Bioavailability of voriconazole in critically ill patients

Voriconazole is considered to be a first line antifungal agent for the
treatment of invasive aspergillosis. The bioavailability, based on healthy
volunteers, is estimated to be >90%. Due to the high bioavailability of
voriconazole, switching between oral and intravenous administration is
permitted if clinically allowed. Few data are available for the bioavailability
of voriconazole in critically ill patients. However, to obtain a therapeutic
concentration of voriconazole, one study showed that a higher oral dose is
required compared with the intravenous dose to obtain this therapeutic
concentration. Therefore, the pharmacokinetics can be changed in critically ill
patients, including bioavailability. When a patient switch from intravenous to
oral administration, lower voriconazole levels might occur. If this leads to
insufficient effect the attending physician may decide to stop voriconazole and
switch to a less favorable second line antifungal drug, likely with a less
favorable outcome where an increased dosing would be more appropriate. The
dosage of voriconazole might be adjusted to maintain a therapeutic
concentration. To cope with this problem, knowledge about the bioavailability
of voriconazole in critically ill ICU patients is required. This would probably
result in keeping more patients on first line treatment, voriconazole, and
maintaining efficacy.

The objective of this study is to obtain the absolute bioavailability of
voriconazole in critically ill ICU patients.

An intervention study will be performed in patients treated with oral
voriconazole and admitted to an ICU at the University Medical Center Groningen.
Whether a patient will be treated with voriconazole or not depends on the
choice of the attending physician, as well as the dose and route of
administration. Patients eligible for this study received at least four doses
of voriconazole. To be eligible for inclusion patients must receive oral
voriconazole.

ICU patients who received at least four doses of voriconazole and receive
voriconazol orally at time of inclusion, will receive one intravenous
administration of voriconazole in the same dose as the oral dose. A full
concentration-time curve of voriconazole/voriconazole N-oxide will be obtained
to determine the AUC of an intravenous dose of voriconazole. Plasma samples, 1
ml per sample, are taken before administration, immediately after
administration of the infusion volume and 0,5; 1; 1,5; 2; 4; 8 and 12 hour
after start of the infusion. The next dose of voriconazole will be given orally
as prescribed and plasma samples will be drawn before oral administration of
voriconazole and 0,5; 1; 1,5; 2; 4; 8; and 12 after administration of
voriconazole for determining the AUC of the oral dose. The bioavailability will
be determined, comparing the intravenous AUC (100%) and the oral AUC. For
determining pharmacogenetics an extra blood sample of 4 ml will be taken.

The day the full concentration-time curve of voriconazole will be obtained, the
APACHE IV score will be determined based on clinical parameters that are
routinely recorded for ICU patients.

An intravenous dose of voriconazole.

As ICU patients have vascular access via an indwelling arterial catheter, the
extra plasma samples taken for this study, 1 ml per sample, are not seen as an
extra burden. Subjects benefit from this study because a sub therapeutic
voriconazole level will be noticed and dose adjustments can be made to reach a
therapeutic level. Whether or not dose adjustments will be made depends on the
choice of the attending physician.
Future patients may benefit from the results of this study as efficacy is
maintained when patients treated with voriconazole, switching from intravenous
treatment to oral treatment.
This study cannot be performed without these patients, since they are the
subjects of the investigation.