Voriconazole Pharmacokinetics and Pharmacodynamics in Children

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1 MAJOR ARTICLE Voriconazole Pharmacokinetics and Pharmacodynamics in Children Michael Neely, 1,2,3 Teresa Rushing, 3 Andrea Kovacs, 1 Roger Jelliffe, 2 and Jill Hoffman 1,3 1 Division of Pediatric Infectious Diseases and 2 Laboratory of Applied Pharmacokinetics, Keck School of Medicine, University of Southern California, and 3 Childrens Hospital Los Angeles, Los Angeles, California (See the editorial commentary by Drusano, on pages 37 9.) Background. Voriconazole pharmacokinetic and pharmacodynamic data are lacking in children. Methods. Records at the Childrens Hospital Los Angeles were reviewed for children with 1 serum voriconazole concentration measured from 1 May 2006 through 1 June Information on demographic characteristics, dosing histories, serum concentrations, toxicity and survival, and outcomes was obtained. Results. A total of 207 voriconazole measurements were obtained from 46 patients (age, years). A 2- compartment Michaelis-Menten pharmacokinetic model fit the data best but explained only 80% of the observed variability. The crude mortality rate was 28%, and each trough serum voriconazole concentration!1000 ng/ml was associated with a 2.6-fold increased odds of death (95% confidence interval, ; P p.002). Serum voriconazole concentrations were not associated with hepatotoxicity. Simulations predicted an intravenous dose of 7 mg/kg or an oral dose of 200 mg twice daily would achieve a trough ng/ml in most patients, but with a wide range of possible concentrations. Conclusions. We found a pharmacodynamic association between a voriconazole trough ng/ml and survival and marked pharmacokinetic variability, particularly after enteral dosing, justifying the measurement of serum concentrations. Voriconazole is a triazole antifungal drug with activity against yeasts, endemic fungi, and certain molds, notably Aspergillus species, for which it is currently firstline therapy in adults [1]. In children, voriconazole use has increased steadily since 2002, accounting for 10% of prescribed systemic antifungal therapy in nearly 63,000 US pediatric inpatients in 2006 [2]. Strikingly, voriconazole has almost completely replaced the use of any amphotericin B formulation for the treatment of aspergillosis. However, to our knowledge there are only 2 peer-reviewed publications that document voriconazole pharmacokinetics obtained from prospective clinical trials in children!12 years of age [3, 4] and no Received 25 March 2009; accepted 17 August 2009; electronically published 1 December Presented in part: Meeting of the Population Approach Group Europe (PAGE), June 2009, St Petersburg, Russia. Reprints or correspondence: Dr Michael Neely, Childrens Hospital Los Angeles, 4650 Sunset Blvd, MS 51, Los Angeles, CA (mneely@usc.edu). Clinical Infectious Diseases 2010; 50: by the Infectious Diseases Society of America. All rights reserved /2010/ $15.00 DOI: / studies to measure a pharmacodynamic link between concentration and outcome in children. Although a single target trough voriconazole concentration to maximize efficacy has not been defined, several independent studies have demonstrated a relationship between higher voriconazole serum concentrations in adults and improved outcomes [5 8], such that a target range has emerged, and trough serum voriconazole concentrations are recommended to be ng/ml and!6000 ng/ml [9, 10]. Given the paucity of information on voriconazole pharmacokinetics in children, the known interindividual and intraindividual variability, and the associations between serum concentrations and outcomes in adults, voriconazole concentrations are frequently measured at our hospital as part of the clinical care of children receiving this drug. Therefore, we reviewed our therapeutic drug management experience in hospitalized patients with available voriconazole drug concentrations. Our goal was to refine our voriconazole dosing guidelines by achieving 3 aims: (1) to analyze associations between voriconazole concentrations and various patient outcomes, including toxic effects and sur- Pediatric Voriconazole PK/PD CID 2010:50 (1 January) 27

