Comparison of Pharmacokinetics and Safety of Voriconazole Intravenous-to-Oral Switch in Immunocompromised Adolescents and Healthy Adults

Abstract

The current voriconazole dosing recommendation in adolescents is based on limited efficacy and pharmacokinetic data. To confirm the appropriateness of dosing adolescents like adults, a pharmacokinetic study was conducted in 26 immunocompromised adolescents aged 12 to <17 years following intravenous (IV) voriconazole to oral switch regimens: 6 mg/kg IV every 12 h (q12h) on day 1 followed by 4 mg/kg IV q12h, then switched to 300 mg orally q12h. Area under the curve over a 12-hour dosing interval (AUC_0–12) was calculated using a noncompartmental method and compared to the value for adults receiving the same dosing regimens. On average, the AUC_0–12 in adolescents after the first loading dose on day 1 and at steady state during IV treatment were 9.14 and 22.4 μg·h/ml, respectively (approximately 34% and 36% lower, respectively, than values for adults). At steady state during oral treatment, adolescents also had lower average exposure than adults (16.7 versus 34.0 μg·h/ml). Larger intersubject variability was observed in adolescents than in adults. There was a slight trend for some young adolescents with low body weight to have lower voriconazole exposure. It is likely that these young adolescents may metabolize voriconazole more similarly to children than to adults. Overall, with the same dosing regimens, voriconazole exposures in the majority of adolescents were comparable to those in adults. The young adolescents with low body weight during the transitioning period from childhood to adolescence (e.g., 12 to 14 years old) may need to receive higher doses to match the adult exposures. Safety of voriconazole in adolescents was consistent with the known safety profile of voriconazole.

INTRODUCTION

Voriconazole is a broad-spectrum triazole antifungal agent with activity against a wide range of yeasts and filamentous fungi (2, 5, 6, 10) and is approved for treatment of various invasive fungal infections worldwide. Voriconazole is extensively metabolized by and is also an inhibitor of the cytochrome P450 (CYP) isozymes CYP2C19, CYP2C9, and CYP3A4, which results in extensive drug interactions with concomitant mediations. Voriconazole exhibits nonlinear pharmacokinetics due to saturation of its metabolism. For example, a 4-mg/kg intravenous (IV) maintenance dose (equivalent to a 300-mg oral dose) provides approximately 2.5-fold higher voriconazole exposure than a 3-mg/kg IV maintenance dose (equivalent to a 200-mg oral dose) in adults (12). In adults, intersubject variability in voriconazole exposure is high, and CYP2C19 genotype, gender, and age are key factors which help explain this variability (11).

There are limited efficacy, safety, and pharmacokinetic data for voriconazole in adolescents. As described in the product label (11), 22 subjects aged 12 to 18 years with invasive aspergillosis (IA) were included in the voriconazole clinical safety and efficacy studies. Twelve of 22 (55%) subjects had a successful response after treatment with voriconazole at 4 mg/kg IV every 12 h (q12h) (loading doses of 6 mg/kg IV q12h on the first day of treatment) and 200 mg orally q12h. Based on the limited pharmacokinetic data collected form these adolescent patients, the voriconazole mean concentrations appeared to be comparable to those in adult patients receiving the same dosing regimen.

The nonlinearity of voriconazole pharmacokinetics in children is less pronounced than that in adults. It has been shown that children (2 to <12 years old) require much higher voriconazole doses than adults due to faster metabolism in children (4, 7, 15, 16). Since there is a significant difference in recommended voriconazole dosing regimens between children and adults (e.g., the IV maintenance dose is 7 to 8 mg/kg, versus 4 mg/kg), the question whether 12 years old (i.e., after the 12th birthday) be the appropriate age to switch from the children's regimen to the adults' regimen is frequently asked.

Therefore, this study was designed to provide additional pharmacokinetic and safety data with a focus on young adolescents during the transitioning period from childhood to adolescence to confirm whether the following regimens would provide comparable voriconazole exposures in adolescents and adults: loading doses of 6 mg/kg IV q12h on day 1 followed by a maintenance dose of 4 mg/kg IV q12h with a switch to a maintenance dose of 300 mg orally q12h (150 mg orally q12h for subjects weighing less than 40 kg). In addition, the potential effect of CYP2C19 genotyping status on voriconazole pharmacokinetics in adolescents was evaluated.

MATERIALS AND METHODS

Study design.

This was an open-label, voriconazole IV-to-oral switch, multiple-dose, multicenter study in immunocompromised adolescents aged 12 to <17 years who were at high risk for systemic fungal infection. This study consisted of an initial pharmacokinetic period (voriconazole at 6 mg/kg IV q12h on day 1 followed by 4 mg/kg IV q12h for 6 days and then switched to 300 mg orally q12h for 6.5 days; extended IV treatment up to 20 days was allowed), followed by an optional nonpharmacokinetic period if clinically indicated (voriconazole administration could be continued up to day 30), with a 1-month follow-up after the last dose of study drug. In special cases, the subject was permitted to receive voriconazole for more than 30 days to allow scheduling of serial pharmacokinetic sampling in order to maximize the feasibility of the study's completion. Ten study centers in the United States participated in this study, and this study was approved by the local institutional review boards. Written informed consent and assent were obtained prior to the subject entering the study.

