title: Voriconazole pharmacokinetic variability in cystic fibrosis lung transplant patients.
abstract: BACKGROUND
  Aspergillosis is a high-risk complication in cystic fibrosis (CF) lung transplant patients. Azole antifungal drugs inhibit CYP3A4, resulting in significant metabolic drug-drug interactions. Voriconazole (VRZ) was marketed without therapeutic drug monitoring (TDM) recommendations, consistent with favorable pharmacokinetics, but regular determinations of plasma VRZ concentration were introduced in our center to manage interactions with calcineurin inhibitors and to document the achievement of therapeutic levels.
  
  
  METHODS
  VRZ TDM data analysis for trough concentration (C0) and peak concentration (C2) was carried out, using validated liquid chromatography assay with ultraviolet detection, for 35 CF lung transplant patients (mean age 25 years, mean weight 47 kg, balanced sex ratio) since 2003. Therapeutic range (C0: 1.5 +/- 0.5 - C2 : 4.0 +/- 1.0 mg/L) was expressed relative to pivotal pharmacokinetic trial data.
  
  
  RESULTS
  The duration of VRZ treatment ranged from 9 days to 22 months. The recommended standard dose of VRZ (200 mg twice a day, following the loading dose) resulted in significant plasma concentrations (>0.5 mg/L) in 20% of CF lung transplant patients. Therapeutic concentrations were obtained using higher doses (average 570 +/- 160 mg/day, +43%, P<0.01). Despite adaptation, C0 remained <0.5 mg/L (11%), even when the drug was administered intravenously, highlighting the variability of VRZ pharmacokinetics, possibly enhanced by CYP2C19 polymorphism. The risk of inefficacy during periods of underdosage was overcome by treatment with antifungal drug combinations (caspofungin, n=10). The therapeutic index was limited by neurologic effects (14%) and hepatic abnormalities (30%). VRZ concentrations correlated significantly (P<0.01) with aspartate aminotransferase levels but not with bilirubin levels. VRZ acted as a metabolic inhibitor of tacrolimus (C0 to dose ratio 5.8 +/- 2.6, n=31/VRZ versus 1.7 +/- 0.9 alone, P<0.001). Large changes in azole concentration affected the magnitude of the drug-drug interactions and adjustment requirements.
  
  
  CONCLUSIONS
  TDM is required because VRZ levels are often undetectable in treated CF lung transplant patients, supporting the use of antifungal drug combinations until achievement of VRZ C0 at a steady state between 1 and 2 mg/L. Plasma VRZ concentrations should be determined for the quantitative, individualized management of drug-drug interactions in lung transplant patients, in particular immunosuppressant such as tacrolimus, considering VRZ to be both a target and an inhibitor of CYP3A4.
authors.affiliation: Department of Pharmacology, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Européen Georges Pompidou (HEGP), Faculté de Médecine, Université Paris Descartes, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Berge
authors.forename: R
authors.initials: R
authors.lastname: Guillemain
authors.forename: V
authors.initials: V
authors.lastname: Boussaud
authors.forename: M-H
authors.initials: MH
authors.lastname: Pham
authors.forename: P
authors.initials: P
authors.lastname: Chevalier
authors.forename: A
authors.initials: A
authors.lastname: Batisse
authors.forename: C
authors.initials: C
authors.lastname: Amrein
authors.forename: E
authors.initials: E
authors.lastname: Dannaoui
authors.forename: M-A
authors.initials: MA
authors.lastname: Loriot
authors.forename: A
authors.initials: A
authors.lastname: Lillo-Le Louet
authors.forename: E M
authors.initials: EM
authors.lastname: Billaud
mesh_terms: D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001228:Aspergillosis / Q000188:drug therapy / Q000382:microbiology / Q000517:prevention & control*; D001230:Aspergillus / Q000187:drug effects; D003550:Cystic Fibrosis / Q000628:therapy*; D004334:Drug Administration Schedule; D004347:Drug Interactions; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000378:metabolism; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D009181:Mycoses / Q000188:drug therapy / Q000382:microbiology / Q000517:prevention & control*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D021681:Scedosporium / Q000187:drug effects; D016559:Tacrolimus / Q000008:administration & dosage / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D065819:Voriconazole; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole; D016559:Tacrolimus