2 Table 1. Characteristics of 46 Patients with 207 Voriconazole Measurements Patient Age, years Sex Weight, kg Underlying and infectious diagnoses EORTC class a Died Dose No. of samples Concentration range, ng/ml Total (low) measured troughs b F 84.3 ALL, relapse, pulmonary aspergillosis Possible Yes 200 mg orally (1) M 85.7 ALL, BMT, Alternaria species sinusitis Probable No 300 mg orally (0) M 18.2 Liver transplantation, pulmonary aspergillosis Possible No 75 mg orally (0) M 45.8 ALL, BMT, pneumonia Possible No 200 mg orally (0) F 75.4 Lymphoma, relapse, pneumonia Possible No 200 mg orally (0) F 47.8 Hemophagocytic lymphocytic histiocytosis, disseminated candidiasis, sinusitis Possible Yes 180 mg intravenously (1) M 65.0 ALL, relapse, pulmonary aspergillosis Possible Yes 200 mg orally (0) M 20.0 Aplastic anemia, brain abscesses Possible No mg orally (0) M 8.8 CGD, Aspergillus versicolor pneumonia and osteomyelitis Proven No mg orally 18 BLQ (0) 10 c 12.8 M 29.0 CF, ABPA Possible Yes 60 mg orally (0) F 47.3 AML, BMT, Candida glabrata esophagitis Proven No 200 mg orally (1) M 54.2 CNS germ cell tumor, Aspergillus fumigatus brain abscess 13 c 18.1 M 56.1 Liver transplantation, Scedosporium apiospermum osteomyelitis Proven No mg orally ,300 1 (0) Proven No 200 mg orally 1 BLQ 0 (0) 14 c 19.7 M 77.3 None, Coccidioidomyces imitis meningitis Proven No NR (0) M 35.4 CGD, pulmonary aspergillosis Possible No 300 mg orally (0) F 20.8 ALL, relapse, pulmonary aspergillosis Possible No 130 mg orally (0) F 58.6 ALL, relapse, disseminated candidiasis Possible No 200 mg orally (0) F 21.4 Aplastic anemia, BMT, pulmonary aspergillosis Possible Yes mg intravenously (1) F 49.0 SLE, Aspergillus niger pneumonia Probable No 200 mg orally (1) F 42.0 CGD, pulmonary aspergillosis Proven Yes mg orally 21 BLQ-11,900 1 (1) M 7.9 CGD, pneumonia Possible No 30 mg orally (0) F 22.3 AML, relapse, disseminated Candida glabrata Possible Yes mg orally 4 BLQ (0) M 21.0 CF, Aspergillus fumigatus pneumonia Proven No mg orally 5 BLQ-13,200 2 (0) M 50.1 Lung sarcoma, pulmonary aspergillosis Proven No mg nasogastrically ,500 1 (0) F 34.0 ALL, relapse, disseminated candidiasis Possible Yes mg orally 8 BLQ (0) 28

3 M 44.0 CF, lung transplantation, Aspergillus fumigatus sinusitis Proven No mg orally 9 BLQ-10,900 1 (0) F 58.3 ALL, pulmonary aspergillosis Possible No 200 mg orally (0) M 47.9 CF, Aspergillus versicolor and terreus pneumonia Probable No mg orally 3 BLQ (0) M 48.3 ALL, disseminated candidiasis Possible No 200 mg orally (0) M 20.6 ALL, relapse, pulmonary aspergillosis Probable Yes mg orally (2) F 14.4 ALL, disseminated candidiasis Proven Yes mg intravenously or orally 3 BLQ (0) M 31.8 CF, ABPA Possible No mg orally (0) M 90.0 ALL, disseminated candidiasis Possible No 200 mg orally (0) M 19.4 ALL high risk, refractory, disseminated Scedosporium apiospermum Proven Yes mg orally (1) M 14.3 SCID, BMT, disseminated aspergillosis Probable Yes mg intravenously (1) F 24.8 CF, ABPA Possible No 150 mg intravenously 4 BLQ (0) M 37.8 ALL, relapse, brain abscess Possible Yes 160 mg intravenously 2 BLQ (0) M 22.1 CF, liver transplantation, pulmonary aspergillosis, Scedosporium apiospermum pneumonia Probable No mg orally 10 BLQ-18,000 1 (0) F 20.2 CF, pulmonary aspergillosis Possible No 140 mg orally (0) M 55.5 SLE, aspergillosis Possible No 200 mg orally (0) M 16.8 Lymphoma, disseminated candidiasis Possible No 110 mg intravenously (0) 42 c 4.6 M 14.3 Toxic epidermal necrosis, cutaneous Aspergillus niger 43 c 17.8 M 59.8 CF, lung transplantation, Aspergillus versicolor pneumonia Proven No 100 mg intravenously 2 BLQ 0 (0) Probable No mg orally (0) M 27.2 CGD, pneumonia Possible No 250 mg orally 17 BLQ-12,400 0 (0) 45 c 14.4 M 29.0 CGD, pneumonia Possible No NR (0) F 11.9 ALL, BMT, pneumonia Possible No mg orally (3) Median or percentage 12.0 M: 65%; F: 35% 33.3 Proven: 26%; probable: 44%; possible: 59% Died: 28% Intravenous: 150 mg, 6.0 mg/kg; orally or nasogastrically: 200 mg, 5.3 mg/kg Range Intravenously: mg, mg/kg; orally or nasogastrically: mg, mg/kg ng/ml 1 21 BLQ (np23) to 21,300 ng/ml NOTE. ABPA, allergic bronchopulmonary aspergillosis; ALL, acute lymphoblastic leukemia; AML, acute myelogenous