Study population.

Male or female adolescents from 12 to <17 years of age, who required systemic antifungal prophylaxis and were expected to tolerate oral therapy after 7 to 20 days of parenteral voriconazole, were eligible for the study. Subjects were expected to develop neutropenia (absolute neutrophil count <500 cells/μl) lasting more than 10 days following chemotherapy for leukemia, lymphoma, or aplastic anemia or as a hematopoietic stem cell transplant (HSCT)-preparative regimen. Subjects were excluded if they had known hypersensitivity to azoles, abnormal laboratory safety findings at screening [aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN) or total bilirubin >2.5 times ULN], moderate or severe renal impairment (i.e., estimated creatinine clearance < 50 ml/min), prior or current evidence of cardiac arrhythmia, or any condition possibly affecting drug absorption (e.g., gastrectomy). Subjects were excluded if they were receiving inhibitors of CYP450 enzymes that affect voriconazole exposure (e.g., fluconazole, itraconazole, posaconazole, or omeprazole) or drugs with potential QT interval prolongation (e.g., terfenadine, astemizole, cisapride, pimozide, or quinidine) within 24 h prior to study start, or anticipated to receive any of these drugs during the study. Subjects were excluded if they were receiving inducers of CYP450 enzymes (e.g., rifampin, rifabutin, carbamazepine, phenytoin, nevirapine and long acting barbiturates, efavirenz and ritonavir) within 14 days prior to study start or were expected to receive any of these drugs during the study. Subjects were excluded if they would need to receive any other drugs prohibited in the voriconazole product label during the study (e.g., sirolimus or ergot alkaloids). Subjects were also excluded if they had any other condition which, in the opinion of the investigator, made the subject unsuitable for enrollment.

Study treatment.

Voriconazole IV doses were administered at an infusion rate of approximately 3 mg/kg/h (i.e., the 6 and 4 mg/kg were administered by infusion over 120 and 80 min, respectively). Voriconazole 300-mg oral tablets were administered at least 1 h before or after meals (as food intake decreases voriconazole exposure during oral administration). Per the label instructions, if a subject weighs less than 40 kg, half of the standard oral dose (150 mg) should be administered. Both IV and oral voriconazole were administered every 12 h ± 30 min.

Pharmacokinetic sampling.

A total of 27 blood samples (1 to 2 ml per sample to provide approximately 0.5 ml plasma) were to be collected from each subject. Specifically, on day 1 of IV treatment, plasma samples were collected predose and at 60 min, 118 min (2 min prior to the end of infusion), 4 h, 6 h, 8 h, and 12 h after the start of infusion; on day 7 of IV treatment, plasma samples were collected predose and at 40 min, 78 min (2 min prior to the end of infusion), 4 h, 6 h, 8 h, and 12 h after the start of infusion; then, on the 7th day of oral treatment, samples were collected predose and at 1, 2, 4, 6, 8, and 12 h after dosing. Additionally, plasma samples were collected just prior to dosing (trough sample) on the 4th through the 6th day of IV and oral treatments. If subjects could not be scheduled for serial sampling on the 7th day of IV or oral dosing, subjects could remain on IV or oral treatment to allow sample collection at a later date.

Analytical methods.

PPD Development (Richmond, VA) analyzed all the plasma samples for voriconazole using a previously validated liquid chromatography coupled to tandem-mass spectrometry (LC-MS/MS) method (1). The plasma samples (0.100 ml) were extracted using a solid-phase extraction procedure followed by LC-MS/MS separation and detection. The dynamic range of the assay for voriconazole was 10 to 5,000 ng/ml. The accuracy of the quality control samples used during sample analysis ranged from −3.28% to 3.91% with a precision of ≤8.58% for voriconazole. All the samples were analyzed within an established long-term stability period.

Pharmacokinetic analysis.

Noncompartmental pharmacokinetic analysis was performed using the internally validated system eNCA v2.2.1. Maximum observed plasma concentration (C_max), time to reach C_max (T_max), and trough concentration (C_min) for voriconazole were estimated directly from concentration-time data. The area under concentration-time curve over a 12-hour dosing interval (AUC_0–12) for voriconazole was estimated using the linear/log trapezoidal approximation. The achievement of steady state was assessed by visual inspection of trough concentrations. Samples above the limit of quantification were diluted appropriately within the range for the assay. Samples below the lower limit of quantification were set to 0 ng/ml for analysis. Actual sample collection times were used for the pharmacokinetic analysis.

CYP2C19 genotyping.

Buccal swab or whole-blood samples were collected and analyzed for CYP2C19 genotyping at Pfizer Pharmacogenomics Laboratory (Groton, CT). Genomic DNA was purified using a QIAamp DNA minikit (Qiagen). Five single-nucleotide polymorphisms for CYP2C19, *2, *3, *4, *5, and *17, were analyzed. Ultrarapid extensive metabolizer (UM) was defined as *17, *17. Homozygous extensive metabolizer (EM) was defined as *1, *1. Poor metabolizer (PM) was defined as *2, *2. Heterozygous extensive metabolizer (HEM) was defined as any combination of two of the above (i.e., *1, *2; *2,*17).

