Voriconazole (Page 10 of 19)

11 DESCRIPTION

Voriconazole, an azole antifungal agent is available as film-coated tablets for oral administration. The structural formula is:

Voriconazole Structural Formula

Voriconazole is designated chemically as (2R ,3S)-2-(2, 4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H -1, 2, 4-triazol-1-yl)butan-2-ol with a molecular formula of C16 H14 F3 N5 O and a molecular weight of 349.31.

Voriconazole, USP drug substance is a white to almost white powder.

Voriconazole tablets contain 50 mg or 200 mg of voriconazole. The inactive ingredients include croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch (corn), titanium dioxide and triacetin.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Voriconazole is an antifungal drug [see Microbiology (12.4)].

12.2 Pharmacodynamics

Exposure-Response Relationship For Efficacy and Safety

In 10 clinical trials (N = 1121), the median values for the average and maximum voriconazole plasma concentrations in individual patients across these studies was 2.51 μg/mL (inter-quartile range 1.21 to 4.44 μg/mL) and 3.79 μg/mL (inter-quartile range 2.06 to 6.31 μg/mL), respectively. A pharmacokinetic-pharmacodynamic analysis of patient data from 6 of these 10 clinical trials (N = 280) could not detect a positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy. However, pharmacokinetic/pharmacodynamic analyses of the data from all 10 clinical trials identified positive associations between plasma voriconazole concentrations and rate of both liver function test abnormalities and visual disturbances [see Adverse Reactions (6)].

Cardiac Electrophysiology

A placebo-controlled, randomized, crossover study to evaluate the effect on the QT interval of healthy male and female subjects was conducted with three single oral doses of voriconazole and ketoconazole. Serial ECGs and plasma samples were obtained at specified intervals over a 24-hour post dose observation period. The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200, and 1600 mg of voriconazole and after ketoconazole 800 mg were all < 10 msec. Females exhibited a greater increase in QTc than males, although all mean changes were < 10 msec. Age was not found to affect the magnitude of increase in QTc. No subject in any group had an increase in QTc of ≥ 60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec. However, the QT effect of voriconazole combined with drugs known to prolong the QT interval is unknown [see Contraindications (4) and Drug Interactions (7)].

12.3 Pharmacokinetics

The pharmacokinetics of voriconazole have been characterized in healthy subjects, special populations and patients.

The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. The interindividual variability of voriconazole pharmacokinetics is high. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg every 12 hours to 300 mg every 12 hours leads to an approximately 2.5-fold increase in exposure (AUCτ ); similarly, increasing the intravenous dose from 3 mg/kg every 12 hours to 4 mg/kg every 12 hours produces an approximately 2.5-fold increase in exposure (Table 12).

Table 12: Geometric Mean (% CV) Plasma Voriconazole Pharmacokinetic Parameters in Adults Receiving Different Dosing Regimens
Note: Parameters were estimated based on non-compartmental analysis from 5 pharmacokinetic studies.AUC12 = area under the curve over 12 hour dosing interval, Cmax = maximum plasma concentration, Cmin = minimum plasma concentration. CV = coefficient of variation

6 mg/kg IV (loading dose)

3 mg/kg IV every 12 hours

4 mg/kg IV every 12 hours

400 mg Oral (loading dose)

200 mg Oral every 12 hours

300 mg Oral every 12 hours

N

35

23

40

17

48

16

AUC12

(μg·h/mL)

13.9 (32)

13.7 (53)

33.9 (54)

9.31 (38)

12.4 (78)

34.0 (53)

Cmax

(μg/mL)

3.13 (20)

3.03 (25)

4.77 (36)

2.30 (19)

2.31 (48)

4.74 (35)

Cmin

(μg/mL)

0.46 (97)

1.73 (74)

0.46 (120)

1.63 (79)

When the recommended intravenous loading dose regimen is administered to healthy subjects, plasma concentrations close to steady state are achieved within the first 24 hours of dosing (e.g., 6 mg/kg IV every 12 hours on day 1 followed by 3 mg/kg IV every 12 hours). Without the loading dose, accumulation occurs during twice daily multiple dosing with steady state plasma voriconazole concentrations being achieved by day 6 in the majority of subjects.

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