PMID- 26346408
OWN - NLM
STAT- MEDLINE
DCOM- 20161102
LR  - 20181113
IS  - 1399-3062 (Electronic)
IS  - 1398-2273 (Print)
IS  - 1398-2273 (Linking)
VI  - 17
IP  - 6
DP  - 2015 Dec
TI  - Voriconazole therapeutic drug monitoring: results of a prematurely discontinued 
      randomized multicenter trial.
PG  - 831-7
LID - 10.1111/tid.12454 [doi]
AB  - BACKGROUND: Voriconazole (VOR) levels are highly variable, with potential 
      implications to both efficacy and safety. We hypothesized that VOR therapeutic 
      drug monitoring (TDM) will decrease the incidence of treatment failures and 
      adverse events (AEs). METHODS: We initiated a prospective, randomized, 
      non-blinded multicenter study to compare clinical outcomes in adult patients 
      randomized to standard dosing (clinician-driven) vs. TDM (doses adjusted based on 
      levels). VOR trough levels were obtained on day 5, 14, 28, and 42 (or at 
      completion of drug; +/- 3 days). Real-time dose adjustments were made to maintain a 
      range between 1-5 mug/mL on the TDM-arm, while levels were assessed 
      retrospectively in the standard-arm. Patient questionnaires were administered to 
      assess subjective AEs. RESULTS: The study was discontinued prematurely, after 29 
      patients were enrolled. Seventeen (58.6%) patients experienced 38 AEs: visual 
      changes (22/38, 57.9%), neurological symptoms (13/38, 34.2%), and liver 
      abnormalities (3/38, 7.9%). VOR was discontinued in 7 (25%) patients because of 
      an AE (4 standard-arm, 3 TDM-arm). VOR levels were frequently out of range in the 
      standard-arm (8 tests >5 mug/mL; 9 tests <1 mug/mL). Three dose changes occurred in 
      the TDM-arm for VOR levels <1 mug/mL. Levels decreased over time in the 
      standard-arm, with mean VOR levels lower at end of therapy compared to TDM (1.3 
      vs. 4.6 mug/mL, P = 0.008). CONCLUSIONS: VOR TDM has become widespread clinical 
      practice, based on known variability in drug levels, which impaired accrual in 
      this study. Although comparative conclusions are limited, observations of 
      variability and waning levels over time support TDM.
CI  - (c) 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
FAU - Neofytos, D
AU  - Neofytos D
AD  - School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA.
FAU - Ostrander, D
AU  - Ostrander D
AD  - School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA.
FAU - Shoham, S
AU  - Shoham S
AD  - School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA.
FAU - Laverdiere, M
AU  - Laverdiere M
AD  - Hopital Maisonneuve-Rosemont, University of Montreal, Montreal, Quebec, Canada.
FAU - Hiemenz, J
AU  - Hiemenz J
AD  - University of Florida, Gaineville, Florida, USA.
FAU - Nguyen, H
AU  - Nguyen H
AD  - University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
FAU - Clarke, W
AU  - Clarke W
AD  - School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA.
FAU - Brass, L
AU  - Brass L
AD  - School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA.
FAU - Lu, N
AU  - Lu N
AD  - School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA.
FAU - Marr, K A
AU  - Marr KA
AD  - School of Medicine, The Johns Hopkins University, Baltimore, Maryland, USA.
LA  - eng
GR  - K24 AI085118/AI/NIAID NIH HHS/United States
GR  - P30 CA006973/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20151125
PL  - Denmark
TA  - Transpl Infect Dis
JT  - Transplant infectious disease : an official journal of the Transplantation 
      Society
JID - 100883688
RN  - 0 (Antifungal Agents)
RN  - JFU09I87TR (Voriconazole)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antifungal Agents/adverse effects/*blood/therapeutic use
MH  - Dose-Response Relationship, Drug
MH  - *Drug Monitoring
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Voriconazole/adverse effects/*blood/therapeutic use
PMC - PMC4715512
MID - NIHMS721646
OTO - NOTNLM
OT  - therapeutic drug monitoring
OT  - transplant monitoring
OT  - voriconazole
COIS- Potential conflicts of interest: D.N. has received research grants from Pfizer 
      and served as a consultant and/or advisory board member for Roche and Astellas. 
      He is currently employed by Roche Diagnostics. S.S. is the recipient of research 
      grants from Pfizer, Merck, and Astellas and has performed data review committee 
      work for Astellas. All funds from these entities have been paid to Johns Hopkins 
      University School of Medicine and managed as per that institution's policies. 
      M.L. has received research grants from Pfizer, Astellas, and Merck & Co. He 
      served as a consultant and or as advisory board member for Pfizer Canada, and 
      Merck Canada M.H.N. has received research grants from Pfizer, Merck, and 
      Astellas. K.A M. has served as a consultant and received research funding from 
      Astellas, Merck, and Pfizer. D.O., J.H., W.C., L.B., and N.L.: No conflicts of 
      interest.
EDAT- 2015/09/09 06:00
MHDA- 2016/11/03 06:00
PMCR- 2016/12/01
CRDT- 2015/09/09 06:00
PHST- 2015/02/13 00:00 [received]
PHST- 2015/04/24 00:00 [revised]
PHST- 2015/08/11 00:00 [revised]
PHST- 2015/08/15 00:00 [accepted]
PHST- 2015/09/09 06:00 [entrez]
PHST- 2015/09/09 06:00 [pubmed]
PHST- 2016/11/03 06:00 [medline]
PHST- 2016/12/01 00:00 [pmc-release]
AID - 10.1111/tid.12454 [doi]
PST - ppublish
SO  - Transpl Infect Dis. 2015 Dec;17(6):831-7. doi: 10.1111/tid.12454. Epub 2015 Nov 
      25.