Safety assessment.

Adverse events (AEs) were monitored closely throughout the study. Safety assessments, including safety laboratory tests (hematology, chemistry, and urinalysis), testing of vital signs (blood pressure and pulse rate), and physical examination, were performed at screening, on day 1 IV (prior to dosing), every 5 to 7 days during the study treatment period, and at the 1-month follow-up visit. Extra efforts were made to monitor potential visual side effects of voriconazole in adolescents. Visual assessments (visual questionnaire, distance visual acuity testing, and color vision testing) were performed on day 1 IV (within 24 h prior to the first dose), every 5 to 7 days during the study treatment period, and at the 1-month follow-up visit. If a change in visual acuity or color vision testing from day 1 was noted and/or the subject reported any new visual symptoms based on the response to the questionnaire, a formal ophthalmologic examination (dilated fundoscopy) was performed to evaluate the significance of the findings. In addition, single 12-lead ECGs were collected at screening, on day 1 IV (prior to dosing), on day 7 IV, and on the 7th day of oral treatment.

Statistical analysis.

A sample size of 18 adolescents was chosen based on the need to minimize exposure to this special population and the requirement to provide adequate pharmacokinetic, safety, and tolerability information. Assuming an 18% dropout rate, it was decided that 25 subjects should participate to ensure that at least 18 subjects completed the pharmacokinetic period. No formal inferential statistics were applied to the pharmacokinetic, genotyping, or safety data, and all the data were summarized with descriptive statistics.

Voriconazole pharmacokinetic parameters were evaluated by gender, age, body weight, and CYP2C19 genotyping status. The exposure data (based on the noncompartmental method) from three adult pharmacokinetic studies (6 → 4 mg/kg IV q12h and 300 mg orally q12h) were utilized for comparison with the corresponding adolescent data (4, 11, 12). Given the large intersubject variability in voriconazole exposure and the limitation of the sample size for the adolescents, an informal statistical comparison of exposure parameters was performed. If there was a substantial overlap between the distribution of AUC_0–12 in adolescents and that in reference adults, and if the median AUC_0–12 in adolescents was similar to that in reference adults, the exposures would be considered comparable. Analysis of the relationship between voriconazole exposure parameters (e.g., AUC_0–12, C_max, and C_min) and safety endpoints (e.g., hepatic and visual AEs) in adolescents was descriptive.

RESULTS

Subject disposition and demography.

The demographic characteristics of immunocompromised adolescents and reference adults are presented in Table 1 . Twenty-six subjects were enrolled between June 2008 and December 2009 from 7 of 10 centers in the U.S. and received IV voriconazole. Twenty-two subjects were able to switch to oral voriconazole, and 20 subjects completed the study. There was one special case: a 13-year-old, 65.7-kg white male completed only 2 days of oral dosing due to intolerance to all oral medications (severe mucositis). He was then switched back to IV voriconazole and discontinued participation in the study during the second IV dosing period.

Table 1.

Demographic characteristics of adolescents and reference adults

Characteristic	Adolescents (n, 26)	Adults (IV) (n, 35)a	Adults (oral) (n, 16)b
Gender and race
No. of males (no. of race [white/black/other])	17 (16/0/1)	24 (20/3/1)	11 (10/1/0)
No. of females (no. of race [white/black/other])	9 (6/2/1)	11 (10/0/1)	5 (3/2/0)
Age (yr)
12	4
13	10
>13-<17	12
Mean (SD)	13.7 (1.3)
Median (range)	13 (12–16)	34 (22–55)	37.5 (19–60)
Wt
No. with wt <50 kg	8
No. with wt ≥50 kg	18
Mean wt (SD) (kg)	56.7 (14.2)
Median (wt) (range) (kg)	57.1 (30.4–92.2)	76.0 (49.0–97.0)	69.4 (47.4–95.5)
CYP2C19 genotyping status
UM	2
EM	6	20	4
HEM	14	14	2
PM	2	1	1
Not reported	2	0	9

^aData are from reference 4.

^bData are from references 11 and 12.

There were 17 male subjects (65.4%), and 54% of the subjects (14/26) were <14 years old (four 12-year-olds and 10 13-year-olds). The median (range) weight was 57.1 (30.4 to 92.2) kg.

Twenty-three (88%) subjects had hematologic malignancies (17 subjects with leukemia, 3 with lymphoma, 2 with myelodysplastic syndrome, and 1 with refractory anemia). One subject had Ewing's sarcoma, and two subjects had familial or genetic disorders (chronic granulomatous disease and mucopolysaccharidosis) which required stem cell transplant. The majority of subjects (20/26, 76.9%) had an HSCT prior to the start of study treatment or during the study.

Over 70% of the subjects (19/26) received voriconazole IV for 8 or more days, with a median (range) duration of 14 (3 to 31) days. Over 70% of the subjects (16/22) received oral voriconazole for 7 or fewer days, with a median (range) duration of 7 (2 to 20) days.

All subjects were taking at least one drug treatment prior to the start of study and during the study. The most common concomitant medications taken prior to and during the study were antibacterial agents, immunosuppressants, and electrolyte replacements. Antiviral agents, analgesics, antihistamines, parenteral nutrition, and corticosteroids were also common.