leukemia; BLQ, below the limit of quantification; BMT, bone marrow transplantation; CF, cystic fibrosis; CGD, chronic granulomatous disease; CNS, central nervous system; EORTC, European Organisation for Research and Treatment of Cancer; NR, not recorded; SCID, severe combined immunodeficiency; SLE, systemic lupus erythematosus. a From [12]. b Total number of samples obtained at least 10 h after previous dose and subset of these with voriconazole concentration!1000 ng/ml c These patients were excluded from the population model because all measured concentrations were BLQ, not after a dose with a verified time (ie, outpatient), or after an unverified dose amount. The remaining patients may have had some measurements excluded for the same reasons but had at least 1 valid sample available for modeling. 29

4 vival; (2) to create a population model of voriconazole pharmacokinetics across all ages of childhood and adolescence; and (3) to select the optimal dose(s) based on concentration profiles simulated from the model. PATIENTS AND METHODS Data collection. We reviewed the laboratory and pharmacy records at the Childrens Hospital Los Angeles (CHLA), a tertiary care, 324-bed pediatric referral hospital with an electronic medical record system. Eligible patients were identified as those who had voriconazole serum concentrations measured during hospitalization for a 1-year period from 1 May 2006 through 1 June This project was approved by the institutional review board with a waiver of informed consent for anonymous data collection and analysis. Extracted data included demographic information; voriconazole serum concentrations; timing, amount, route, and formulation of voriconazole doses; underlying and infectious diagnoses; concomitant use of drugs known or strongly suspected to influence voriconazole serum concentrations; alanine transferase (ALT) and alkaline phosphatase (ALKP) concentrations; and mortality. Consistent with definitions used in previous adult and pediatric studies [8], we defined hepatotoxicity as a 1.5-fold to 5-fold increase in ALT or ALKP level over baseline, depending on the age-specific degree of elevation at baseline. Voriconazole assay. Serum concentrations of voriconazole were determined by Focus Diagnostics, Inc., using a validated high-performance liquid chromatography assay. Voriconazole was extracted from serum and concentrations determined using a C18 column, autosampler, column oven, degasser, UV-VIS diode array detector and Chemstation software. The serum standard curve for voriconazole was linear through a concentration range of ,000 ng/ml. The mean recovery from serum was 94%. The validation interassay coefficient of variation was!5%. No interference was detected with 14 other antimicrobial agents, including 4 additional antifungal agents. Turnaround time ranged from 7 to 10 days. Data analysis. Descriptive and analytic statistics and plots were generated using the open-source software R, version (R Foundation; For survival and hepatotoxicity analyses, Cox proportional hazards models were constructed to examine associations with measures of voriconazole exposure, all adjusted for time receiving therapy. Because of the retrospective nature of the study, we performed a population analysis to estimate group and individual voriconazole pharmacokinetic parameters (eg, clearance and volume of distribution) and the variability in those parameters. Population analysis was essential given the diversity in number and timing of samples from each patient, as well the dose amounts, routes, and other clinical characteristics of the patients. For the population analysis, we used the nonparametric adaptive grid modeling component of the MM-USCPACK software (available by license from the University of Southern California; to test the fit of the observed data to various candidate models, including the one used by Karlsson et al [4]. All models included weight as a covariate on volume and clearance terms. In addition, we explored the influence on model variables of age, sex, creatinine clearance, ALT level, and ALKP level. We did not include the CYP2C19 genotype in the model, which is known to be associated with fast, intermediate, and slow