Pharmacokinetic/pharmacodynamic analysis of voriconazole againstCandida spp. and Aspergillus spp. in children, adolescents and adultsby Monte Carlo simulationGaoqi Xu a, Liqin Zhu b,*, Tingyue Ge a, Shasha Liao a, Na Li a, Fang Qi a

a Basic Medical College, Tianjin Medical University, 22# Qixiangtai Road, Heping District, Tianjin 300070, Chinab Department of Pharmacy, Tianjin First Central Hospital, 24# Fukang Road, Nankai District, Tianjin 300192, China

A R T I C L E I N F O

Article history:Received 1 December 2015Accepted 26 February 2016

Keywords:VoriconazoleCandida sppAspergillus sppChildrenAdolescentsAdults

A B S T R A C T

The objective of this study was to investigate the cumulative fraction of response of various voriconazoledosing regimens against six Candida and six Aspergillus spp. in immunocompromised children,immunocompromised adolescents, and adults. Using pharmacokinetic parameters and pharmacody-namic data, 5000-subject Monte Carlo simulations (MCSs) were conducted to evaluate the ability ofsimulated dosing strategies in terms of fAUC/MIC targets of voriconazole. According to the results of theMCSs, current voriconazole dosage regimens were all effective for children, adolescents and adults againstCandida albicans, Candida parapsilosis and Candida orthopsilosis. For adults, dosing regimens of 4 mg/kgintravenous every 12 h (q12h) and 300 mg orally q12h were sufficient to treat fungal infections by sixCandida spp. (C. albicans, C. parapsilosis, Candida tropicalis, Candida glabrata, Candida krusei and C. orthopsilosis)and five Aspergillus spp. (Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Aspergillus niger andAspergillus nidulans). However, high doses should be recommended for children and adolescents in orderto achieve better clinical efficacy against A. fumigatus and A. nidulans. The current voriconazole dosageregimens were all ineffective against A. niger for children and adolescents. All voriconazole dosage regi-mens were not optimal against Aspergillus versicolor. This is the first study to evaluate clinical therapyof various voriconazole dosing regimens against Candida and Aspergillus spp. infections in children, ado-lescents and adults using MCS. The pharmacokinetic/pharmacodynamic-based dosing strategy provideda theoretical rationale for identifying optimal voriconazole dosage regimens in children, adolescents andadults in order to maximise clinical response and minimise the probability of exposure-related toxicity.

© 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

1. Introduction

The past two decades have witnessed a remarkable increase inthe prevalence and severity of invasive fungal infections, which areassociated with significant morbidity and mortality, mainly inimmunocompromised and debilitated patients. Candida spp. and As-pergillus spp. are the major causes of invasive fungal infections [1].The prevalence of invasive aspergillosis (IA) is increasing with therise in the number of immunocompromised patients, including se-verely immunocompromised or critically ill children [2].

The second-generation antifungal triazole voriconazole was ef-fective against a wide range of clinically significant fungal pathogens,including Aspergillus and Candida spp. [3]. Voriconazole was ap-proved for use in the first-line setting for acute IA in 2002 owingto its favourable efficacy against Aspergillus spp. and few side effects

[2]. Intravenous (i.v.) voriconazole and oral voriconazole are bothrecommended to treat patients with IA, candidaemia, dissemi-nated infections caused by Candida spp., oesophageal candidiasis,etc. [4].

However, the pharmacokinetic behaviour of voriconazole is non-linear, and large interindividual and intraindividual variabilities havebeen observed in plasma concentrations. Small changes in dosageregimens may cause disproportionately large changes in the plasmaconcentrations of voriconazole [4,5]. Because of the complex phar-macokinetic behaviour of voriconazole and the narrow therapeuticwindow for the treatment of patients, it is necessary to assess variousdosage regimens in order to maximise favourable clinical efficacy.

Thus, a pharmacokinetic/pharmacodynamic (PK/PD) analysisshould be used for evaluating, rationalising and optimising anti-fungal therapy. Monte Carlo simulation (MCS) is utilised as a valuabletool for determining dosage regimens and assisting in the selec-tion for appropriate empirical antibiotic therapies. It is able to linkpharmacodynamic data with the pharmacokinetic profile to predictthe probability of a certain therapeutic outcome, thereby improv-ing antimicrobial effectiveness and the quality of patient care [5].

