CaM
Calcineurin
Nfat
BACKGROUND: In adults, pravastatin reduces the development and progression of
transplant vasculopathy, the main long-term risk
after cardiac transplantation. The pharmacokinetics of pravastatin
is not known in children taking calcineurin
inhibitors. Our aim was to determine the single-dose pharmacokinetics and
short-term safety of pravastatin in children
undergoing regular triple-drug immunosuppressive therapy after cardiac
transplantation. METHODS: Nineteen pediatric cardiac transplant recipients
(aged 4.4 to 18.9 years) receiving triple immunosuppression
therapy consisting of methylprednisolone (19
patients), cyclosporine (INN, cyclosporin) (17
patients) or tacrolimus (2 patients), and azathioprine (18 patients) or mycophenolate
mofetil (1 patient) ingested a single 10-mg dose of pravastatin, and plasma pravastatin
concentrations were measured up to 24 hours. Subsequently, the patients took 10
mg pravastatin orally once daily for 8 weeks. The
lipid-lowering effect and the safety of pravastatin
therapy were studied. RESULTS: The mean peak plasma concentration (C(max)) of pravastatin was 122.2
+/- 88.2 ng/mL (range, 11.4-305.0 ng/mL),
and the area under the plasma concentration-time curve of pravastatin
from 0 to 10 hours [AUC(0-10)] was 264.1 +/- 192.4 ng.h/mL
(range, 30.8-701.6 ng.h/mL). These C(max)
and AUC(0-10) values are nearly 10-fold higher than the corresponding values
reported in hypercholesterolemic children in the
absence of immunosuppressive therapy. The time of peak concentration (t(max)) of pravastatin was 1.1 +/-
0.4 hours (range, 0.5-2 hours), and the mean elimination half-life (t(1/2)) was
1.2 +/- 0.3 hours (range, 0.7-2.2 hours); these parameters were similar to
those in the hypercholesterolemic children. By 8
weeks of treatment, the concentration of serum total cholesterol decreased by
13% (P =.005), low-density lipoprotein cholesterol by 27% (P <.0001), and
triglycerides by 6% (not significant, P =.28); the concentration of
high-density lipoprotein cholesterol increased by 7% (not significant, P =.30).
No clinically significant increases in serum ALT, creatine
kinase, or creatinine
levels were observed. CONCLUSIONS: The plasma concentrations of pravastatin in pediatric cardiac recipients receiving
triple immunosuppressive medication are nearly 10-fold higher than in hypercholesterolemic children after the same pravastatin dose. However, the short-term therapy of pravastatin was well tolerated and effective in lowering
serum cholesterol levels in cardiac recipients.