phenotypes in voriconazole clearance [11], because this information was not available. However, nonparametric modeling excels at capturing subpopulations such as fast and slow metabolizers because no parameter distribution (eg, normal) is assumed; therefore, the absence of the CYP2C19 data was unlikely to affect the model fit except for increasing the variability in parameter estimates. Models were evaluated on the basis of the calculated log-likelihood and inspection of observed versus predicted plots. MM-USCPACK was also used to simulate the effect of differing voriconazole dosing strategies on the predicted range of concentration profiles: 10,000 sets of parameter values were randomly selected, with replacement, from the weighted, multivariate distribution of parameter values in the final model, including the full covariance matrix, and predicted concentrations were calculated for each parameter set. RESULTS Study population and sample characteristics. From 1 May 2006 until 1 June 2007, a total of 207 voriconazole concentrations were measured from 46 CHLA patients (Table 1). As indicated in Table 1, there was a wide range in doses and serum voriconazole concentrations, both between and within individual patients. Overall, 90% of the doses were administered enterally versus intravenously. Of the 207 samples, 99 (48%) were obtained after outpatient dosing with no verified preceding dose time; these were excluded from population modeling because time after dose was a necessary factor. Twenty-six (13%) of the 207 samples were reported as below the limit of quantification of 200 ng/ml, all of which were obtained after outpatient dosing. Because the mean outpatient dose of 6.4 mg/kg was not significantly different from the mean inpatient enteral dose of 5.8 mg/kg ( P p.14), it is possible that suboptimal adherence contributed to these low concentrations. For the remaining 108 inpatient samples, the median sampling time was 9.0 h (range, h) after the preceding dose, reflecting the clinical practice of monitoring trough serum voriconazole. These samples, from 40 patients, were used for modeling. Of the medications listed in the voriconazole package insert 30 CID 2010:50 (1 January) Neely et al

5 Figure 1. Observed versus individual model-predicted concentrations. Solid line, linear regression through the points; dashed line, line of unity; triangles, patients aged 12 years; squares, patients aged!12 years; filled symbols, concentrations obtained after enteral dosing; open symbols, concentrations obtained after intravenous dosing. known to alter voriconazole serum concentrations, only 2 patients also received phenytoin, which decreases serum voriconazole levels; none received other medications known to alter serum voriconazole levels. Toxic effects. Overall, 16 (42%) of 28 patients with baseline and on-therapy ALT or ALKP measurements met the definition for significant hepatoxic effects by ALT level (10 patients), ALKP level (2 patients), or both (4 patients). The median increase in ALT level over baseline was 8.3-fold (range, fold). The ALT level peaked 63 days (range, days) days after starting voriconazole therapy and resolved to baseline 49 days (range, days) later in 71%, at least two-thirds of Table 2. Geometric Mean (GM) and Geometric Relative Standard Error (GRSE%) of Voriconazole Pharmacokinetic Parameter Estimates in Patients Stratified by Age Characteristic Patients aged 12 years (n p 18) Patients aged!12 years (n p 22) Published values for children aged 2 12 years GM GRSE% GM GRSE% Mean GRSE% Ka, h CL, L/kg hourly a Vc, L/kg a Q, L/kg hourly Vp, L/kg a Km, mg/l F, % Tlag, h NOTE. Published values in children 2 12 years of age [4] are provided for comparison. CL, clearance; F, bioavailability; Ka, Rate constant of absorption; Km, Michaelis-Menten constant; Q, intercompartmental clearance; Tlag, lag (delay) before absorption; Vc, volume of the central compartment; Vp, volume of the peripheral compartment. a P.05 for comparison between patients!12 years old and 12 years old, by Student t test. Pediatric Voriconazole PK/PD CID 2010:50 (1 January) 31