* Corresponding author. Department of Pharmacy, Tianjin First Central Hospital,24# Fukang Road, Nankai District, Tianjin 300192, China. Tel.: +86 22 2362 7023.

E-mail address: zlq0713@aliyun.com (L. Zhu).

http://dx.doi.org/10.1016/j.ijantimicag.2016.02.0160924-8579/© 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

International Journal of Antimicrobial Agents 47 (2016) 439–445

Contents lists available at ScienceDirect

International Journal of Antimicrobial Agents

journal homepage: www.elsevier.com/ locate / i jant imicag

In this study, the probabilities of attaining optimal pharmacody-namic targets of various voriconazole dosage regimens againstclinical isolates of Candida and Aspergillus spp. were calculated usingan MCS technique in children, adolescents and adults.

2. Materials and methods

2.1. Pharmacokinetics

Data from three previously published studies on non-linear pop-ulation pharmacokinetic (PPK) analysis of voriconazole conductedin children, adolescents and adults were applied [6–8]. In the studyby Friberg et al, a PPKmodel was built by analysing the study design,study population and timing of plasma samples collected from fivepharmacokinetic studies published previously, and exposure pa-rameters of voriconazole in immunocompromised children (2 to <12years old) and young adolescents (12–14 years old, weighing <50 kg)were predicted [6]. In the study by Driscoll et al, an open-label,multiple-dose, multicentre study was conducted following i.v.voriconazole to oral switch regimens: 6mg/kg i.v. every 12 h (q12h)on Day 1 followed by 4 mg/kg i.v. q12h, then switched to 300 mgorally q12h for immunocompromised adolescents (12 to <17 yearsold) [7]. The pharmacokinetic data of adults receiving a range of i.v.and oral voriconazole regimens were reported by Hope [8]. Thesethree studies included the pharmacokinetic data of voriconazole inpatients of different ages (2 to <12 years old, 12 to <17 years oldand adults). The areas under the concentration–time curve at steady-state (AUCs) from the three studies, which were implied in the PK/

PD model as voriconazole pharmacokinetic parameters, aresummarised in Table 1.

2.2. Minimum inhibition concentration (MIC) distribution ofCandida spp. and Aspergillus spp.

The MIC distribution data for Candida spp. were obtained fromCantón et al [9]. In their study, six Candida spp. aggregated from 43public tertiary-care hospital laboratories from January 2009 to Feb-ruary 2010 were tested by the Sensititre YeastOne method [9]. Inanother study reported by Espinel-Ingroff et al, discrete MIC distri-butions for six Aspergillus spp. from five independent laboratories inEurope and the USA were tested using the Clinical and LaboratoryStandards Institute (CLSI) M38-A2 microdilution method [10]. ThepercentageMIC distributions of voriconazole for Candida spp. and As-pergillus spp. were calculated and were used for each simulation tocalculate the cumulative fraction of response (CFR) (Table 2).

2.3. Monte Carlo simulation

MCS accounts for the variability in pharmacokinetic parametersas well as the MIC distribution in order to estimate the probabilityof achieving the pharmacodynamic target value of fAUC0–24/MIC (free-drug area under the concentration–time curve over 24 h/minimuminhibition concentration ratio) >25 in plasma [11]. In addition, otherpharmacodynamic targets (1–50) were also evaluated for each sim-ulation. To calculate free-drug concentrations of voriconazole, a valueof 58% protein binding was used in all simulations [12].

Using pharmacokinetic parameters and pharmacodynamic data,MCSs were iterated from the 1st to the 5000th subject using a com-mercially available risk analysis software (Crystal Ball® v.7.2.2;Decisioneering Inc.; http://www.crystalball.com) to estimate theprobability of target attainment (PTA), defined as the percentageof subjects who achieved the requisite pharmacodynamic expo-sure (fAUC0–24/MIC) for each antibiotic dosage regimen/bacterialpopulation combination. During simulations, pharmacokinetic pa-rameters (AUCs) were assumed to follow a log-Gaussian distribution,and pharmacokinetic data (MICs) followed a discrete distribution.Protein binding of voriconazole was set as a constant value (58%).The CFR was calculated using weighted summation, with the fol-lowing formula:

CFR PTA MIC MIC= ( )⋅ ( )=∑ i ii

n

p1

The PTA at each MICi level was multiplied by the relative fre-quency of that MIC in the study population, p(MICi). A CFR

Table 1Summary of voriconazole pharmacokinetic parameters following voriconazole ad-ministration in children, adolescents and adults.