Except for two subjects, the concomitant medications taken by study subjects had no known potential to affect voriconazole exposure. One subject (a 12-year-old, 39-kg white male) inadvertently received phenytoin from 2 days prior to the first study dose until day 5 of IV treatment. As expected, the voriconazole exposures on day 1 and day 7 IV (AUC_0–12, 4.96 and 2.47 μg·h/ml) in this subject were the lowest, and they were excluded from summary statistics. The other subject (a 13-year-old, 65.7-kg white male) inadvertently received oxcarbazepine throughout the study. The effect of oxcarbazepine on the pharmacokinetics of voriconazole is unknown, since oxcarbazepine is described as a CYP2C19 inhibitor and CYP3A4/5 inducer. The exposure data in this subject were obtained only at steady state during IV treatment (AUC_0–12, 6.24 μg·h/ml), which was the second lowest obtained. This might indicate that oxcarbazepine decreases voriconazole exposure, and this possibility needs to be confirmed.

In the adult reference group, 35 healthy adults provided the exposure data for the IV regimen, and 7 healthy male subjects and 9 (4 males) patients at risk for aspergillosis (e.g., malignant neoplasms of lymphatic or hematopoietic tissue) provided the exposure data for the oral regimen.

Voriconazole pharmacokinetics in adolescents compared to adults.

Based on the visual inspection of voriconazole trough concentrations on day 4 through day 7, the steady state was reached by day 7 for the IV and oral regimens in adolescents. As shown in Table 2, at all the dosing regimens (the first IV loading dose on day 1 and steady state for both IV and oral treatment), both the geometric mean and median AUC_0–12 in adolescents were lower than those observed in adults. Nonetheless, there was a significant overlap of distributions of AUC_0–12 between adolescents and adults, indicating that voriconazole exposures in the majority of adolescents were comparable to those in adults (Fig. 1). Approximately 30 to 35% of adolescents had exposures below the range observed in adults at these dosing regimens. None of the adolescents had total exposure higher than the range observed in adults. The intersubject variabilities for AUC_0–12 and C_max in adolescents appeared to be higher than those in adults (expressed as coefficients of variation, in percents, in Table 2).

Table 2.

Summary of plasma voriconazole pharmacokinetic parameters following voriconazole administration in adolescents compared to adults^a

Parameter	Value for group at indicated dosage on:
	Day 1, first IV dose	Day 7 of IV treatment (SS)	Day 7 of oral treatment (SS)
Adolescents	6 mg/kg	4 mg/kg q12h	300 mg q12h
n (M/F)	22 (14/8)	23 (14/9)	19 (12/7)
AUC0–12 (μg·h/ml)
Geometric mean (CV, %)	9.14 (48)	22.4 (73)	16.7 (62)
Median (range)	9.51 (2.52–21.6)	27.9 (6.24–95.3)	18.7 (1.17–49.7)
Cmax (μg/ml)
Geometric mean (CV, %)	2.25 (35)	3.89 (58)	2.35 (49)
Median (range)	2.36 (0.66–4.02)	3.72 (1.71–9.99)	2.84 (0.18–5.88)
Cmin (μg/ml)
Geometric mean (CV, %)		1.05 (100)b	0.72 (73)
Median (range)		1.59 (0.08–7.78)b	1.05 (0.04–2.84)
Tmax (h)
Median (range)	1.97 (1.90–2.08)	1.30 (1.17–3.95)	2.00 (0.67–8.10)
Adults (reference)	6 mg/kg	4 mg/kg q12h	300 mg q12h
n (M/F)	35 (24/11)	33 (23/10)	16 (11/5)
AUC0–12 (μg·h/ml)
Geometric mean (CV, %)	13.9 (32)	34.9 (53)	34.0 (53)
Median (range)	13.3 (7.43–29.7)	37.6 (13.7–104)	35.2 (14.0–84.3)
Cmax (μg/ml)
Geometric mean (CV, %)	3.13 (20)	4.65 (36)	4.74 (35)
Median (range)	3.05 (2.08–4.88)	4.60 (2.48–9.92)	5.30 (2.48–8.66)
Cmin (μg/ml)
Geometric mean (CV, %)		1.78 (72)	1.51 (74)
Median (range)		2.08 (0.38–7.35)	1.69 (0.36–5.28)
Tmax (h)
Median (range)	1.97 (1.97–1.97)	1.30 (1.30–1.30)	1.75 (1.00–5.40)

^aData for adults are from references 4, 11, and 12. M, male; F, female; AUC_0-12, area under the curve over a 12-h dosing interval; C_max, maximum plasma concentration; C_min, minimum plasma concentration; T_max, time to reach C_max; SS, steady state.

^bn = 21.

Fig. 1.

Comparison of observed voriconazole AUC_0–12 in adolescents to that in adults on day 1 of IV dosing (a), day 7 of IV dosing (steady state) (b), and day 7 of oral dosing (steady state) (c). Box plots provide medians with 10th, 25th, 75th, and 90th percentiles; values outside the 10th to 90th percentiles are presented as solid circles.

Voriconazole exposure in adolescents by body weight, age, and gender.

