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Anti-Fungal Voriconazole Well Tolerated

The anti-fungal agent voriconazole is well tolerated, with only mild to moderate adverse effects, report researchers.

The most common of side effects are headache, rash and abnormal vision. Visual function tests detected no further abnormalities during treatment, report Pfizer researchers in Sandwich, Kent, England, and Brussels, Belgium.

They evaluated the safety, tolerability and pharmacokinetics of intravenous and oral doses of voriconazole in 42 healthy men, all but one of whom completed the study.

One cohort (n=28) took part in two 14-day study periods separated by at least seven days of washout. In the first period, 14 men received twice daily intravenous doses of 6.0 mg/kg on the first day and 3.0 mg/kg on the following six days. These men were then switched to 200 mg. orally twice daily for seven more days.

In the second period, these 14 men received twice daily intravenous doses of 6.0 mg/kg on the first day and 5.0 mg/kg on the following six days. They were then switched to 400 mg. orally twice daily for seven more days. The remaining 14 men in this cohort received matching placebo throughout the study.

In a second cohort (n =14), seven men received twice daily intravenous doses of 6.0 mg/kg on the first day and then 4.0 mg/kg for six further days. They were then switched to 300 mg. twice daily oral doses for seven days. The remaining seven men in this second cohort received matching placebo.

Blood samples were taken before dosing on days 1- 6 and 8-13. The samples were drawn before dosing and at frequent intervals up to 12 hours after the morning dose on days seven and 14 of each study period.

The samples were assayed for voriconazole by high-performance liquid chromatography. The maximum concentration in plasma occurred at the end of the one-hour intravenous infusion and 1.4-1.8 hours after oral dosing.

Voriconazole showed non-linear pharmacokinetics, possibly due to saturable metabolism. In the first cohort, both maximum concentration and the area under the concentration-time curve within a dosage interval rose disproportionately with dose for both intravenous and oral dosing.

After the switch from intravenous to oral dosing, most of the men achieved steady state by the fourth day, and mean minimum concentrations in plasma remained above clinically important minimum inhibitory concentration levels. The pharmacokinetic profiles for saliva followed a similar pattern to those for plasma.
Antimicrobial Agents and Chemotherapy 2002;46(8):2546-53 "Pharmacokinetics and Safety of Voriconazole following Intravenous- to Oral-Dose Escalation Regimens"

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