Table 1. Physiochemical & Elimination

Parameters of Voriconazole

Pharmacokinetic (PK) Analysis

In order to assess differences between age groups, blood concentration simulations were

generated for a single IV infusion dose of 7- and 6 mg/kg in children and adults, respectively.

Next, determination of model linearity was made for 3-6 mg/kg doses in children and adults.

Finally, clinically effective doses, based on previously published clinical trials, were used for

single IV infusion, multiple IV infusion and multiple oral dosing simulations (Table 2).6 The

output was analyzed using non-compartmental analysis with Phoenix WinNonlin (version

6.2, Pharsight Mountain View, CA). Final PK parameters included AUCinf, AUC0-12, Cmax, Cl,

Vd, T1/2 and bioavailability (F), with the AUC being determined by the linear trapezoidal

method. Lastly, in order to determine bioavailability for each age group, the area under the

curve values from the multiple oral and infusion outputs were used.

Model Validation

A sensitivity analysis was performed

to examine and validate the variation

in the generated blood concentrations

model output corresponding to the

input parameters. Sensitivity coefficients

are reported as log-normalized values.7 Relevant metabolic and dosing parameters,

including Vmax, Ka, body weight & renal clearance, were included in the analysis

A Physiologically Based Pharmacokinetic Model of Voriconazole Disposition in Children Suggests

Extrahepatic First-Pass Metabolism Nicole R. Zane1, Garrett R. Ainslie2, Mary F. Paine1, and Dhiren R. Thakker 1

1Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, and 2Curriculum in Toxicology, The University of

North Carolina at Chapel Hill, Chapel Hill, NC, 27599.

Materials and Methods

Introduction Results

1. Yanni SB, Annaert PP, Augustijns P, Ibrahim JG, Benjamin DK, Jr., Thakker DR. In vitro hepatic metabolism explains higher clearance of

voriconazole in children versus adults: role of CYP2C19 and flavin-containing monooxygenase 3. Drug metabolism and disposition: the

biological fate of chemicals 2010;38:25-31.

2. Williams LR, Leggett RW. Reference values for resting blood flow to organs of man. Clinical physics and physiological measurement : an

official journal of the Hospital Physicists' Association, Deutsche Gesellschaft fur Medizinische Physik and the European Federation of

Organisations for Medical Physics 1989;10:187-217.

3. Bjorkman S. Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling:

theophylline and midazolam as model drugs. British journal of clinical pharmacology 2005;59:691-704.

4. Basic anatomical and physiological data for use in radiological protection: reference values. A report of age- and gender-related differences

in the anatomical and physiological characteristics of reference individuals. ICRP Publication 89. Annals of the ICRP 2002;32:5-265.

5. Weiler S, Fiegl D, MacFarland R, et al. Human tissue distribution of voriconazole. Antimicrobial agents and chemotherapy 2011;55:925-8.

6. Driscoll TA, Yu LC, Frangoul H, et al. Comparison of pharmacokinetics and safety of voriconazole intravenous-to-oral switch in

immunocompromised children and healthy adults. Antimicrobial agents and chemotherapy 2011;55:5770-9.

7. Clewell HJ, 3rd, Lee TS, Carpenter RL. Sensitivity of physiologically based pharmacokinetic models to variation in model parameters:

methylene chloride. Risk analysis : an official publication of the Society for Risk Analysis 1994;14:521-31.

8. Driscoll TA, Yu LC, Frangoul H, et al. Comparison of pharmacokinetics and safety of voriconazole intravenous-to-oral switch in

immunocompromised children and healthy adults. Antimicrobial agents and chemotherapy 2011;55:5770-9.

9. Walsh TJ, Driscoll T, Milligan PA, et al. Pharmacokinetics, safety, and tolerability of voriconazole in immunocompromised children.

Antimicrobial agents and chemotherapy 2010;54:4116-23.

10. Leveque D, Nivoix Y, Jehl F, Herbrecht R. Clinical pharmacokinetics of voriconazole. International journal of antimicrobial agents

2006;27:274-84.

11. Karlsson MO, Lutsar I, Milligan PA. Population pharmacokinetic analysis of voriconazole plasma concentration data from pediatric studies.

Antimicrobial agents and chemotherapy 2009;53:935-44.

References

Voriconazole, a potent antifungal agent used for life-threatening infections, is cleared

predominantly via oxidative metabolism by cytochrome P450 (CYP) 3A4, CYP2C19,

and flavin containing monooxygenase (FMO). Its clearance is 3-fold higher and oral

bioavailability is approximately half in children compared to adults. In vitro oxidative

metabolism of voriconazole by liver microsomes from children forms voriconazole

N-oxide, the major circulating metabolite of voriconazole, at approximately 3X the rate

in adults, which reflects the observed differences in voriconazole disposition between

adults and children. The aim of this study is use in vitro voriconazole metabolism data

to develop a physiologically based pharmacokinetic (PBPK) model that describes the

time course of voriconazole plasma concentrations and its disposition.

Figure 3: Semi-logarithmic Plots of Blood Concentration versus Time for

Increasing Doses of Voriconazole

Figure 2: Semi-logarithmic Plot of Blood Concentration versus Time Profile for

Single IV Infusion

Figure 6: Normalized Sensitivity Analysis

Acknowledgment Nicole R. Zane is supported by a Pre-doctoral Fellowship from the American Foundation of Pharmaceutical Education.

