficient to support the 219 routine use of TDM for these agents. However, it seems reasonable that monitoring 220 exposure should be considered for patients in whom PK is unpredictable or still unknown 221 [32]. Inadequate antifungal dosing contributes not only to suboptimal outcomes but also 222 to the emergence of resistance. 223 224 Antifungals with routine recommendations for TDM monitoring 225 Azoles 226 Voriconazole (VRC): TDM should be routinely performed in most patients receiving VRC. 227 This azole exhibits highly variable intra- and inter-individual PK, attributed to different 228 factors, such as pharmacogenetic polymorphisms, drug-drug interactions, altered 229 gastrointestinal absorption, and even inflammation and body weight (Table 2). The 230 optimal VRC trough concentration for clinical response/safety is controversial 231 [16,20,33,34]. Two recent meta-analysis suggest a VRC Cmin target for TDM between 1 232 and 6 mg/L when the drug is used to treat an established invasive infection [35,36]. For 233 prophylactic use, the target concentration is less clear. Ashbee et al. recommend that 234 the target should be the ratio between Cmin and MIC if VRC susceptibility (MIC value) of 235 the invading pathogen is known [16]. The primary metabolic pathway of VCR involves 236 fluoropyrimidine N-oxidation to produce the inactive metabolite VRC N-oxide. Regular 237 11 VRC N-oxide blood level monitoring is not routinely indicated, although determination 238 of the VRC N-oxide/voriconazole ratio may provide information about the patient’s 239 metabolic phenotype and may play a role in VRC associated toxicity. Exposure-240 dependent hepatotoxicity has been convincingly shown for VRC only [36], although 241 phototoxicity associated to VRC treatment is probably related to its metabolite [37]. In 242 special circumstances such as cystic fibrosis (CF) or treatment in children [38], TDM is 243 required to maintain blood concentrations between 1 and 6 mg/L. 244 Itraconazole (ITC): While newer antifungal agents are currently recommended for 245 management of deep fungal infections, ITC is still used for the treatment of allergic 246 mycosis and remains a key agent in cases of endemic mycosis worldwide [39]. It is 247 available in oral and intravenous formulations (the latter not available in all countries). 248 However, ITC has shown unpredictable oral bioavailability and clinically important drug-249 drug interactions, making it difficult to determine the optimal dosing regimen. This is 250 the main reason for ITC TDM in clinical practice. A trough level range of 0.5-1 mg/L is 251 generally used as PD target. A minimum concentration below 0.5 mg/L has been 252 associated with an increased likelihood of breakthrough infections [40,41]. According to 253 a recently published meta-analysis, the use of this azole is restricted because of its 254 adverse reactions compared to new safer and more effective antifungals [42]. ITC 255 exhibits dose‐dependent PK and is partially eliminated by CYP3A4 oxidation to 256 hydroxyitraconazole (OH-ITC), a metabolite with similar antifungal properties. 257 Concentrations of OH-ITC are around two-fold higher than those of the parent 258 compound in healthy volunteers [43]. Its concentration should be measured as ITC TDM, 259 since several studies show that the metabolites contribute to CYP3A4 inhibition and 260 need to be considered in the quantitative rationalization of the treatment [44], although 261 12 there is not a common criteria about this point (Table 2). It is worth noting that ITC 262 bioassay concentration measurements are typically 2-10 times higher than those 263 estimated using HPLC (due to the active metabolite). When measured by bioassay, a 264 reasonable lower limit for TDM is approximately 5 mg/L [39]. 265 Posaconazole (PSC): PSC is structurally similar to ITC. Some of its main PK peculiarities 266 are summarized in Table 2. Currently, PSC plays an important role in the prophylaxis of 267 IFI. Three formulations are available in most countries: two oral formulations, a solid 268 delayed release tablets and an oral suspension, and the intravenous formulation with 269 significant differences regarding bioavailability (tables higher than oral suspension). 270 Experts recommend the use of PSC oral tablets in prophylactic regimens over any other 271 formulation, particularly during induction chemotherapy [45]. However, PSC oral 272 suspension is still widely used and available worldwide. This formulation is a good option 273 for patients with nasogastric tubes or those unable to take tablets. Thus, when PSC oral 274 suspension is used, TDM is mandatory if there are concerns regarding gastrointestinal 275 absorption, uncertainty about compliance or suspicious of breakthrough IFI. It is 276 important to consider that the two oral formulations are not interchangeable because 277 they have different doses and PK. Further exposure-toxicity data are needed to fully 278 assess potential dose-dependent hepatic adverse effects for the new formulations and 279 possible influence of drug-drug interactions. A trough level should be measured seven 280 days post-initiation of the therapy or after dose adjustment, although a lower target has 281 also been proposed after 48 h of treatment [16]. A trough level higher than 0.5 mg/L has 282 been proposed in a recent meta-analysis [46], although despite clinical evidence, a 283 consensus of 0.5-0.7 mg/L is accepted as the lower bound in prophylactic regimens. 284 13 Several reports conclude that PSC tablet form increases the possibility of achieving this 285 target due to high bioavailability, so whether TDM is useful in this case needs future 286 investigation with large sample size, also exploring the relationship between PSC 287 exposure and adverse events. 288 Pyrimidines 289 5-Flucytosine 290 The antifungal drug 5-flucytosine (5FC) is a synthetic compound originally assessed for 291 the treatment of tumours [47] and then fungal infections. 5FC containing combination 292 therapy remains an efficient option in the treatment of cryptococcal meningitis [48]. 293 Although it is on the WHO essential medicines list, 5FC is currently unavailable in low- 294 and middle-income countries where the disease burden is greatest [49]. This compound 295 exhibits significant inter-patient PKv. Furthermore, PD studies show a correlation 296 between serum concentration and toxicity, particularly renal and marrow toxicity 297 [50,51]. TDM is mandatory for this antifungal agent to prevent serious toxicity [52]. 298 Serum concentration should be determined 72 hours post-initiation of therapy, after 299 dose adjustment, if there is uncertain compliance with oral therapy, or if there are signs 300 of clinical or laboratory toxicity. To date there is no agreement on a precise PD target. 301 Recommendations are based on in vitro evidence in which yeast exposed to 302 concentrations <20-40 mg/L (Cmin) developed resistance and Cmax (peak) >100 mg/L are 303 most frequently associated with toxicity. 304 305 In summary, in spite of close monitoring of systemic antifungal treatments is not 306 universally recommended, recently studies provide new evidences of the usefulness of 307 14 establishing an adequate antifungal exposure for adequate response, prevention of 308 toxicity or development of resistance. TDM should guide dosage to achieve adequate 309 PD target in cases of therapeutic failure, serious toxicity, important PKv due to certain 310 morbidities, obesity, non-compliance, interacting medication, or to provide data on new 311 treatments without sufficient clinical evidence. The high degree of PKv in children and 312 infants (largely excluded from clinical trials) and in any other cases makes TDM an 313 essential procedure to ensure adequate therapeutic exposure in these special 314 circumstances [53]. A less explored application related to TDM is the ability to ensure 315 optimal exposures for reducing the emerging problem of antifungal resistance. Clinical 316 data are urgently needed to define thresholds that can minimise resistance and whether 317 they are safe for patients. This particular connexion has already been described for 318 antifungals such as echinocandins or fluconazole [18,31]. However, TDM requires 319 continuous clinical input. While it may be ideal to have assays performed on site, the 320 cost of developing and running assays may mean that many TDM services are only 321 available in specialist centres. 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