The voriconazole exposure in adolescents was further evaluated by body weight and age (Fig. 2). As shown in Fig. 2a, on day 1 IV (the loading dose), there was a trend for the voriconazole exposure (AUC_0–12) to increase as weight increased. Since weight and age are highly correlated, a similar trend was also seen between exposure and age (Fig. 2b). However, at steady state during the IV treatment, the tendency for the voriconazole exposure to increase as weight increased was less obvious (Fig. 2c), and there was no clear trend for the voriconazole exposure to increase as age increased (Fig. 2d). At steady state during the oral treatment, the tendency for the voriconazole exposure to increase as weight and age increased was also observed (Fig. 2e and f).

Fig. 2.

Individual observed voriconazole AUC_0–12 in adolescents receiving 6→4 mg/kg IV q12h and 300 mg orally q12h by weight and age.

In general, young adolescents with low body weight appeared to be located in the lower end of the distribution of the exposure. Table 3 lists the adolescents with oral exposures below or close to the lowest exposure (AUC_0–12, 14 μg·h/ml) observed in adults at 300 mg orally q12h, together with the corresponding exposures at steady state during IV treatment.

Table 3.

Individual voriconazole exposure parameters in young adolescents receiving 300 mg orally q12h^a

Subject (age [yr], sex)b	Wt (kg)	CYP2C19 type	IV steady state		Oral steady state
			AUC0–12 (μg·h/ml)	Cmax (μg/ml)	AUC0–12 (μg·h/ml)	Cmax (μg/ml)
23 (12, F)	30.4	HEM	40.1	9.82	NA	NA
26 (12, M)c	39.0	UM	2.47	0.53	4.63	1.91
9 (12, F)d	39.8	EM	6.27	2.26	1.17	0.18
25 (13, M)	43.0	UM	8.29	2.44	14.6	2.84
21 (13, M)	50.8	EM	16.3	2.95	14.8	1.96
24 (13, M)	52.1	NA	49.9	4.87	15.5	2.09
12 (13, F)	53.4	HEM	16.7	2.61	12.1	1.63
6 (12, M)	56.8	HEM	37.2	4.69	26.5	3.59
4 (14, M)	58.7	HEM	8.14	2.06	5.59	0.81
1 (14, M)e	60.0	EM	10.4	2.5	11.9	1.54
7 (14, M)	65.5	HEM	17	3.24	15.8	2.18

^aThe subset with AUC_0-12 of <16 μg·h/ml.

^bEM, homozygous extensive metabolizer; F, female; HEM, heterozygous extensive metabolizer; M, male; NA, not available; UM, ultrarapid extensive metabolizer.

^cThis subject inadvertently received phenytoin 2 days prior to the first dose until day 5 of IV treatment.

^dThis subject received 150 mg orally q12h (a reduced dose for subjects weighing less than 40 kg).

^eThis subject missed the morning doses on the fourth day and sixth day of oral voriconazole.

Gender had no apparent effect on the voriconazole exposure in adolescents at the IV and oral dosing regimens.

Correlation between voriconazole AUC_0–12 and C_min.

A good correlation between voriconazole total exposures and trough concentrations at steady state in adolescents was identified (Fig. 3). The linear regression equation for adolescent data is expressed as AUC_0–12 = 8.68 + 12.05 · C_min (R² = 0.92).

Fig. 3.

Observed voriconazole AUC_0–12 versus C_min at steady state in adolescents receiving 6→4 mg/kg IV q12h and 300 mg orally q12h (top, all subjects; bottom, subset with a C_min of ≤2 μg/ml).

Voriconazole exposure by CYP2C19 genotyping status.

The genotyping samples were collected from 24 of 26 adolescents. Among them, there were 2 UMs, 6 EMs, 14 HEMs, and 2 PMs (Table 1). In the reference adult group, the genotyping samples were collected from 42 healthy subjects but not from the patients who were at risk for aspergillosis. Among 35 adults providing IV exposure data, there were 20 EMs, 14 HEMs, and 1 PM; among 7 adults providing oral exposure data, there were 4 EMs, 2 HEMs, and 1 PM (Table 1).

In adolescents, voriconazole exposures in the two PMs (a 13-year-old, 47.2-kg Asian-American female and a 13-year-old, 43.5-kg Asian male) were above the average exposure observed in this study (Table 4). Their exposures during the IV dosing regimen were not among the highest, but the female PM had the highest oral exposure. One of the CYP2C19 UMs inadvertently received phenytoin (which accelerates the metabolism of voriconazole) during the study. As described above, this adolescent had the lowest exposure. The voriconazole exposures in the other UMs were not among the lowest exposures (AUC_0–12 on day 1 of IV treatment and at steady state during IV and oral treatment, 11.5, 8.29, and 14.6 μg·h/ml, respectively). As shown in Table 4, although the median AUC_0–12 in the CYP2C19 HEM adolescent group was higher than that in the UM/EM adolescent group, the distributions of AUC_0–12 in the HEM and UM/EM groups overlapped substantially. Overall, voriconazole exposure in adolescents could not be predicted based on CYP2C19 genotype status only in this study.

Table 4.