Patientpopulation

AUC0–12 (μg·h/mL)a

Childrenb 4 mg/kg i.v. q12h 8 mg/kg i.v. q12h 9 mg/kg orally q12h(maximum of 350 mg)

9.92 (69) 29.2 (99) 15.7 (113)Adolescentsc 4 mg/kg i.v. q12h 300 mg orally q12h —

22.4 (73) 16.7 (62) —Adults 4 mg/kg i.v. q12h 200 mg orally q12h 300 mg orally q12h

34.9 (53) 17.99 (21.57)d 34.0 (53)

AUC0–12, area under the concentration–time curve from time zero to the end of 12-hdosing interval at steady-state; i.v., intravenous; q12h, every 12 h.

a Values are expressed as the geometric mean (CV%) unless otherwise stated.b Immunocompromised children (2 to <12 years old) and young adolescents (12–

14 year old, weighing <50 kg).c Immunocompromised adolescents aged 12 to <17 years.d Value expressed as median ± standard deviation.

Table 2Minimum inhibitory concentration (MIC) distribution of voriconazole for Candida spp. and Aspergillus spp.

Species Total no. ofisolates

% of isolates susceptible at an MIC (μg/mL) ofa:

0.008 0.015 0.03 0.06 0.125 0.25 0.5 1 2 4 8 16 32

Candida spp.C. albicans 849 81.04 11.19 3.18 1.30 0.94 0.59 0.24 0.00 0.00 0.35 0.94 0.24 0.00C. parapsilosis 559 33.09 25.58 16.46 11.81 8.05 2.68 1.25 0.89 0.18 0.00 0.00 0.00 0.00C. tropicalis 167 1.80 11.38 26.35 22.16 20.96 7.78 3.59 0.00 0.60 0.60 2.99 1.80 0.00C. glabrata 205 4.88 3.90 6.34 19.02 19.02 30.24 7.80 4.88 2.44 0.98 0.49 0.00 0.00C. krusei 48 0.00 0.00 2.08 2.08 33.33 43.75 12.50 4.17 2.08 0.00 0.00 0.00 0.00C. orthopsilosis 73 36.99 21.92 15.07 13.70 6.85 4.11 1.37 0.00 0.00 0.00 0.00 0.00 0.00Aspergillus spp.A. fumigatus 2778 0.00 0.04 0.58 4.43 42.94 39.27 10.48 1.40 0.61 0.25 0.00 0.00 0.00A. flavus 589 0.00 0.00 0.17 2.55 19.52 49.24 26.83 1.70 0.00 0.00 0.00 0.00 0.00A. terreus 462 0.00 0.43 0.00 5.19 21.43 46.97 22.94 2.16 0.00 0.00 0.22 0.65 0.00A. niger 479 0.00 0.63 1.04 3.97 12.32 36.33 35.28 9.81 0.63 0.00 0.00 0.00 0.00A. nidulans 139 0.00 2.88 10.07 36.69 23.74 8.63 10.07 7.19 0.00 0.72 0.00 0.00 0.00A. versicolor 81 0.00 3.70 3.70 14.81 28.40 12.35 17.28 16.05 0.00 0.00 3.70 0.00 0.00

a Calculations were based on the data reported by Cantón et al. [9] and Espinel-Ingroff et al. [10].

440 G. Xu et al. / International Journal of Antimicrobial Agents 47 (2016) 439–445

expectation value of >90% was considered optimal for a dosageregimen against a population of organisms, as established previ-ously by the OPTAMA programme [13].

3. Results

3.1. Probability of target attainment analysis

The probabilities of PK/PD target attainment by MIC for eachvoriconazole dosage regimen against Candida spp. and Aspergillusspp. in children, adolescents and adults are presented in Fig. 1.

Immunocompromised children (2 to <12 years old) and youngadolescents (12–14 years old, weighing <50 kg) with the voriconazoledosage regimens of 4 mg/kg i.v. q12h, 8 mg/kg i.v. q12h and 9 mg/kg orally q12h (maximum of 350 mg) achieved PTA values of ≥90%for MICs ≤0.125, 0.25 and 0.06 μg/mL, respectively (Fig. 1a). Thedosing regimens with 4 mg/kg i.v. q12h and 300 mg orally q12h inimmunocompromised adolescents (12 to <17 years old) achievedtarget attainment at MICs of ≤0.25 μg/mL and 0.125 μg/mL (Fig. 1b).In the case of adults administered a voriconazole dosage regimenof 4 mg/kg i.v. q12h, 200 mg orally q12h and 300 mg orallyq12h, the maximumMICs with a PTA value ≥90% were 0.5, 0.06 and0.5 μg/mL, respectively (Fig. 1c).

