title: Pharmacokinetics of intravenous voriconazole in obese patients: implications of CYP2C19 homozygous poor metabolizer genotype.
abstract: There is a paucity of pharmacokinetic studies describing weight-based dosing of intravenous voriconazole in obese patients. In this case report, we describe the pharmacokinetics of intravenous voriconazole in an obese CYP2C19 homozygous poor metabolizer and review previously reported data regarding the use of intravenous voriconazole in obese patients. A 17-year-old obese Hispanic male patient (body mass index 35 kg/m(2) ) received intravenous voriconazole for the treatment of suspected aspergillosis. After 2.5 days of voriconazole 4 mg/kg intravenously every 12 hours based on adjusted body weight, the voriconazole area under the serum concentration-time curve over the course of a single (12-hr) dosing interval and trough concentration were 86,100 ng · hr/ml and 6.2 µg/ml, respectively. Six days later, the voriconazole dosage was decreased. A trough concentration measured just before the dosage reduction (after 8.5 days of voriconazole 4 mg/kg intravenously every 12 hours based on adjusted body weight) remained elevated at 5.8 µg/ml. Genotyping revealed a CYP2C19 homozygous poor metabolizer (CYP2C19*2/*2). Voriconazole was subsequently discontinued due to QTc prolongation. These data and those from two recent publications suggest that voriconazole does not distribute extensively into human adipose tissue and that obese patients should be dosed on an adjusted body weight basis. If an obese patient dosed on total body weight is also a CYP2C19 poor metabolizer, serum voriconazole concentrations will be further elevated, potentially leading to drug-induced toxicity.
authors: Pharmacy Department, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA. bmoriyama@cc.nih.gov
authors: Brad
authors: B
authors: Moriyama
authors: Paul F
authors: PF
authors: Jarosinski
authors: William D
authors: WD
authors: Figg
authors: Stacey A
authors: SA
authors: Henning
authors: Robert L
authors: RL
authors: Danner
authors: Scott R
authors: SR
authors: Penzak
authors: Alan S
authors: AS
authors: Wayne
authors: Thomas J
authors: TJ
authors: Walsh
mesh_terms: D000293:Adolescent; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000097:blood* / Q000627:therapeutic use; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D001228:Aspergillosis / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D001835:Body Weight; D065731:Cytochrome P-450 CYP2C19; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005838:Genotype; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D009765:Obesity / Q000097:blood / Q000150:complications / Q000201:enzymology / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage* / Q000097:blood* / Q000627:therapeutic use; D014230:Triazoles / Q000008:administration & dosage* / Q000097:blood* / Q000627:therapeutic use; D065819:Voriconazole
chemical_list: D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D065819:Voriconazole
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