Pharmacokinetics and optimal dosage of caspofungin in critically ill patients with suspected invasive candidiasis.

Intensive care unit (ICU) patients are especially at risk for invasive
candidiasis due to the presence of risk factors. Prompt initiation of effective
antifungal therapy in the appropriate dosage is required to improve outcome in
patients with candidemia. An efficacy study showed a lower response rate for
caspofungin among patients with a higher disease severity score.
Furthermore, it is known that in critically ill patients, alterations in
function of various organs and body systems can influence the pharmacokinetics
and hence the plasma concentration of a drug. A study of caspofungin in ICU
patients has found a high inter- and intra-individual variability in
caspofungin trough concentration. The pharmacokinetic parameters of caspofungin
in critically ill patients are most likely different, however, this has not
been specifically studied to date. As a result of the altered pharmacokinetics,
under-exposure of caspofungin can occur in critically ill patients and a higher
dosage might be necessary in these patients.

Determine the pharmacokinetics of caspofungin, and the optimal dosage of
caspofungin in relation to adequate exposure in critically ill patients.

Intervention study. On day 3 (± 1 day) of treatment with caspofungin, blood
samples are taken just before administration of caspofungin and 1, 2, 3, 4, 6,
8, 12 and 24 hours after the start of the infusion, to determine the AUC (Area
Under the concentration-time Curve) and pharmacokinetic parameters of
caspofungin. The AUC is used as a measure for the exposure, an AUC of >= 98
mg*h/L is established as an adequate exposure. A decline in AUC of >= 20% below
98 mg*h/L is considered a clinically relevant decline in AUC, and in this case
a dose adjustment of caspofungin is required. An AUC > 200 mg*hr/L is
considered too high and in this case the dosage will be reduced. If the
caspofungin dosage is adjusted, blood samples are taken on day 3 (± 1 day)
after dose adjustment, just before administration of caspofungin and 1, 2, 3,
4, 6, 8, 12 and 24 hours after the start of the infusion, to determine the AUC
at the adjusted dosage. When the patient is on an adequate dosage regimen,
trough levels will be followed every three days during treatment on the ICU,
with a maximum of 28 days, to evaluate potential fluctuations in caspofungin
concentration over time.
On the day the first AUC of caspofungin is obtained, blood samples are drawn
for determination of procalcitonin, interleukin-6 and interleukin-8 to assess
correlation of caspofungin concentration with inflammation parameters.
If the patient is on dialysis, samples from the dialysate will be obtained at
the same time points as the blood sampling to determine the amount of
caspofungin that is lost in dialysis.
Different disease severity scores will be calculated to evaluate their
correlation with the plasma concentration and pharmacokinetic parameters of
caspofungin. The calculation of the different scores is based on clinical
parameters that are routinely recorded for ICU patients. The APACHE II, APACHE
IV, LODS, MODS, MPM II, ODIN, SAPS 3 and SOFA score will be calculated on the
day the first AUC of caspofungin is obtained.

Dose-adjustment of caspofungin in case of under-exposure (AUC >= 20% below AUC
that is required for an adequate exposure), or in case of over-exposure (AUC >
200 mg*hr/L, twice the AUC for an adequate exposure).

Dose adjustment in case of under- or over-exposure leads to an adequate
exposure of caspofungin and can lead to a better outcome among the subjects
included in this study. Caspofungin has shown good tolerability in dosages up
to 200 mg per day. Results of this study can contribute to future dosing
schedules in critically ill patients treated with caspofungin and to practical
decision rules for therapeutic drug monitoring. The extra blood samples needed
to study exposure and the pharmacokinetic parameters of caspofungin are a minor
burden as these patients already have an indwelling vascular catheter. This
study cannot be conducted without these patients, as they are the subjects of
investigation.