6 Figure 2. Distribution of individual values for nonparametric model variables in the study population. Vertical dashed line, geometric mean for patients aged 12 years; dashed-dotted line, geometric mean for patients aged!12 years. P values are for the difference between the geometric means according to age. CL, clearance; F, bioavailability; Ka, rate constant of absorption; Km, Michaelis-Menten constant; Q, intercompartmental clearance; Tlag, lag (delay) before absorption; Vc, volume of the central compartment; Vp, volume of the peripheral compartment. whom were still receiving voriconazole. The median increase in ALKP level over baseline was 6.6-fold (range, 5.2-fold to 12.7-fold). The ALKP level peaked 69 days (range, days) after starting voriconazole therapy and was not documented to resolve to baseline in any patients by the end of the data extraction period. By Cox proportional hazards analysis, the risk of hepatotoxicity was not significantly associated with voriconazole dose, area under the curve, average concentration, or maximum or minimum concentration. Survival. Of the 46 patients, 12 (26%) had proven invasive fungal disease [12], with a positive fungal culture from a normally sterile site and radiographic and/or clinical evidence of disease at that site. An additional 7 patients (15%) had probable disease [12], with at least 1 positive fungal culture from respiratory secretions (eg, deep endotracheal suction or bronchoalveolar lavage) and/or galactomannan test, and clinical or radiographic evidence of localized disease. Recovered organisms included Aspergillus species (Aspergillus fumigatus and Aspergillus versicolor), Alternaria species, Scedosporium apiospermum, and Candida species (Candida albicans and Candida glabrata). As indicated in Table 1, the crude mortality rate in this population was 28%. Seventy-five percent of those who died had at least 1 low voriconazole trough versus only 20% of those who survived. Adjusted for annualized observation time and peak fold-increase in ALT over the age-specific upper limit of normal, each voriconazole trough concentration!1000 ng/ ml increased the relative risk of death by 6.3-fold (95% confidence interval, fold; P p.008, by Cox proportional hazards). Modeling: nonparametric population analysis. The final population model was a 2-compartment model with absorption after a delay and Michaelis-Menten elimination, which implies a constant amount of drug cleared per unit of time. As shown in Figure 1, overall, the model explained 80% of the observed variability in individual voriconazole concentrations, with no difference in accuracy according to dosing route, despite the small number of samples obtained after intravenous dosing. The model underpredicted observed concentrations by an average of 36% at the lower limit of the assay (200 ng/ml) and only 3% at the highest concentrations. The 5 most underpre- 32 CID 2010:50 (1 January) Neely et al

7 Figure 3. Simulated voriconazole concentration-time plot. Shaded bands are the indicated percentiles of 10,000 concentration-time profiles simulated from the final nonparametric model. Triangles, measured concentrations obtained in patients aged 12 years; squares, concentrations from patients aged!12 years; filled symbols, concentrations obtained after enteral dosing; open symbols, concentrations obtained after intravenous dosing; horizontal dashed line, target minimum concentration of 1000 ng/ml. Concentrations have been normalized to the median population dose, which was the same dose used for the simulations; hence, 2 measured concentrations appear to be at or below the assay limit of quantification (200 ng/ml). dicted concentrations occurred in 3 children!12 years of age, with 3 of them from a single 9-year-old child with unexpectedly high trough concentrations. Estimates for the population model variables are detailed in Table 2. Because nonparametric analysis does not assume any distribution in the values of model variables (such as a normal or gaussian distribution), means and standard deviations can obscure information. Therefore, Figure 2 shows the distributions of values in the patients for each variable in the model. Volumes and clearances were indexed to weight in kilograms, and there was a modestly significant additional effect of age (Table 2 and Figure 