3.2. Cumulative fraction of response analysis

Table 3 shows the assessment of CFR expectation values forvarious dosing regimens of voriconazole in children, adolescents andadults against six Candida spp. and six Aspergillus spp.

Overall, all of the simulated dosage regimens achieved CFR valuesof >90% in children, adolescents and adults against Candidaalbicans, Candida parapsilosis and Candida orthopsilosis. Regardingimmunocompromised children (2 to <12 years old) and young ado-lescents (12–14 years old, weighing <50 kg), only a voriconazoledosage regimen of 8mg/kg i.v. q12h achieved high CFR values againstCandida tropicalis, Aspergillus fumigatus and Aspergillus nidulans(91.84%, 90.48% and 90.01%, respectively). In immunocompromisedadolescents (12 to <17 years old), both 4mg/kg i.v. q12h and 300mgorally q12h had an optimal likelihood of antifungal success againstC. tropicalis, and 4 mg/kg i.v. q12h was sufficient for these patientsagainst A. fumigatus. Moreover, 4 mg/kg i.v. q12h and 300mg orallyq12h in adults achieved ≥90% CFR against six Candida spp. (C. albicans,C. parapsilosis, C. tropicalis, Candida glabrata, Candida krusei andC. orthopsilosis) and five Aspergillus spp. (A. fumigatus, Aspergillusflavus, Aspergillus terreus, Aspergillus niger and A. nidulans). However,the simulated dosage regimens were ineffective against A. niger forimmunocompromised children and adolescents. In addition, thesimulated dosing regimens were not effective against Aspergillus ver-sicolor, with CFR expectation values <90%.

Various PK/PD-related targets for Candida spp. and Aspergillusspp. (from 1 to 50) were also simulated to calculate species-specific CFR expectation values (Figs 2 and 3). The higher PK/PDtargets represent the ‘worse-case’ scenario, which may be impor-tant in some severe fungal infections where higher antimicrobialexposure may be required [14]. It is obvious that each CFR expec-tation value decreases with the increase in the PK/PD target.

Immunocompromised children (2 to <12 years old) and youngadolescents (12–14 years old, weighing <50 kg) administered a

Fig. 1. Probability of target attainment (PTA) of voriconazole against Candida spp. and Aspergillus spp. for each voriconazole dosing regimens in children, adolescents andadults. fAUC/MIC, free-drug area under the concentration–time curve/minimum inhibition concentration ratio; i.v., intravenous; q12h, every 12 h; MIC, minimum inhibi-tion concentration.

Table 3Cumulative fraction of response (CFR) expectation values (%) against six Candida spp. and six Aspergillus spp. for each voriconazole dosing regimen in children, adolescentsand adults.

Species Children Adolescents Adults

4 mg/kgi.v. q12h

8 mg/kgi.v. q12h

9 mg/kg orally q12h(maximum of 350 mg)

4 mg/kgi.v. q12h

300 mgorally q12h

4 mg/kgi.v. q12h

200 mgorally q12h

300 mgorally q12h

Candida spp.C. albicans 97.91 98.34 97.95 98.33 98.26 98.46 98.00 98.46C. parapsilosis 95.77 98.44 95.86 98.37 97.90 99.31 96.19 99.29C. tropicalis 85.20 91.84 85.54 91.89 90.84 93.81 86.37 93.79C. glabrata 69.26 87.41 72.86 86.76 83.25 93.39 74.98 93.26C. krusei 60.50 86.63 65.90 86.15 81.23 95.17 68.94 95.03C. orthopsilosis 96.22 99.06 96.36 99.09 98.65 99.91 96.70 99.90Aspergillus spp.A. fumigatus 67.05 90.48 71.18 90.54 86.52 97.73 73.97 97.65A. flavus 52.34 85.10 60.50 84.43 77.34 97.24 64.18 97.14A. terreus 54.97 85.38 62.27 84.80 78.39 96.41 65.71 96.31A. niger 43.33 77.72 52.76 75.58 66.79 92.28 56.59 92.04A. nidulans 77.31 90.01 79.20 89.05 86.05 95.17 80.76 95.03A. versicolor 57.70 78.39 62.30 76.21 70.74 87.50 64.73 87.22

i.v., intravenous; q12h, every 12 h.