Summary of plasma voriconazole pharmacokinetic parameters in adolescents by CYP2C19 genotype status

Parameter and genotype group (n)a	Median (range) at dosageb
	6 mg/kg IV loading dose	4 mg/kg IV q12h	300 mg orally q12hc
AUC12 (μg·h/ml)
UM/EM (7)d	9.26 (2.52–19.8)	16.3 (6.27–30.9)	14.6 (1.17–37.9)
HEM (12)e	9.26 (4.36–21.6)	32.3 (6.24–95.3)	26.3 (5.59–46.5)
PM (2)	10.6, 11.7	31.1, 37.0	30.3, 49.7
Cmax (μg/ml)
UM/EM (7)d	2.55 (0.66–4.02)	2.95 (2.26–4.99)	1.96 (0.18–3.92)
HEM (12)e	2.49 (1.12–3.82)	3.72 (1.71–9.99)	3.59 (0.81–4.39)
PM (2)	1.89, 2.34	3.72, 8.74	4.20, 5.88

^aUM, ultrarapid extensive metabolizer; EM, homozygous extensive metabolizer; HEM, heterozygous extensive metabolizer; PM, poor metabolizer.

^bIndividual values for the PM type are given.

^cOnly one subject (a 39.8-kg white female) received 150 mg orally q12h.

^dOne UM was excluded from summary statistics on IV exposures due to concomitant use of phenytoin.

^en = 13 for 4 mg/kg IV q12h and 9 for 300 mg orally q12h.

In the adult reference group, both CYP2C19 PMs had the highest voriconazole exposures. Specifically, AUC_0–12 on day 1 and at steady state during IV treatment in the PM (who provided IV exposure data) were 29.7 and 104 μg·h/ml, respectively; AUC_0–12 at steady state during oral treatment in the other PM (who provided oral exposure data) was 84.3 μg·h/ml.

Safety assessment in adolescents. (i) Serious adverse events.

There was no death during the study reporting period. Seven subjects experienced a total of 22 serious adverse events (SAEs), and the majority were attributed to the disease under study, concomitant drug therapy, or concurrent illness, and only one SAE (hyperbilirubinemia) was assessed as being related to study drug. SAEs reported by more than one subject were mucositis (two subjects) and renal failure (two subjects).

(ii) Discontinuations.

Of the six subjects who discontinued the study, two discontinued because of treatment-related severe hepatic AEs: hyperbilirubinemia (also reported as an SAE) occurred during the oral regimen, and hepatic enzymes increased during IV regimen.

(iii) All-causality and treatment-related AEs.

All subjects experienced all-causality AEs during the study, and most AEs were mild to moderate in severity. The most common all-causality AEs, reported by at least 20% of subjects in either the IV or oral treatment period, were mucositis, fever, nausea, vomiting, diarrhea, hypertension, fluid retention, rash, hematuria, pain in the extremities, bone pain, dysuria, hypotension, and decreased oxygen saturation. These events were often related to accompanying illness and/or concomitant drug or nondrug treatments, and the pattern of these events was typical of those expected for subjects with immunosuppression and malignancies.

Three subjects experienced a total of five treatment-related AEs. One subject experienced hyperbilirubinemia (an SAE), prolonged QT interval, and increased immunosuppressant drug level, one subject experienced color blindness (trouble distinguishing between black and blue), and one subject experienced an increase in hepatic enzymes.

(a) Hepatic adverse events.

Thirteen subjects experienced hepatobiliary disorders during the study. Among them, two subjects experienced treatment-related severe hepatic AEs, which led to permanent treatment discontinuation. The corresponding voriconazole exposures are described below (also see Table 5).

Table 5.

All-causality hepatic and visual adverse events versus corresponding observed voriconazole exposure parameters^a

Event type and subject (age [yr], sex)	Adverse event(s)	AE onset study day	Treatment period and day	AUC0–12 (μg·h/ml)	Cmax (μg/ml)	Cmin (μg/ml)
Hepaticb
1 (14, M)	Moderate increase in GGT	8	IV, 8	10.4	2.5	0.22
3 (14, M)	Mild increase in AST (intermittent)	7	IV, 7	64.8	7.48	4.73
	Moderate ascites	20	Oral, 1	NA	NA	NA
	Severe hyperbilirubinemiac	20	Oral, 1	NA	NA	NA
4 (14, M)	Mild increase in transaminases (intermittent)	12	Oral, 5	5.59	0.81	0.17
5 (13, F)	Moderate hyperbilirubinemia	8	IV, 8	95.3	9.99	7.78
8 (13, F)	Mild cholelithiasis	9	IV, 9	37	8.74	1.93
	Moderate hyperbilirubinemia	11	IV, 11	37	8.74	1.93
12 (13, F)	Moderate increase in transaminases	18	IV, 18	16.7	2.61	0.71
16 (16, M)	Mild jaundice	9	IV, 9	45.3	8.35	2.34
	Mild hyperbilirubinemia	10	IV, 10	45.3	8.35	2.34
19 (16, F)	Severe increase in hepatic enzymed	6	IV, 6	6.82	1.71	0.14
22 (13, M)	Mild hyperbilirubinemia	10	IV, 10	6.24	1.89	NA
	Moderate increase in hepatic enzyme (intermittent)	10	IV, 10	NA	NA	NA
25 (13, M)	Mild increase in hepatic enzyme	7	IV, 7	8.29	2.44	0.11
26 (12, M)	Moderate hyperbilirubinemiae	24	IV, 24	NA	NA	NA
Visual
12 (13, F)	Moderate visual impairment (dark spots in lateral visual fields in left eye)	23	Oral, 1	NA	NA	NA
16 (16, M)	Mild color blindness (trouble distinguishing between black and blue)f	29	Oral, 7	24.1	2.93	1.3
17 (16, M)	Moderate photophobia	22	Oral, 15	46.5	4.39	2.72
24 (13, M)	Mild blurring of vision	1	IV, 1	NA	NA	NA