2). Sex, race, ethnicity, and ALT and ALKP concentrations were not significantly associated with mean values of any of the variables in the model. Inclusion of all of these covariates accounted for only 10% 40% of the variability, suggesting that unmeasured covariates, such as CYP219C genotype, disease state, gut motility, or others, were important. Simulation scenarios. Figure 3 shows the distribution of 10,000 model-simulated steady-state concentration-time curves after dosing 5.8 mg/kg every 12 h, with 10% administered intravenously (the median dose and percentage of intravenous doses in the CHLA population). The median simulated 12-h trough concentration was 1315 ng/ml, and the 5th and 95th percentiles were 242 and 6411 ng/ml, respectively. Included in Figure 3 are the observed voriconazole concentrations in the CHLA patients, stratified symbolically by age 112 years and dosing route. These observed concentrations have been normalized to the median dose of 5.8 mg/kg and condensed to a single dosing interval of 12 h to enable comparison with the simulated concentrations. On the basis of the observed versus predicted voriconazole concentrations in Figure 1 and Figure 3, the model was judged a good representation of the data and appropriate for further simulations. With a regimen of 7 mg/kg intravenously every 12 h, as approved for use in Europe [13], the median simulated steadystate trough concentration was 1287 ng/ml, with the 5th and 95th percentiles of 176 and 3406 ng/ml; 66% of patients with this dose would be expected to be above a trough concentration of 1000 ng/ml. Figure 4 shows the simulated range of steadystate voriconazole trough concentrations after the recommended European enteral dose of 200 mg twice daily at all ages from 2 to 12 years. The simulated median trough concentration ranges from 3600 ng/ml at the age of 2 years to 880 ng/ml at the age of 12 years, although there is significant variability around these median values. As a fixed dose, 200 mg can result in doses in excess of 15 mg/kg in the youngest children. The highest enteral dose in our population was 12.9 mg/kg, so the model may not be generalizable to higher doses. Finally, the relationship between the median simulated voriconazole trough concentration and enteral dose is shown in Pediatric Voriconazole PK/PD CID 2010:50 (1 January) 33

8 Figure 4. Predicted voriconazole trough concentrations based on 1000 simulated patients at each age at the licensed European dose of 200 mg enterally every 12 h. Lines are (top to bottom) the 95th, median, and 5th percentiles of simulated concentrations. The target trough concentration is the horizontal reference line at 1000 ng/ml. Figure 5. There is a constant increase of 520 ng/ml for every increase in dose of 1 mg/kg, which is consistent with the Michaelis-Menten kinetics of the drug. For example, a 50% increase in dose from 4 to 6 mg/kg does not increase the median trough by 50% but from 750 to 1800 ng/ml, an increase of 240%. DISCUSSION The data from the present report indicate that monitoring serum concentrations is important in children. A statistically significant association was found between crude mortality and voriconazole 12-h trough concentrations!1000 ng/ml, even in this relatively small population. This breakpoint is consistent with several other investigations [5 7, 14, 15]. There was also a great deal of between-patient and interoccasion pharmacokinetic variability, as noted by Karlsson et al [4]. Failure to account for interoccasion variability increases model error and introduces biases in some parameter estimates [16]. Because 98% of the samples used for our model were obtained during different dosing intervals, in some cases during a period of months, and often after different dose amounts or routes, we were unable to model the changes in parameter values within a single individual over time. This likely contributed to the large variability in estimates of pharmacokinetic parameters (Table 2). Despite this, simulation of 10,000 concentration profiles closely matched the observed distribution of concentrations in the CHLA patients (Figure 3). Significant features of our model that differ from that of Karlsson et al [4], as indicated in Table 2, are the delay in voriconazole absorption after an oral dose and the higher bioavailability. These differences may be due to our relative lack of samples early in the dosing interval and within-individual, interoccasion variability. Our oral bioavailability was 80%, compared with 96% reported for adults in the package insert and 45% reported by Karlsson et al [4]. Although not known to be ph dependent, absorption of voriconazole is reduced by food [17], which may explain some of the differences. Because the calculation of bioavailability depends on ratios of achievable concentrations after enteral and intravenous dosing, the small number of samples obtained after intravenous dosing in our population may have caused bias. However, our estimate was closer to that in the package insert, and we are unaware of any drug that has as large a discrepancy in bioavailability as that reported by Karlsson et al [4] that could be attributed to age alone. On the basis of our simulations, an intravenous dose of 7 mg/kg every 12 h in children up to the age of 12 years, as approved in Europe, is likely to achieve a voriconazole trough concentration of ng/ml in about two-thirds of children and appears to be a good starting dose. The recommended 34 CID 2010:50 (1 January) Neely et al

9 Figure 5. Median simulated trough voriconazole concentration for a given enteral dose, showing the regression line with associated P value. European enteral dose of 200 mg every 12 h, regardless of age or weight, was chosen to best match the voriconazole exposure (area under the curve) in children to that in adults who also receive 200 mg every 12 h. The somewhat surprising dose equivalence, which can result in doses in excess of 15 mg/kg in the youngest children, is due to the single report of voriconazole s markedly decreased bioavailability and increased clearance in children relative to adults [4]. Despite the higher bioavailability in our data, simulation predicts that a fixed dose of 200 mg will result in reasonable trough concentrations close to 1000 ng/ml in many children. However, physicians should be aware that concentrations may be markedly above or below this target because of the variability in absorption. Furthermore, we are not aware of any actual reported experience of children receiving an enteral dose as great as 18 mg/kg. The largest enteral dose in the CHLA patients was 12.9 mg/kg twice daily (with associated trough concentrations of 13,200 ng/ml and 4200 ng/ml on different occasions), and there is 1 report of a 4-year-old child who tolerated 13.3 mg/kg twice daily based on measured serum concentrations [18]. The tolerability and absorption of higher doses are not reported in the peer-reviewed literature, although a prospective trial to study this dose is under way. Given the uncertainty associated with the pharmacokinetics of enteral voriconazole in children, it may be appropriate to prolong intravenous therapy until there is clear evidence of sustained improvement. These doses should be considered as initial, with measurement of serum trough concentrations at a minimum, followed by rational dosage adjustment as necessary. Our data suggest that for every increase in dose of 1 mg/kg, serum concentrations will increase 520 ng/ml. However, measured concentrations outside the desired range should prompt a careful examination of other factors, such as fasting status, concomitant medication use, or organ function. We did not find any significant association between voriconazole concentrations and ALT or ALKP levels. One-half of the CHLA children started voriconazole therapy with elevated ALT and ALKP levels, and further elevations after starting voriconazole therapy were common, regardless of baseline values. However, most patients returned to baseline ALT levels or below by 2 4 weeks after peak values, without interrupting voriconazole therapy. The obvious limitation of this study is the retrospective design. We did not control for which children had concentrations measured or any other factor associated with voriconazole therapy. However, population modeling is the analytic technique of choice under these circumstances because the individual doses, sample