441G. Xu et al. / International Journal of Antimicrobial Agents 47 (2016) 439–445

Fig. 2. Cumulative fraction of response (CFR) expectation values of various voriconazole dosage regimens at various fAUC/MIC (free-drug area under the plasma concentration–time curve over minimum inhibitory concentration ratio) targets against six Candida spp. (Candida albicans, Candida parapsilosis, Candida tropicalis, Candida glabrata, Candidakrusei and Candida orthopsilosis) in children, adolescents and adults. i.v., intravenous; q12h, every 12 h.

442 G. Xu et al. / International Journal of Antimicrobial Agents 47 (2016) 439–445

Fig. 3. Cumulative fraction of response (CFR) expectation values of various voriconazole dosage regimens at various fAUC/MIC (free-drug area under the plasma concentration–time curve over minimum inhibitory concentration ratio) targets against six Aspergillus spp. (Aspergillus fumigatus, Aspergillus flavus, Aspergillus terreus, Aspergillus niger,Aspergillus versicolor and Aspergillus nidulans) in children, adolescents and adults. i.v., intravenous; q12h, every 12 h.

443G. Xu et al. / International Journal of Antimicrobial Agents 47 (2016) 439–445

voriconazole dosage regimen of 4mg/kg i.v. q12h against C. tropicalisachieved a CFR value of 90.35% at an fAUC/MIC ≥15. When PK/PDtarget values of ≥25 and ≥35 were considered, the probability ofachieving each value decreased to 85.36% and 80.22%, respective-ly (Fig. 2a). CFR expectation values at various PK/PD targets for eachvoriconazole dosage regimen in children, adolescents and adultsagainst Candida and Aspergillus spp. are displayed in Figs 2 and 3.

4. Discussion

This is the first study evaluating the probability of voriconazoledosage regimens achieving their requisite PK/PD target byMCS usingpharmacokinetic parameters and pharmacodynamic data againstsix Candida spp. and six Aspergillus spp. in children, adolescents andadults. The results of these simulations suggest that all of the dosageregimens simulated for children, adolescent and adults were ef-fective against C. albicans, C. parapsilosis and C. orthopsilosis.Consistently, dosing regimens of 4mg/kg i.v. q12h and 300mg orallyq12h were sufficient for adults to treat fungal infections by sixCandida spp. (C. albicans, C. parapsilosis, C. tropicalis, C. glabrata,C. krusei and C. orthopsilosis) and five Aspergillus spp. (A. fumigatus,A. flavus, A. terreus, A. niger and A. nidulans). However, none of thesimulated dosage regimens were effective against A. niger inimmunocompromised children and adolescents. In addition, noneof the voriconazole dosage regimens was effective against A. ver-sicolor, with CFR expectation values of <90%.

The pharmacokinetic behaviour of voriconazole is complex anddiffers in children, adolescents and adults [15]. Voriconazole ex-hibits non-linear pharmacokinetics in adults owing to its capacity-limited elimination, and its pharmacokinetics are thereforedependent on the administered dose [3]. However, in contrast toobservations in adults, the pharmacokinetic profile in childrenbetween 2 and 11 years of age appears to be linear followingvoriconazole doses of 3–4 mg/kg q12h [16]. In addition, paediat-ric patients have a much higher ability for elimination of the drugper kilogram of body weight than adults, resulting in a lower, po-tentially non-therapeutic exposure at similar dosages [16]. For thisreason, relatively higher dosage regimens of voriconazole are re-quired for paediatric patients than in adults to achieve similar plasmaconcentrations (the mean plasma AUC0–12 for 8 mg/kg i.v. in chil-dren is approximately equivalent to 4 mg/kg i.v. in adults [17], and4 mg/kg in children is approximately equivalent to adults admin-istered a dosage of 3 mg/kg [16]).

In this study, the pharmacokinetic parameters of variousvoriconazole dosage regimens in children, adolescents and adultswere obtained from three published studies [6–8]. These threestudies included pharmacokinetic data of voriconazole in patientsof different ages. PPK studies were conducted on pooled data fromimmunocompromised children, immunocompromised adoles-cents, or adults (including patients and healthy volunteers). It shouldbe noted that young adolescents with a low body weight (<50 kg)during the transitioning period from childhood to adolescence (12–14 years old) should be dosed like children to achieve voriconazoleexposures comparable with those of adults as described by Friberget al and Driscoll et al [6,7].

