Blood Concentrations and Toxicity of Voriconazole and its Metabolites

Ref ID: 19305

Author:

D. Zonios, H. Yamazaki, V. Natarajan, J. E. Bennett

Author address:

NIAID, NIH, Bethesda, MD; Showa Pharmaceutical Univ., Machida, Tokyo, JAPAN; NCI/SAIC-Frederick, Frederick, MD.

Full conference title:

53rd Interscience Conference on Antimicrobial Agents and Chemotherapy

Date: 10 September 2014

Abstract:

Background: Prospective evaluation of the antifungal drug, voriconazole, is needed to determine whether genotype or serum concentrations of voriconazole or its metabolites correlates with toxicity.Methods: NIH Clinical Center patients over 12 years of age receiving voriconazole were enrolled in a prospective study of voriconazole (V). Toxicity was evaluated in 96 patients. Serum V levels were measured in 95 and metabolites in 60 patients. Results: Hepatotoxicity occurred in 6.2 % and hallucinations in 16.7 %, almost all in the first week. Serum V levels were slightly higher in patients with hallucinations but not with hepatotoxicity. Visual changes occurred in 17.7% and photosensitivity in 10.5%, neither correlated with blood concentrations of V. Ten of 33 patients who received 200 mg twice daily (mean dose 3.2 mg/kg) had at least one undetectable serum V concentration, though V-N-oxide was measurable. CYP2C19 genotype was determined in 93 patients and serum concentrations of V-N-oxide and 4-hydroxy-V, in 60. Although V levels were highly variable, genotype had little impact on drug or metabolite concentrations. Only 4 patients (4%) were homozygous for the slow metabolizer genotype CYP2C19*2 and had slightly higher average serum concentrations of voriconazole (4.3 vs 2.5 mcg/ml), together with lower concentrations of V-N-oxide (1.7 vs 2.5 mcg/ml) Eighteen patients were CYP2C19 heterozygotes (*1/*2) and did not differ in levels of V or
its metabolites from the 64 patients with the most common
genotype, CYP2C19 *1. Neither the rapid metabolizer
genotype, CYP2C19*17 or CYP2C9 affected the
concentrations of V or its metabolites. There were too few
patients in 6 uncommon CYP2C19 genotypes to ascertain a
significant difference due to those genotypes.
Concentrations of 4-hydroxy-V were low and not correlated
with genotype. Drug accumulation during prolonged
treatment was not observed. Conclusions: (1) The
recommended 200 mg dose may be too low for some nonobese
adults. (2) In our largely Caucasian adult population,
CYP genotypes 2C19 and 2C9 were not important determinants of toxicity or drug concentrations

Abstract Number: NULL

Conference Year: 2013

Link to conference website: NULL

New link: NULL

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