^aAST, aspartate aminotransferase; F, female; GGT, gamma glutamyltransferase; IV, intravenous; M, male; NA, not available.

^bTwo subjects were not included because the hepatic AEs occurred during the follow-up period.

^cThis subject discontinued study treatment on day 21 (day 2 of oral treatment) due to severe hyperbilirubinemia (treatment related).

^dThis subject discontinued study treatment on day 8 of IV treatment due to a severe increase in hepatic enzyme (treatment related).

^eThis subject inadvertently received phenytoin up to day 5 IV, AUC_0-12 on day 7 IV was 2.47 μg·h/ml, but it could not be used to estimate the exposure on day 24 IV.

^fTreatment related.

(b) Visual adverse events.

Ten subjects experienced 14 events of eye disorders (e.g., dry eye, conjunctivitis) during the study. Among them, five subjects reported visual disturbances (five events), and only one event was assessed as being related to study drug. During the treatment period, one subject reported color blindness (trouble distinguishing between black and blue; attributed to the study drug), one subject reported visual impairment (dark spots in lateral visual fields in the left eye; attributed to scopolamine patch use), one subject reported photophobia (attributed to methadone taper use), and one subject reported blurred vision (attributed to broken glasses and watching computer screen for too long). During the 1-month follow-up period, one subject reported hypermetropia (unknown cause).

The subject who experienced treatment-related mild color blindness was a 16-year-old white male. He had trouble distinguishing between black and blue stripes on his shorts on study day 29 (oral treatment day 7, the last dosing day). This subject received an ophthalmology examination on the same day for this event, and the results from the fundoscopy examination were normal. On that day, the results from the color vision test and distance visual acuity test were unchanged from baseline results. It was noted that this subject had mild red-green deficiency in both eyes at baseline and on day 7 oral treatment. No action was taken in regard to the study drug in response to the event. This event was considered resolved on study day 33 (posttreatment day 4). The corresponding voriconazole exposures are described below (also see Table 5).

(iv) ECGs.

Because of the high heart rate in certain adolescent subjects, Fridericia's correction of the QT interval (QTcF) was considered to provide a better estimation than Bazett's correction (QTcB). The mean change from baseline in QTcF after 7 days of IV voriconazole was 2.3 ms, and the mean change after 7 days of oral voriconazole was 4.9 ms. One subject developed a mild borderline prolonged QT interval on day 7 IV that was considered clinically significant and related to the study drug by the investigator. None of the other changes in ECG data was considered clinically significant relative to the baseline based on the assessments by local cardiologists.

Relationship between voriconazole exposure and adverse events of interest in adolescents.

Table 5 presents individual subjects with all-causality hepatic or visual AEs and corresponding observed voriconazole exposure parameters. Steady-state IV and oral voriconazole exposures were used as the estimates for AEs that occurred on nonpharmacokinetic days.

For hepatic and visual AEs assessed as unrelated to study drug, the corresponding exposures ranged from 5.59 to 95.3 μg·h/ml, and no trend was observed. Only one visual AE and two hepatic AEs were assessed as being treatment related. The total exposure in the subject with mild color blindness was 24.1 μg·h/ml. The exposure in the subject with severe hepatic enzyme increased was 6.82 μg·h/ml. The exposure in the subject with severe hyperbilirubinemia (day 20, day 1 of oral treatment) was not available, since he discontinued study treatment on day 2 of oral treatment. However, this subject had the second highest exposure at steady state during IV treatment (AUC_0–12, 64.8 μg·h/ml; C_max, 7.48 μg/ml; C_min, 4.73 μg/ml). He also experienced an intermittent mild increase in AST, which was ongoing at the time of last reporting and which was assessed as related to preconditioning therapies and bone marrow transplant. This subject had a history of increased transaminases.

A 13-year-old, 78-kg black female (a CYP2C19 HEM) had the highest exposure (AUC_0–12, 95.3 μg·h/ml; C_max, 9.99 μg/ml; C_min, 7.78 μg/ml [at steady state during IV treatment]). She experienced transient moderate hyperbilirubinemia on day 8 IV, which resolved on day 24 (oral treatment day 4) without any alteration of the study drug and assessed as related to transplant conditioning regimen.

Although the data on treatment-related AEs were limited, there was no apparent relationship between voriconazole exposure and treatment-related hepatic or visual AEs.

DISCUSSION

A comparison of the adolescent and adult exposure data revealed that the dosing regimens need to be refined for young adolescents during the transitioning period from childhood to adolescence.