Currently, the recommended voriconazole dosing regimen forchildren (2–11 years old) is 7mg/kg i.v. twice daily (b.i.d.) and 200mgb.i.d. for the oral suspension, without a loading dose [18]. For ado-lescents (>12 years old), the i.v. dosages are 6mg/kg i.v. b.i.d. on Day1 followed by 4 mg/kg i.v. b.i.d., and the oral dosages are 400 mgb.i.d. on Day 1 (200mg b.i.d. for weight <40 kg) followed by 200mgb.i.d. (100mg b.i.d. for weight <40 kg) [16]. The recommended dosingregimen for adults is a standard loading dose of 6 mg/kg i.v. q12hon Day 1 followed by a maintenance dose of 4 mg/kg i.v. b.i.d. withthe option to switch to an oral maintenance dose of 100mg (<40 kg)or 200 mg (>40 kg) b.i.d. For serious infections, the oral mainte-

nance dose may be increased from 200 mg to 300 mg (>40 kg) orfrom 100mg to 150mg q12h (<40 kg) [3]. In this PK/PD study, variousmaintenance dosage regimens (which are presented in Table 1) ofvoriconazole were evaluated to investigate whether they achievedeffective treatment in children, adolescents and adults.

The PK/PD parameter for voriconazole has been characterisedpreviously, demonstrating that the AUC0–24/MIC ratio is the criticalPK/PD parameter associated with treatment efficacy [11]. An in vivostudy conducted with voriconazole in a murine candidiasis modelshowed that the voriconazole fAUC/MIC ratios ranged from 11 to58 (mean ± standard deviation, 24 ± 17; P = 0.45) [11]. However, manyPK/PD-based simulations implied a value of fAUC0–24/MIC ≥25 as apredictor of voriconazole therapy [4,5,19]. Therefore, in this presentstudy various PK/PD target values (1–50) were used to calculate CFRsof various voriconazole dosage regimens in children, adolescentsand adults. The probability of treatment success can be obtainedfor any given target values from Figs 2 and 3.

Voriconazole has potent activity against a broad range of clin-ically significant fungal pathogens, such as Candida and Aspergillusspp., and is considered as the first-line therapy for treating IA [3,20].Currently, voriconazole is also indicated for use in adolescents andadults for some invasive candidal infections, such as candidaemiain non-neutropenic patients [21]. However, the recommended oraldosage regimens of voriconazole monotherapy should not be ad-ministered empirically for treating Candida infections because of theazole cross-resistance among selected Candida [5,22].

There are two limitations to the present study. First, we did notconsider other PK/PD surrogates such as trough serum concentra-tion (Cmin) >1 mg/L [23,24]. fAUC0–24/MIC >25 was used as the PK/PD index to evaluate each voriconazole dosage regimen as in otherMCS studies [4,5,19]. In addition, dosage regimens of voriconazoleon Day 1 were not simulated owing to the lack of pharmacoki-netic parameters of the first dose. Thus, further studies need to beperformed for the first dose of voriconazole in severe fungalinfections.

5. Conclusion

In conclusion, various dosage regimens of voriconazole wereevaluated using pharmacokinetic parameters and pharmacody-namic data by theMCS technique against Candida spp. and Aspergillusspp. in children, adolescents and adults. The results suggest thatcurrent simulated dosage regimens of voriconazole were all suffi-cient for children, adolescents and adults to treat fungal infectionsby C. albicans, C. parapsilosis and C. orthopsilosis. High doses shouldbe recommended for children and adolescents to achieve better clin-ical efficacy against A. fumigatus and A. nidulans. However, none ofthe simulated voriconazole dosage regimens were effective againstA. niger for children and adolescents. In addition, none of the currentdosage regimens achieved optimal activity against A. versicolor. ThisPK/PD-based dosing strategy for Candida spp. and Aspergillus spp.infections provides a theoretical rationale for identifying optimalvoriconazole dosage regimens in children, adolescents and adults.Further fungal infection studies and optimal dosage regimens ofvoriconazole should be designed for maximising clinical responseand minimising the probability of exposure-related toxicity.

Funding: None.Competing interests: None declared.Ethical approval: Not required.

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