Vol.53 No.S-2 November 2005
Pharmacokinetics of voriconazole
Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NG, UK
Abstract
Voriconazole (VRCZ), a broad-spectrum triazole, is served in two dosage forms-injection and tablet. VRCZ shows excellent absorption and high bioavailability even in oral administration. It must be administered, however, between meals because absorption is delayed after fatty food intake compared to fasting administration.
VRCZ shows excellent tissue penetration with the concentration in tissues exceeding the MIC of major fungal species. VRCZ also penetrates well into the cerebrospinal fluid (CSF). In humans, 1-10 h after receipt of VRCZ, the ratio of CSF to plasma concentration ranged from 0.22 to 1.0 (median, 0.46).
Three microsome enzymes are involved in VRCZ metabolism, CYP2C9, CYP2C19, and CYP3A4, and polymorphisms in CYP2C19 may result in individual differences in VRCZ metabolism. In a phase I study, subjects classified as poor metabolizers (PM), which would include 19% of the Japanese population, had higher serum VRCZ concentrations than other subjects. Because VRCZ concentration varies greatly among individuals of the same genotype and the condition of a patient, however, a concomitant drug or the like will influence the exposure of VRCZ, it is difficult to adjust the amount of VRCZ by genotyping alone.
In patients with renal damage, VRCZ dose adjustment is not required when administered in tablet form because VRCZ is not excreted by the kidneys. One agent added to the injection formula, sulfobutylether-β-cyclodextrin, is excreted by the kidneys, however, and may accumulate in patients with renal damage. Children show lower serum VRCZ concentration than adults, probably due to higher enzyme activity and more rapid drug clearance.
This drug is given with a loading dose. The loading dose in intravenous administration is 6 mg/kg administered twice a day every 12 hours. For dosage from day 2 onward, it is recommended to administer 3 mg/kg for maintenance therapy and 4 mg/kg twice a day if the effect is insufficient with that amount. With oral administration, it is appropriate to administer 300 mg twice a day every 12 hours for the loading dose and 150-200 mg for the maintenance dose from the second day 2 onward.
Key word
voriconazole, pharmacokinetics, CYP2C19, genetic polymorphism, loading dose
Received
July 8, 2005
Accepted
August 22, 2005
Jpn. J. Chemother. 53 (S-2): 16-23, 2005
