Abstract

There are limited data on the effects of drug levels on therapeutic success in fungal infections. Low itraconazole trough levels have been associated with breakthrough fungal infections (

Glasmacher et al.
Mycoses
1999
;
42
:
443
–51
). Low voriconazole levels have been associated with a higher failure rate in patients with confirmed fungal infections (
Smith et al.
Antimicrob Agents Chemother
2006
;
50
:
1570
–2
). Success rate in patients with mean voriconazole plasma levels <0.5 μg/mL was 46% compared to 56% with mean plasma levels >0.5 μg/mL (www.fda.gov/ohrms/dockets/ac/01/briefing/3792b2_02_FDA-voriconazole.htm). The period after HSCT is characterized by the use of multiple drugs that can affect the liver cytochrome P450 system. The CYP450 isoenzyme 2C19 plays a significant role in voriconazole metabolism, and exhibits significant genetic polymorphism. Homozygous extensive metabolizers have a significantly lower exposure to voriconazole than heterozygous extensive metabolizers and poor metabolizers. Steady-state plasma trough voriconazole levels were measured after at least 5 days of therapy in 87 patients with hematologic malignancies on 201 separate occasions (1–5 levels per patient; median 2). Most patients had undergone allogeneic HSCT. Drug levels were monitored using HPLC (
Pennick et al.
Antimicrob Agents Chemother
2003
;
47
:
2348
–50
). The daily voriconazole dose (divided into 2) was 200 mg (n=4), 400 mg (n=151), 500 mg (n=20), 600 mg (n=18), and 800 mg (n=8); corresponding to 2.0–16.3 mg/kg (median 5.4). The voriconazole levels were <0.2–12.5 μg/mL (median 1.2). In keeping with the non-linear pharmacokinetic profile of the drug, a strong correlation was not seen between the dose and levels (figure).

The table below shows the relationship between levels and dose. While the amount of drug administered in mg/kg was significantly higher when the levels were >5.0 μg/mL, there was no consistent relationship between dose and level below that threshold.

Voriconazole levelnDose (mg)Dose (mg/kg)P (Dose in mg/kg; compared to the >5.0 level group)
<0.2 (undetectable) 30 (15%) 400 (200–800) 5.6 (3.5–11.5) 0.008 
0.2–0.5 25 (12%) 400 (400–800) 6.2 (3.8–10.2) 0.18 
>0.5 to 2.0 70 (35%) 400 (400–800) 5.2 (3.7–13.3) 0.062 
>2.0 to 5.0 53 (26%) 400 (400–800) 4.9 (2.0–9.8) 0.0008 
>5.0 23 (11%) 400 (400–800) 6.9 (3.4–16.3)  
Voriconazole levelnDose (mg)Dose (mg/kg)P (Dose in mg/kg; compared to the >5.0 level group)
<0.2 (undetectable) 30 (15%) 400 (200–800) 5.6 (3.5–11.5) 0.008 
0.2–0.5 25 (12%) 400 (400–800) 6.2 (3.8–10.2) 0.18 
>0.5 to 2.0 70 (35%) 400 (400–800) 5.2 (3.7–13.3) 0.062 
>2.0 to 5.0 53 (26%) 400 (400–800) 4.9 (2.0–9.8) 0.0008 
>5.0 23 (11%) 400 (400–800) 6.9 (3.4–16.3)  

These data show that in adult patients getting standard doses of voriconazole orally, the drug levels are highly variable. Based on the data on the FDA files, 27% of these levels would be associated with a lower likelihood of response. Based on the data of Smith et al, 65% of these levels would be associated with a higher likelihood of failure. We suggest that future voriconazole studies should incorporate prospective therapeutic drug monitoring, and that pending further clarification, consideration should be given to checking levels in patients receiving the drug for confirmed, life-threatening fungal infections.

Disclosures: Voriconazole for prophylaxis of fungal infections.

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