Table 3: Pharmacokinetic Parameters in Children versus Adults with Increasing

Voriconazole Doses from 3 to 6 mg/kg

Table 4: Pharmacokinetic Parameters in Children versus Adults Generated with

Clinically Effective Doses

Figures 4 & 5: Semi-logarithmic Plots of Blood Concentration versus Time for Multiple IV & Oral

Dosing of Voriconazole

Simulation of a single IV infusion where children

received 7 mg/kg over 140 minutes and adults

received 6 mg/kg over 120 minutes. The curves

for both children and adults exhibited a biphasic

profile. In addition, the profile displays an

increased half-life and decreased clearance in

adults compared to children. These results are

consistent with published data revealing a 2-

compartment model for voriconazole and support

the base model.

Table 3 presents the PK parameters associated with multiple IV infusion

simulations of 3 to 6 mg/kg of voriconazole given every 12 hours for 7 days.

Ratios of dose and AUC, compared against the 3 mg/kg dose, are depicted in the

last two columns. Children displayed a linear increase in AUC ratio as compared

to the non-linear increase in adults. In addition, T1/2 remained similar in children,

but increased in adults.

Pediatric Cl & Vd differ from clinical trial data of 6.7 mL/min/kg & 4.6 L/kg by 11 &

60%, respectively. AUC0-12 values differ from published data of 21.4 & 18.6 mg*h/L

for multiple IV & oral doses by 9 & 38%, respectively. Cmax values differ from

published data of 2.2, 4.3, and 3.6 mg/L for single IV, multiple IV & multiple oral

doses by 46, 3.3 & 43%, respectively. If data for 2 year old was excluded,

variance for multiple oral doses decreased to 8 & 19% for AUC0-12 & Cmax,

respectively. Bioavailability was ≥100%, which is more than double that of

published range of 45-60%. 8-10

Figure 3 represents multiple IV infusion simulations of 3 to 6 mg/kg doses given

every 12 hours for 7 days. Panel [A] displays the blood concentration versus time

profile for children and panel [B] represents the profile for adults. Panel [A]

increases linearly. Panel [B] increases non-linearly over the same dose range.

Adult Cl & Vd results differ from clinical trial data of 2.0 mL/min/kg & 4.6 L/kg by

25 & 10%, respectively. AUC0-12 values differ from published data of 34.9 & 13.7

mg*h/L for multiple IV & oral doses by 38 & 17%, respectively. Cmax values differ

from published data of 3.13, 4.65, and 2.51 mg/L8 for single IV, multiple IV &

multiple oral doses by 35, 20 & 18%, respectively. Bioavailability is within the

published range of 80-96%.8,11

Frozen tissues from adults and children were obtained from

Comparative Human Tissue Network (Columbus, OH) under

an approved UNC-Chapel Hill IRB. Normal liver tissues, free

of disease, were snap frozen within 6 hours post mortem from

children donors aged between 2 to 8 years old and adult

donors aged >18 years old. Characterization & metabolic

assays were performed as previously described.1

Physiologic Characteristics & Model Structure

Tissue-plasma partition coefficients (Kp), age-dependent

physiologic volumes, and perfusion rates were generated

utilizing GastroPlus (version 7.0, Simulations Plus, Lancaster,

CA). Kp values for target organs were generated using the

Poulin & Theil (Homogenous) prediction method. Physiochemical & elimination properties are

shown in Table 1. Berkeley Madonna (version 8.3.18; University of California at Berkeley,

Berkeley, CA) was utilized to run simulations. In order to simulate differences in voriconazole

exposure due to changes in physiologic characteristics, children were split into groups of 2-,

5-, & 8 year olds. Adult physiologic characteristics were used for humans aged 35 years old,

which has been the reference age used in previously published review articles.2 The

Population Estimates for Age-Related Physiology yielded average body weight, cardiac

output, tissue volumes and perfusion rates based on gender, age, and American heritage.

Male & female characteristics were averaged. Volumes

of target organs and the “other” compartment were

combined to equal the average body weight. Flow rates

to each organ were converted to a fraction of the total

cardiac output and then compared against published

pediatric fractional flow rates.3,4 The sum of all the flow

rates totaled the cardiac output. A perfusion limited

model (Figure 1) was utilized for an initial model, with

compartments determining distribution in human tissues

based on published data.5 The “other” compartment

grouped tissues not specified in the model for mass

balance. Figure 1. Model Structure

Table 2. Dosing regimens of Voriconazole

Figure 4 represents multiple IV infusion simulations where children received doses of 7 mg/kg

over 140 minutes and adults received 4 mg/kg over 80 minutes. Figure 5 represents multiple

oral dosing where children and adults both received 200 mg every 12 hours for 7 days.

[A] 2 year olds, [B] 5 year olds, [C] 8 year olds, and [D] adults.

Normalized sensitivity coefficients of Vmax, renal clearance (Cl_renal), body weight (BW), and the

first-order absorption constant (Ka) for AUC during IV infusions and oral dosing of voriconazole

stratified by age.

Conclusions and Discussion

1. The PBPK model provided a sound initial base model for voriconazole behavior in

humans, with the majority of calculated PK parameters agreeing well with clinical

observations.

2. Unexpectedly, calculated oral bioavailability in adults was similar to the observed

value but was over-predicted in children by nearly 2-fold.

3. Since the model incorporated only hepatic and renal clearance as routes of

elimination, the results suggest that voriconazole undergoes intestinal first-pass

metabolism in children but not in adults.

4. Further studies are planned to investigate the in vitro metabolism of voriconazole

using microsomes prepared from pediatric intestinal tissues.