times, sample numbers, serum concentrations, and patient characteristics are all included in the modeling process. It is reassuring that our findings do not differ from the published prospective study [4] in terms of recommendations for initial dosing. In conclusion, we wish to emphasize 2 major points for the physician who uses voriconazole therapy in children. First, we found a significant survival benefit when voriconazole trough concentrations were ng/ml. To our knowledge, this is the first such demonstration in children, and it is consistent with evidence in adults. Second, this study confirms that vor- Pediatric Voriconazole PK/PD CID 2010:50 (1 January) 35

10 iconazole pharmacokinetics in children are highly variable, particularly with the enteral formulations. Although 7 mg/kg intravenously and 200 mg enterally every 12 h may be reasonable starting doses, we suggest, as has been done for adults, that voriconazole concentrations be measured and the dose adjusted to maintain a trough of at least 1000 ng/ml. This strategy is especially important before the prospective validation of these doses that is currently under way. Acknowledgments We sincerely thank Rosa Cruz for data abstraction. Financial support. The National Institute of Allergy and Infectious Diseases (1 K23 AI to M.N.) and The National Institute of Biomedical Imaging and Bioengineering (R01 EB A1 to M.N. and R.J.). Potential conflicts of interest. M.N. is on the speaker s bureau for Virco and Merck and has attended an advisory meeting for Virco. All other authors: no conflicts. References 1. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl JMed2002; 347: Prasad PA, Coffin SE, Leckerman KH, Walsh TJ, Zaoutis TE. Pediatric antifungal utilization: new drugs, new trends. Pediatr Infect Dis J 2008; 27: Walsh TJ, Karlsson MO, Driscoll T, et al. Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration. Antimicrob Agents Chemother 2004; 48: Karlsson MO, Lutsar I, Milligan PA. Population pharmacokinetic analysis of voriconazole plasma concentration data from pediatric studies. Antimicrob Agents Chemother 2009; 53: Denning DW, Ribaud P, Milpied N, et al. Efficacy and safety of voriconazole in the treatment of acute invasive aspergillosis. Clin Infect Dis 2002; 34: Pascual A, Calandra T, Bolay S, et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis 2008; 46: Smith J, Safdar N, Knasinski V, et al. Voriconazole therapeutic drug monitoring. Antimicrob Agents Chemother 2006; 50: Tan K, Brayshaw N, Tomaszewski K, Troke P, Wood N. Investigation of the potential relationships between plasma voriconazole concentrations and visual adverse events or liver function test abnormalities. J Clin Pharmacol 2006; 46: Smith J, Andes D. Therapeutic drug monitoring of antifungals: pharmacokinetic and pharmacodynamic considerations. Ther Drug Monit 2008; 30: Goodwin ML, Drew RH. Antifungal serum concentration monitoring: an update. J Antimicrob Chemother 2008; 61: Weiss J, Ten Hoevel MM, Burhenne J, et al. CYP2C19 genotype is a major factor contributing to the highly variable pharmacokinetics of voriconazole. J Clin Pharmacol 2009; 49: De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46: EPARs for authorised medicinal products for human use Vfend. Available at vfend/vfend.htm. Accessed 13 January Andes D, Marchillo K, Stamstad T, Conklin R. In vivo pharmacokinetics and pharmacodynamics of a new triazole, voriconazole, in a murine candidiasis model. Antimicrob Agents Chemother 2003;47: Pfaller MA, Diekema DJ, Rex JH, et al. Correlation of MIC with outcome for Candida species tested against voriconazole: analysis and proposal for interpretive breakpoints. J Clin Microbiol 2006; 44: Karlsson MO, Sheiner LB. The importance of modeling interoccasion variability in population pharmacokinetic analyses. J Pharmacokinet Biopharm 1993; 21: Purkins L, Wood N, Kleinermans D, Greenhalgh K, Nichols D. Effect of food on the pharmacokinetics of multiple-dose oral voriconazole. Br J Clin Pharmacol 2003; 56(Suppl 1): Destino L, Sutton DA, Helon AL, et al. Severe osteomyelitis caused by Myceliophthora thermophila after a pitchfork injury. Ann Clin Microbiol Antimicrob 2006; 5: CID 2010:50 (1 January) Neely et al