In this study, three of four 12-year-old subjects had body weights below 40 kg, and two of them received oral treatment. Only one subject (a 12-year-old, 39.8-kg white female; CYP2C19 type, EM) received the recommended reduced dosing regimen (150 mg orally q12h), and she had the lowest oral exposure (AUC_0–12, 1.17 μg·h/ml) (Table 3). The other subject (a 12-year-old, 39-kg white male; CYP2C19 type, UM) inadvertently received the standard dosing regimen (300 mg orally q12h), but he still had the second lowest oral exposure (AUC_0–12, 4.63 μg·h/ml). The oral exposure in the 12-year-old subject with high body weight (a 56.8-kg, white male; CYP2C19 type, HEM) was 26.5 μg·h/ml, above the average value observed in this study. In addition, at 300 mg orally q12h, some young adolescents (e.g., 13 to 14 years old) had voriconazole exposures lower than or close to the lowest exposure (14 μg·h/ml) observed in adults (Table 3).

These findings were not unexpected. It is speculated that maturation may play an important role in voriconazole metabolism during the transitioning period from childhood to adolescence (e.g., 12 to 14 years old). Since the maturation of the body does not occur over a short period of time, the metabolism rate of voriconazole may continue to decrease slightly as adolescents grow older and heavier and eventually approximate that of adults. The body weight appeared to be more closely correlated with voriconazole exposure than age in this age group (Fig. 2).

In order to optimize the pediatric (including young adolescents) dosing regimens to match the adult exposures, an integrated population pharmacokinetic modeling and simulation was performed based on the pooled data from children, adolescents, and adults, and the detailed results are being presented separately (L. E. Friberg, P. Ravva, M. O. Karlsson, and P. Liu, submitted for publication).

The good correlation between voriconazole AUC_0–12 and C_min at steady state allows rough estimation of voriconazole total exposure based on the trough concentration only (Fig. 3). For example, based on the correlation equation, with a target AUC_0–12 of 15 μg·h/ml, the corresponding C_min is approximately 0.52 μg/ml. With a target AUC_0–12 of 20 μg·h/ml, the corresponding C_min is approximately 0.94 μg/ml. Also, with a target AUC_0–12 of 80 μg·h/ml, the corresponding C_min is approximately 5.9 μg/ml. With a target AUC_0–12 of 100 μg·h/ml, the corresponding C_min is approximately 7.6 μg/ml.

It is known that monitoring voriconazole trough concentrations would assist in guiding dose adjustment, especially for identifying subjects at the extreme ends of the range (e.g., too low or too high exposure). However, no definitive therapeutic target for voriconazole has been identified, since patients' responses to voriconazole treatment are variable and a clear correlation between voriconazole exposure and clinical efficacy has not been established (11). Several proposals for voriconazole trough concentrations based on retrospective analyses have been made (e.g., 0.5, 1, or 2 μg/ml as the lower limit; 5.5 to 6 μg/ml as the upper limit) (3, 8, 9, 13, 14). This remains to be confirmed in future studies, and more analysis will be needed to help predict and prevent toxicity based on voriconazole exposure. The fine tuning of the dose adjustment of voriconazole in each patient would have to rely on clinical response and the tolerability profile.

The CYP2C19 status appears to be predictive of voriconazole exposure in adults in a well-controlled setting (e.g., healthy subjects without concomitant use of other medications). However, the significance of CYP2C19 status is diminished in the clinical setting, since other factors (e.g., concomitant use of medications, subject's underlying condition) also contribute to the intersubject variability in voriconazole exposure. Thus, no dose adjustment based on CYP2C19 status is recommended for adults in clinical practice. Likewise, it was not unexpected that CYP2C19 status was not predictive of voriconazole exposure in immunocompromised adolescents in this study (Table 4).

This study was conducted in a patient population that was restricted from receiving CYP450 inhibitors or inducers. It should be noted that drug-drug interaction with many other medications is the major extrinsic factor contributing to the intra- and intersubject variability in voriconazole exposure in clinical setting, which affects the prediction of voriconazole exposure at a given dosage. Therefore, concomitant use of other medications in a specific patient at initiation of voriconazole therapy or during the therapy should be taken into consideration for voriconazole dosing management.

The safety and tolerability of voriconazole in adolescents from this study, in terms of hepatic, visual, and cardiac events and laboratory abnormalities, were consistent with the known safety profile of voriconazole in adults (11). Where differences in the reporting frequencies of AEs were noted between adolescents and adults, these could be explained by subjects' underlying conditions or concomitant treatment (e.g., mucositis, hypertension, and hypotension). No new causes for concern were seen in these adolescents.

In summary, at the same IV and oral dosing regimens, voriconazole exposures in the majority of adolescents were comparable to those in adults. Young adolescents with low body weight during the transitioning period from childhood to adolescence (e.g., 12 to 14 years old) may need to receive higher doses in order to match the adult exposures. Gender and CYP2C19 genotype had no apparent effect on the voriconazole exposure in adolescents. The safety and tolerability of voriconazole in adolescents during both IV and oral administration were consistent with the known safety profile of voriconazole.