P. Mehta et al., Increased clearance of tacrolimus in children: need for higher doses and earlier initiation prior to bone marrow transplantation, BONE MAR TR, 24(12), 1999, pp. 1323-1327
Citations number
11
Categorie Soggetti
Hematology,"Medical Research Diagnosis & Treatment
The pharmacokinetics of tacrolimus have been studied in healthy volunteers
and in adults undergoing bone marrow transplantation. However, there is lit
tle information on the pharmacokinetics of tacrolimus in children undergoin
g BMT, We studied pharmacokinetics of tacrolimus in seven patients (age 8-1
7 years) undergoing allogeneic stem cell transplantation. Four patients rec
eived matched unrelated donor (MUD) transplants, two underwent HLA-matched
related donor transplants, and one underwent an umbilical cord blood donor
transplant. All patients received tacrolimus by continuous infusion at 0.03
-0.04 mg/kg/day beginning on the day prior to transplant. Tacrolimus whole
blood concentrations were monitored by microparticle enzyme immunoassay. Ou
r goal was to maintain a blood tacrolimus level of 10-20 mu g/ml, Once pati
ents were tolerating oral medications, tacrolimus infusion was converted to
oral dosing using a 4:1 conversion. Dose of tacrolimus and resulting tacro
limus concentrations were recorded and the total body clearance of tacrolim
us was calculated retrospectively. The mean clearance, based on first stead
y-state tacrolimus concentrations necessary for achieving a therapeutic lev
el (10-20 mu g/ml), was 108.1 ml/h/kg (range 79.7-142.0 ml/h/kg), greater t
han that reported in adult BMT patients (71 +/- 34 ml/h/kg). The average do
se required to achieve that therapeutic range was 0.0354 mg/kg/day as an in
travenous continuous infusion. Over the entire course of intravenous tacrol
imus, mean clearance was 97.0 ml/h/kg (range 33.4-153.3 ml/h/kg). In six of
the seven patients, clearance values dropped after 2-4 weeks of therapy by
an average of 32.5 ml/h/kg. In two patients, sharp drops in clearance were
temporally related to changes in liver function tests. Three of the seven
patients died of severe acute GVHD; all these had undergone matched unrelat
ed donor transplantation, and two of these three had initial clearance leve
ls over 120 ml/h/kg. Thus, children appear to have more rapid tacrolimus cl
earance than adults and may need to begin therapy earlier in order to obtai
n stable and optimal levels. More studies are needed to confirm these preli
minary results.